Badyal - Practical Manual of Pharmacology

Practical Manual of Pharmacology

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTDNew Delhi • Ahmedabad • Bengaluru • Chennai • Hyderabad • Kochi

Kolkata • Lucknow • Mumbai • Nagpur

Dinesh Badyal MBBS, MD (PGI)

Associate ProfessorDepartment of Pharmacology

Christian Medical CollegeLudhiana, Punjab

India


®

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First Edition: 2008ISBN 978-81-8448-362-8

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ToMy beloved students

(who have been my teachers too)and

My daughterAnvi

Preface

We are what we repeatedly do,

excellence then is not an act,

but becomes a habit.

—AristotleTo impart skills to budding doctors practical pharmacology is an essential area of teaching.This practical manual describes what you do with your own hands which will help youthroughout the life. This manual has been written keeping in view the desired shift in thepharmacology practical teaching from pharmacy based redundant experiments to moremeaningful, clinically relevant problem based exercises. The topics covered in the manualhave been carefully selected based on the most recent (2007) improvised problem basedcurriculum design for pharmacology (Appendix I). The book covers all essential componentsto impart the necessary required skills to students in the subject of pharmacology as perprevailing regulations in the country. The manual highlights the important skills to be imbibedby budding doctors which will aid in rational therapeutics.

The manual covers all feasible exercises in pharmacology. The manual is flexible enoughto suggest various modifications for various medical colleges as per availability of materialfor practicals. A time schedule is also included (Appendix II), which can be modified as perrequirements. The exercises vary from simple demonstrations to computer simulation models.Special care is taken to keep the cost of material needed for practicals as low as possible.There are sufficient examples for students to apply the concepts learned in practicals. Thereare also new topics like ethics, which has become very important now after implementationof consumer protection Act to doctors.

I am thankful to all my students for sharing their concern about existing pharmacologypracticals and for their views on modifications in pharmacology practical training. That in away, encouraged me to write this manual. I am thankful to Mr Tarun Duneja of M/s JaypeeBrothers Medical Publishers (P) Ltd, New Delhi for expediting the publication. I hope thatstudents and teachers would benefit from this manual. Suggestions for improvements fromteachers and students are most welcome.

Dinesh [email protected]

Contents

Section 1: Clinical Pharmacy

1. Introduction to Clinical Pharmacy ........................................................................ 32. Weights, Measures and Abbreviations ............................................................... 73. Labeling of Drugs ....................................................................................................134. Pharmacy Preparations ..........................................................................................215. Common Dosage Forms and Routes of Administration-I .............................306. Common Dosage Forms and Routes of Administration-II ............................397. Common Dosage Forms and Routes of Administration-III ..........................54

Section 2: Experimental Pharmacology

8. Introduction to Experimental Pharmacology ....................................................739. Effects of Drugs on Rabbit Eye ............................................................................75

10. Effect of Drugs on Frog Heart ...............................................................................8011. Effect of Drugs on Rabbit Intestine ....................................................................8612. Effect of Drugs on Dog Blood Pressure .............................................................9013. Short Experiments for Efficacy and Safety .......................................................9414. Ethics and Animals .................................................................................................98

Section 3: Clinical Pharmacology

15. Introduction to Clinical Pharmacology ........................................................... 10316. Pharmacokinetic Parameters and Calculations ............................................ 104

x Practical Manual of Pharmacology

17. Prescription Writing Through Problem Based Learning(Rational Prescribing) .......................................................................................... 112

18. Critical Evaluation of Prescription (Audit of Prescriptions) ..................... 15719. Problem Based Drug Interactions .................................................................... 16220. Adverse Drug Reaction (ADR) Monitoring ................................................... 17821. Therapeutic Drug Monitoring (TDM) ............................................................. 18722. Drug Use in Special Population/Diseases/Physiological Conditions ...... 19423. Critical Appraisal of Drug Promotional Literature ..................................... 20724. Therapeutic Follow-up Cases/Problems ......................................................... 21525. New Drug Development ..................................................................................... 21926. Calculation of Drug Doses and Dilutions ...................................................... 22327. Evaluation of Drug Formulations ..................................................................... 23228. Ethics and Humans .............................................................................................. 23829. Management of Some Common Poisonings .................................................. 24330. Objective Structured Practical Examination (OSPE) ................................... 253

Appendix I ............................................................................................................... 257Appendix II ............................................................................................................. 259Appendix III ............................................................................................................ 261Appendix IV ............................................................................................................ 262Terminologies Used in Pharmacology ............................................................... 283

Index ......................................................................................................................... 287

Section 1Clinical Pharmacy

C H A P T E R

Introduction to Clinical Pharmacy1

Earlier, pharmacy used to be typically related to preparing and dispensing of drugs only. Inthose days, a doctor would himself prepare or formulate the drug in his dispensary anddispense it to his patients. This practice is now almost obsolete. These days doctor gets allthe drugs in ready-made form. The pharmaceutical industry (Ranbaxy, Cipla, etc.) are nowmanufacturing these drugs on mass scale. The doctor’s job is to rationally prescribe and usethese drugs. With this, there is now shift in pharmacy practicals. The redundant practicalscomprising of preparing and dispensing can be replaced by more clinically relevant clinicalpharmacy practicals. That’s why this chapter focusses on clinical pharmacy and not justpharmacy.

I feel that a budding doctor needs to be trained better in recognizing various dosageforms available to be used for patients, correct way of administration of these drugs andinterpretation of information on drug labels. A number of medical colleges have reduced/deleted pharmacy preparation practicals from the course. The MCI also insists on replacingunnecessary pharmacy practicals with more relevant clinical pharmacy practicals. Some peopleare still continuing with pharmacy preparation practicals as they find no alternative available.However, we can generate alternatives with the available resources in the department. Thesealternatives can be easily arranged with no cost involved.

To achieve this, total number of pharmacy practicals can be divided into 12 practicalsessions assuming that there is one practical session per week, so this comes out to be initialthree months of pharmacology practical course (Appendix 2).

Conventional pharmacy is art of preparation, compounding and dispensing of drugs. Italso includes interpretation and evaluation of prescriptions. Some hospitals have their ownpharmacies. Usually it is managed by a qualified pharmacist. There can be main pharmacyand satellite pharmacies throughout the hospital. These hospitals usually follow a computerisedcoded system for drugs. The common source to get drugs is usually chemist shops which canbe labeled as retail pharmacies. There is a difference between functioning of pharmacies inhospitals and chemist shops. The pharmacies in hospitals, these days do not manufacture/prepare a large number of drugs. Only few preparations related with dermatological sciencesare prepared. In chemist shops only ready-made drugs are available. The common functionsof both is to advise proper use of drugs and other precautions to patients. At some placesthey also provide information to doctors, nurses and other health care providers.

4 Practical Manual of Pharmacology

Instruments which are used in pharmacy are:

DISPENSING BALANCE

It is meant for weighing of more than 100 mg of a substance, i.e. sensitivity is 100 mg. Leftpan is made up of metal (for putting weights). Right pan is made up of glass/metal forputting substances to be weighed. Advantages of glass pan is that it is inert, non-reactive,can be easily washed and anything sticking to it can be seen. A butter paper can be used toweigh salts, salts do not stick to butter paper. This balance is sensitive for most of pharmacywork for common preparations (Fig. 1.1). It can be dismantled and packed in a small woodenbox.

These days electronic balances (Fig. 1.2) are available which can be conveniently used tomeasure even a very small quantity of drugs. The information about balance will help adoctor in clinics when you need to give a small dose to a child or when you want to divideone dose into multiple doses. Usually pharmacist/pharmacologist is approached by pediatricdepartment to divide the dose into small multiple fractions.

WEIGHTS

Students are provided with a box containing weights ranging from 1 to 100 gm. There is oneadditional small box containing very small weights ranging from 1 to 500 mg.

MEASURING CYLINDERS AND FLASK (FIG. 1.3)

The capacity can vary from 5 to 1000 ml. They are used for measuring liquid or solution, butthey are less accurate as compared to pipettes. They are safer as compared to pipettes. Withpipettes there are chances of contact of liquid with oral cavity, hence manual pipettes are notrecommended.

MORTAR AND PESTLE

It is made up of porcelain. It is used to grind the drug to powder form and also used to mixingredients of powders, liquid or semiliquid, ointments, mixtures, suspensions, etc. Thesedays glass mortar and pestle are available (Fig. 1.4). An advantage is that less drug sticks toglass and they are easy to clean.

Fig. 1.1: Dispensing balance and weights

Introduction to Clinical Pharmacy 5

CONTAINERS (FIG. 1.5)

Prescription bottle is used for liquids of low viscosity like mixtures, suspensions and solutions.It is made up of glass or plastic. Wide mouth bottle is used for solutions of high viscosity likeointment, etc. Amber coloured bottle prevents degradation of solution inside by absorptionof UV rays, e.g. calamine lotion.

SPATULAS

They are used to mix various chemicals, e.g. powders or ointments. They are formed ofplastic or metal (Fig. 1.6).

PILL TILE

It is used to mix the powders or ointments.

WASH BOTTLE

It contains tap or demineralised water.

Fig. 1.2: Electronic Balance Fig. 1.3: Measuring cylinder and flask Fig. 1.4: Mortar and Pestle

Fig. 1.5: Dispensing bottle Fig. 1.6: Spatula


PHARMACEUTICAL CONTAINERS

The basic requirement for a container is that it should not interact with the formulation.Glass, plastics are commonly used components of containers.

Glass containers have some disadvantages, e.g. leaching of alkali and insoluble flakesinto the formulation. These can be offset by the choice of an appropriate glass material, e.g.phenytoin has the ability to (in dilute solution) to react with glass. When added to glassinfusion bottles much of the drug remains stuck to the glass and does not reach the patient.

Plastic containers are convenient to handle but the major disadvantage is the two-waypermeation or ‘breathing’ through the container walls. Volatile oils, perfumes and flavouringagents can permeate through plastics to some extent. Components of emulsions and creamshave been reported to migrate through the walls of some plastics causing either a deleteriouschange in the formulation or collapse of the container. Loss of moisture from a formulationis also common, e.g. paraldehyde (a hypnotic) is one example. This liquid dissolves plastic soit must be injected parenterally using glass syringe.

Closure must form an effective seal for the container. It must not react chemically orphysically with the formulation. Rubber is a common component of stoppers, cap liners, andparts of dropper assemblies. Absorption of the active ingredients, preservatives into therubber and the extraction of one or more components of rubber into the formulation is acommon problem.

The application of an epoxy lining to the rubber closure reduces the amount of leachedextractives but has no effect on the absorption of the preservative from the solution. Teflon-coated rubber stoppers may prevent most of the leaching and absorption.

OBJECTIVES

At the end of this session a student shall be able to:1. Identify various instruments used in pharmacy.2. Describe uses of instruments used in pharmacy.

These are important to know dose and other details about administration of drugs. Thedrugs and solutions can be measured by using various units. Metric or decimal system ofmeasure is usually used to measure due to two advantages:

i. Its tables are simple as they are based on decimal system of notationii. Its tables of length, volume and weight are conveniently correlated.

METRIC SYSTEM

In metric system:• Base for weight is kilogram (kg)• Base for volume is litre (l)

Measures of weight (mass) in metric system

1 kilogram (kg) = 1000 grams (G or g)1 gram = 1000 milligrams (mg)1 milligram (10-3 g) = 1000 micrograms (μg or mcg)1 microgram (10-6 g) = 1000 nanograms (ng)1 nanogram (10-9 g) = 1000 picograms (pg)1 picogram (10-12 g) = 1000 femtograms (fg)

Measures of capacity (volume) in metric system

1 liter (L) = 1000 milliliters (ml)1 ml = 1000 μl

Another less commonly used system is imperial system. It can be:a. Avoirdupois system

Standard for weight = pounds (lb)1 lb = 7000 grains1 lb = 16 ounce (oz)

C H A P T E R

Weights, Measuresand Abbreviations

2


b. Apothecary system (UK)/Troy systemStandard for weight is grains1 oz = 480 grains1 lb = 12 oz

Measure for volume in both these system is Gallon1 gallon (C. or gal.) = 4 quarts = 8 pints1 quart (qt.) = 2 pints = 32 fluid ounces1 pint (pt.) = 16 fluid ounces (fl. oz. or )

CONVERSION BETWEEN SYSTEMS

Weight 2.2 pounds = 1 kilogram (kg.)1 grain (gr.) = 60 milligrams (mg.)

Fluid Measure 1 fluid ounce (fl. oz.) = 30 milliliters1 pint = 473 milliliters

There are also domestic measures to measure:

Domestic weights and measures

Domestic measures Metric equivalent1 drop = 1/20 ml, 1 ml = 20 drops (approx.)1 teaspoonful = 5 ml1 dessertspoonful = 10 ml1 tablespoonful = 15 ml1 glassful = 150 ml1 tumblerful = 240 ml

PHARMACEUTICAL CALCULATIONS

1. Percent CalculationThe word percentage can have different meanings under different circumstances. In solution,we are dealing with solids that are weighed and liquids that can be weighed or measured.

There are three different percentage solutions.a. Percentage weight in weight (w/w)—expresses the number of grams of solute in 100

ml of solution.b. Percentage weight in volume (w/v)—expresses the number of grams of solute in 100

ml of solution, regardless of whether water or another liquid is used as the solvent.c. Percentage volume in volume (v/v)—expresses the number of milliliters of solute in

100 ml of solution.a. Percent weight in volume (%w/v)

It is a solution of solid in liquid and represents number of solutes per 100 ml ofsolution.

Weights, Measures and Abbreviations 9

1% w/v is 1 g of solute in a total of 100 ml of solution.1% w/v means 1 part by weight, whereas the solvent is added upto 100 parts.1% = 10 mg/mle.g. To calculate the quantity of CaCl2 required for 200 ml preparation of 1%solution in distilled water1% means 1 g/100 mlfor 100 ml volume, CaCl2 = 1 gFor 200 ml CaCl2 = 1/100 × 200 = 2 g

b. Percent by weight (%w/w)It represents number of grams of solute per 100 gm of solution.1% w/w is 1 g of solute in 100 g solution.Add solid 1 part by wt and then add upto 100 parts, ensuring uniform mixing(Highly viscous substances like glycerin are considered solids and are measuredin grams)e.g. To prepare 25 g of 10% of a drug10% means 10 g/100 g of the preparationif 100 g has drug = 10 g25 g of preparation will have drug = 10/100 × 25 = 2.5 g

c. Percent by volume (%v/v)It is a preparation of a liquid in liquid and represents number of millilitres ofsolute per 100 ml of solution.1% v/v is 1 ml of a liquid constituent in 100 ml of solution, e.g. To make 2% v/v,to 2 part of volume of the constituent add upto 100 parts by volume.

2. Proportion CalculationInvolves mixing of 2 similar preparations of different strength to produce a preparationof intermediate strength.Proportions are equations containing ratios of equal value.For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8. (see chapter 27 formore).

3. Othersi. Units

Potency of certain drugs like heparin, insulin either cannot be determined by chemicalor physical methods or these methods are very costly. The measurement of thesedrugs is expressed in units. The unit is based on the effect/ amount of effect producedby a particular amount of drug in biological systems, i.e. isolated tissues of animals orwhole animals, e.g. 40 units of insulin.

ii. Molality: It is the number of moles of solute in 1000 grams of solvent.iii. Normality: It is the number of gram equivalents of solute dissolved in 1000 ml of

solution.


ABBREVIATIONS USED IN PRESCRIPTIONS

A prescription should be written in simple and/or in regional language without usingabbreviations, however, certain abbreviations are still in use as under:

A. Time of Drug AdministrationPhrase Abbreviation Meaningante cibum ac before mealspost cibum pc after mealshora somni hs at bedtimeopus in die od once a daybis bis twicebis in die bid twice dailyter in die tid three times a dayter die sumendum tds three times a dayquarter in die qid four times a dayquaque q every 6 hourquarta quake qqh every 4 houromni mane om every morningomni nocte on every nightsi opus sit sos when requiredstatim stat immediatelyad libitum Ad lib freely, use as much as one desiresomni die od every day repetatur Rep let it be repeated

B. FormulationsPhrase Abbreviation Meaningcapsula cap capsuletabella tab tabletliquor liq solutionmistula mist mixtureinjectio inj an injectionampoule amp an ampoulesyrupus syr syrupgutta gtt dropsnebula nebul spray

Weights, Measures and Abbreviations 11

C. Routes of Drug AdministrationPhrase Abbreviation Meaningintramuscular IM by Intramuscular injectionintravenous IV by Intravenous injectionsubcutaneous sc by subcutaneous injectionper os po by mouthper vaginam PV by vaginal routebolus bol as a large single dose (usually IV)

D. OthersPhrase Abbreviation MeaningAd Ad to, up toaqua aq waterreceipe R (you) takesigna sig you writeaurio dextra ad right earaurio laeve al left earauris utrae au both earsoculus dexter od right eyeoculus sinister os left eyeoculus uterque ou both eyesex modo prescripto emp as directedmisce M mixdispensa Disp. Dispensesigna sig you writetablespoon tbsp tablespoonteaspoon tsp teaspoon

OBJECTIVES

At the end of this session a student shall be able to:1. Understand meaning of all abbreviations used in Pharmacology.2. Convert various measurements given.3. Understand percent and proportion calculations.


Exercise in examination based on these practical can be:1. Expand the following:

a. Cap. Rifampicin 600 mg od ac

b. Tab. diazepam 5 mg hs

c. Syr. Amoxycillin 5 ml tid po

d. Tab. FeSO4 200 mg 2 bd pc

e. Tab. PCM 500 mg sos

f. Inj. Ampicillin 0.5 g IM qid

2. What do you understand by:a. 1% NaCl solution

b. 15% tannic acid glycerin

c. 5% lignocaine ointment

C H A P T E R

Labeling of Drugs3

If you pick up a strip of any medicine, you will find a lot of information on it, regarding drugname, manufacturer, expiry date, etc. as shown below in Figure 3.1.

Fig. 3.1: Labels on premanufactured medicines

Let us discuss in detail what various components of these labels are.

COMMERCIAL PREPARATIONS

Label of the given dosage form consists of

Name and quantity of the drugPharmacopeias used for preparation


Batch NoManufacturing and expiry dateManufacturing license numberMaximum retail price (MRP)Schedule of the drugs, i.e. H, L, P, X, etc.Instructions about use of drugsAddress of the pharmaceutical companyTo explain these terms let us discuss some general points:

A. DRUGS ARE CLASSIFIED INTO VARIOUS CATEGORIES

1. Prescription-only Drugs:These drugs are dispensed by pharmacist only when you have a prescription from aregistered medical practitioner (RMP), e.g. diazepam, morphine and antimicrobials.Prescription is a written order from physician for pharmacist. Registered medicalpractitioner is a doctor registered with regional or central medical council. Anallopathic RMP can not prescribe drugs from homeopathic stream and vice versa, e.g.an allopathic doctor can not prescribe Liv 52.

These drugs are covered under Schedule 'H' in India(Fig. 3.2). These drugs are considered to be unsafe forgeneral use, except under medical supervision. They aredispensed only on physician's prescriptions.

2. Over-the counter (OTC) drugs:These are non prescription drugs, i.e. these can bepurchased from pharmacies or chemist shops without aprescription. These drugs are considered safe and medicalsupervision is not required; e.g. Paracetamol. The drugswhich are mainly used as OTC drugs are:• H2-antihistamines• NSAIDs• Oral contraceptives• Hydrocortisone cream• Nicotine-cessation of smoking

OTC drugs may lead to adverse drug reactions (ADRs) because of:• Incorrect self-diagnosis and choice of incorrect therapy• Incorrect route of administration• Excessively prolonged use• Risk of dependence and abuse• Food and drug interactions• Storage in incorrect conditions

Fig. 3.2: Schedule H warning

Labeling of Drugs 15

• Failure to recogniseo Contraindicationso Interactionso Warningso Precautions

So to avoid these, whenever you use anover-the-counter (OTC) medicine, reading thedrug label is important for taking care ofyourself and your family. This is especially truebecause you probably take OTC medicineswithout first seeing a doctor. The label tells youwhat a medicine is supposed to do, who shouldor shouldn't take it, and how to use it. The OTCmedicine labels have always contained usageand safety information for consumers, but nowthe information will be more uniform and easierto read and understand (Fig. 3.3).

All nonprescription, over-the-counter (OTC)medicine labels have detailed usage and warninginformation so consumers can properly chooseand use the products. You'll find thisinformation:

• Active Ingredient: Therapeutic substancein product; amount of active ingredientper unit.

• Uses: Symptoms or diseases the productwill treat or prevent.

• Warnings: When not to use the product;conditions that may require advice froma doctor before taking the product;possible interactions or side effects; whento stop taking the product and when tocontact a doctor; if you are pregnant orbreastfeeding, seek guidance from ahealth care professional; keep productout of children's reach.

• Inactive Ingredients: Substances such ascolors or flavors.

• Purpose: Product action or category such as antihistamine, antacid, or coughsuppressant.

Fig. 3.3: Labeling of OTC medicine


• Directions: Specific age categories, how to take, how much, how often, and how long.• Other Information. How to store the product properly, and required information

about certain ingredients such as the amount of calcium, potassium, or sodium theproduct contains.

• The expiry date, when applicable (date after which you should not use the product).• Lot or batch code (manufacturer information to help identify the product).• Name and address of manufacturer, packer or distributor.• Net quantity of contents (how much of the product is in each package).• What to do if an overdose occurs.

B. DRUG NOMENCLATURE

You will frequently find existence of multiple names for a single drug. These names are:1. Chemical name: It indicates full name according to chemical constituents. It is lengthy,

complicated and not commonly used, e.g. 4-[2-Hydroxy-3-[(1-methyl ethyl) amino]propoxy] benzene acetamide for atenolol.

2. Non proprietary name/Generic name/Approved name: Name in official books whichis accepted worldwide, e.g. aspirin. It allows identification of different products withthe same ingredient to be identified, although there are few exceptions, e.g. adrenalinein India is known and epinephrine in United States of America. Drugs if prescribedby generic name are cheaper as promotional expenditure is avoided, but quality controlis difficult for generic drugs.

3. Proprietary name/Trade name/Brand name: Names given by innovativemanufacturing company, e.g. Crocin for paracetamol. Patent protection enablesinnovative pharmaceuticals to market the drug exclusively till the patent expires.After that the same drug is available under various brand names, e.g. paracetamolbrand names are crocin, acemol, bepamol, calpol and dolopar. Brand names are popularnames of the drug and are easy to remember, but so many brand names for a singledrug can create confusion in prescribing. Brand names are expensive also asadvertisement cost is added.

The drugs can have strikingly similar names leading to prescription errors ormedication errors. To overcome these WHO has initiated a programme on selectionof International non-proprietary names (INN) for assigning a unique, globally acceptedand recognized name.

C. PHARMACOPOEIA

Name is usually followed by the reference according to which drug was prepared, e.g. IPmeans Indian pharmacopoeia. Pharmacopoeia is a class of DRUG COMPENDIA (officialbooks of summarized information sources). The term pharmacopoeia is derived from twoGreek words—Pharmakon (means drug) and poiein (means make). Pharmacopoeia containsformula or other standards required for preparation and testing of drugs to ensure uniformpurity and potency. The description of preparation given in pharmacopoeia is known as


monograph. These monographs describes drug, characteristics for identification, standardsof purity and strength limits of impurities, assay method of drugs, storage and instructions.Drug and the information mentioned in pharmacopoeia are official. It also includes officialrange of dosage for drugs, system of weights, measures and the formulations and the methodsused for sterilization of pharmaceutical products. Most of the countries have their ownpharmacopoeia.

Other source for this type of information is National Formulary. These are the books ofstandards for drugs and devises. These are compilations of those drugs, which have beenrecognized as legal standards of purity, quality and strength by government agency of thatcountry.

Official reference books of India:

Indian Pharmacopoeia (IP)National Formulary of India (NFI)Chemical and Medical Formulary of IndiaDrug Bulletins

International official books:

British Pharmacopoeia (BP)British Pharmaceutical Codex (BPC)United States Pharmacopoeia (USP)International Pharmacopoeia (By WHO for those countries who do not have their own

pharmacopoeia)

Others:

British National FormularyMartin Dale's Extra PharmacopoeiaPhysician's Desk Reference

D. THESE DAYS YOU MAY FIND A DRUG NAME CARRYING A POST SUFFIX.

These are:D-dispersible, e.g. Doxycycline-DCR-controlled release, e.g. Indomethacin-CRSR-sustained release, e.g. Diclofenac-SR

E. DRUGS SCHEDULES AND ACTS

Sometimes you will find drug names followed by a boxed warning, e.g. Schedule H drug.These are based on drugs schedules and acts.

There are various drug schedules and acts in India. The important ones are as per Drugsand Cosmetics Act (1940) as amended in 2001 are:


DRUG SCHEDULES

Schedule A: gives specimen of prescribed form.Schedule B: gives fees for test and analysis of drugs.Schedule C: gives details with biological and other special products.Schedule D: is concerned with exemption regarding drug import.Schedule FF: gives details of standard ophthalmic solutions.Schedule G: deals with details of drugs to be labeled 'CAUTION-it is dangerous to take

this medicine except under medical supervision'.Schedule H: deals with drugs and medicine to be sold on prescription-only.Schedule I: lists all ailments for which no cure can be claimed, e.g. AIDS.Schedule Q: deals with cosmetics.Schedule R: deals with standards for contraceptives.Schedule W: gives details of drugs which should be marketed under generic name only.Schedule X: deals with psychotropic drugs which require special license for manufacturing

and sale.Schedule Y (new addition): specifies the requirements and guidelines on conduct of clinical

trials, import and manufacturing of new drugs.

FDA (USA) SCHEDULES ARE:

Schedule I (C-I)

• High abuse potential• No accepted medical use in the United States• Examples: heroin, marijuana, LSD (lysergic acid diethylamide), peyote

Schedule II (C-II)

• Potential for high abuse with severe physical or psychological• dependence• Examples: narcotics such as meperidine, methadone, morphine, oxycodone,

amphetamines and barbiturates

Schedule III (C-III)

• Less abuse potential than schedule II drugs• Potential for moderate physical or psychological dependence• Examples: nonbarbiturate sedatives, nonamphetamine stimulants, limited amounts of

certain narcotics

Schedule IV (C-IV)

• Less abuse potential than schedule III drugs• Limited dependence potential• Examples: some sedatives and anxiety agents, nonnarcotic analgesics


Schedule V (C-V)*

• Limited abuse potentialExamples: small amounts

Drugs which are prepared and dispensed by pharmacist usually have different labelthan the ones prepared by pharmaceutical industry. The label is divided into two:

1. Primary Label2. Secondary Label

PRIMARY LABEL

It is the main label used on pharmacy preparations. It should be proportional to the size ofcontainer and it usually should occupy middle 1/3rd of the container. It should cover less.

This label should have following information:Title of preparation, e.g. The PowderName :Age/Sex :Reg. No. :Directions :Date/SignatureRegistration no.Directions/instructions to patients for proper use of drug.Name of the pharmacy laboratory from which the drugs have been dispensed.

SECONDARY LABEL

As obvious from the name, it is the other label than the primary label. It is smaller in size andis usually put above the primary label with a small gap in between.

This label usually contains some important precautions about the use of drug in capitalletters, for example:

Shake Bottle Well Before Use

The number of secondary labels may be more than one.

OBJECTIVES

At the end of this session a student shall be able to:1. Understand all information written on label of drugs.2. Understand primary and secondary labels.3. Knows drug nomenclature.


Exercise in examination bases on these practical can be:1. Enumerate all the information written on the label of drugs:

A strip of tabletsA container of liquidAn ampouleA vial

2. What do you understand by the following terms? Mention the clinical importance ofeach of them.a. Manufacturing Date

b. Expiry Date

c. Batch Number

d. MRP

e. Schedule H

C H A P T E R

Pharmacy Preparations4

To give an idea to students about how drugs are prepared in pharmacy, a few pharmacypreparations practicals can be demonstrated in two session.

Exercise 1: To prepare and dispense 50 ml of Calamine lotion

Formula:For 100 ml

Calamine 15 gmZinc oxide 5 gmBentonite 63 gmLiquefied phenol 0.5 mlSodium citrate 5 gmGlycerine 5 mlPurified water ad 100 ml

PROCEDURE

• Weigh out the calculated quantities of calamine, zinc oxide and bentonite. Mix themthoroughly in a mortar.

• Take 20 ml of purified water in graduated flask and add the required quantity ofsodium citrate.

• Pour a little of water from flask into mortar containing calamine, bentonite and zincoxide. Triturate to make homogenous paste. Add required amount of glycerin andphenol to this mortar and triturate.

• Transfer the mixture to the flask. Rinse the mortar with a little quantity of purifiedwater and transfer this rinsing into the flask. Add sufficient quantity of water to makeup the final volume 50 ml. Transfer it to an amber coloured bottle, label and dispense.

HOW TO APPLY

• Wash and completely dry the affected area before applying the lotion. Shake lotionwell before use.


Secondary Labels

Primary Label

←

←

• Apply this medication to the affected area of skin, generally three to four times daily oras directed by your physician.

• Do not dilute or mix with other lotions.

LABELING

FOR EXTERNAL USE ONLY

SHAKE WELL BEFORE USE

Name Rajesh Singh Age/Sex 35 MAddress 145, BRS Nagar, LudhianaDirections: Apply on the affected part with cotton swab.

Do not rub.Sign and Regd No. of

24-05-2007 PharmacistPharmacy, ABC Delhi

PHARMACOLOGICAL ACTIONS

Calamine: Calamine is a mixture of zinc oxide (ZnO) with about 0.5% iron (III) oxide (Fe2O3).It is the main ingredient in calamine lotion and is used as an antipruritic to treat sunburn,eczema, rashes, poison ivy, chickenpox, insect bites and stings. It is used as a mild antisepticto prevent infections that can be caused by scratching the affected area. It is also used to dryweeping or oozing blisters and acne abscesses. It is also used as colouring agent in variouscosmetics.

Zinc oxide: It is insoluble in water, used as dusting powder, ointment, lotion and paste.It has soothing and protective action in eczema. It is also used as mild astringent for skin.

Bentonite: It is colloidal aluminum silicate insoluble in water but swells into a homogenousmass. It is used as suspending agent because it increases the viscosity of the vehicle. It is alsoused as a bulk laxative. It should be sterilised before using on open wounds.

Sodium citrate: It helps in the dispersion of solids in this preparation and reduces theviscosity of this preparation.

Liquefied phenol: It has an antiseptic and mild local anesthetic effect. However, in theamount used, it acts as a preservative in this preparation. It is particularly required as glycerinpromotes the growth of microorganisms.

Glycerine: When applied locally it acts as an emollient and helps in penetration ofingredients by making the skin moist and soft. Due to its viscous nature, the lotion stays fora longer time at the site of application. It is hygroscopic in nature, so prevents drying up andcracking of skin and the lesions.

Pharmacy Preparations 23

Secondary Label

Primary Label

←

←

THERAPEUTIC USES

1. In pruritis: used as soothing and protective lotion.2. To allay pain and swelling of sun burns.3. For prickly heat4. Any other irritating skin condition5. It is also used in herpes zoster and chickenpox.

PRECAUTIONS

• Avoid contact with the eyes, on the inside of your nose, mouth or genital area• Contraindicated if known sensitivity or allergy to any ingredient• Ask a doctor before using calamine lotion on children younger than 6 months of age.

Exercise 2: To prepare and dispense 25 ml of Mandle's throat paint

Formula for 100 ml:For 100 ml

Iodine 1.24 gmPotassium iodide 2.48 gmMentha oil 0.40 mlWater 2.48 mlAlcohol 90% 3.76 mlGlycerine upto 100 ml

PROCEDURE

• Weigh out the required amount of iodine and potassium iodide and transfer to a glassjar. 10 drops of water and 5 ml of glycerin. Stir the contents. When contents are completelydissolved, add required amount of Mentha oil and dissolve it.

• Transfer the contents into a measuring cylinder and add glycerin to make volume upto25 ml. Transfer contents into amber colored bottle, label and dispense.

LABELING


Name Rajesh Singh Age/Sex 35 MAddress 145, BRS Nagar, LudhianaDirections: Apply on the affected part with cotton swab.

3 times a day.Sign and Regd No. of

24-05-2008 PharmacistPharmacy, ABC Delhi



Iodine: It is nonmetallic component. It acts locally and has antiseptic properties. It is anoxidising agent and acts as bactericidal.

Potassium iodide: It is used to dissolve iodine as iodine is highly soluble in aqueoussolution.

Water acts as solvent for potassium iodide. Mentha oil acts as flavouring agent and isvolatile. Alcohol is used to dissolve mentha oil and glycerin. It also acts as preservative,antiseptic and astringent. Glycerine helps iodine to stick to affected area for longer period.It also has antiseptic action and reduces edema.

THERAPEUTIC USES

1. Tonsillitis2. Pharyngitis

PRECAUTIONS

Do not take food/water half an hour before and after the application of the paint.

Exercise 3: To prepare and dispense 1:5000 solution of Potassium Permanganate withdirections to dilute it to 1:15000 before use.

Calculations

Prepare 1% stock solution1% stock solution is1 gm in 100 mlor 1000 mg in 100 mlor 100 mg in 10 mlor 100 mg in 1 ml

For 1:5000 solution of KMnO4 we need:1g in 5000 thousand mlor 1000 mg in 5000 mlor 10 mg in 50 ml

Procedure

1. Measure accurately 100 mg of KMnO4 crystals. Dissolve it in 10 ml of distilled water(1% stock solution). Stir with a glass rod to mix potassium permanganate solution.

2. Take 1 ml of solution and add 49 ml of water to make volume 50 ml. This is 1:5000solution.

3. Label and dispense it in an amber coloured bottle to privet oxidation.


Secondary Label

Primary Label

←

←

LABELING


Name Rajesh Singh Age/Sex 35 MAddress 145, BRS Nagar, LudhianaDirections: Dilute the solution before use by mixing 1

part of solution with 2 parts of water.Use it for gargles and mouth washes 3-4 timesin a day.

Sign and Regd No. of24-05-2009 Pharmacist

Pharmacy, ABC Delhi

STORAGE CONDITIONS

It should be stored in a tightly corked container in a cool dark place away from the sunlight.


Potassium permanganate has bactericidal and fungicidal activity. Potassium permanganate,on contact with organic matter, liberates nascent oxygen that oxidizes enzymes essential forliving microorganisms and their metabolism, thus producing antiseptic effects. It also acts asastringent. It is readily soluble in water.

THERAPEUTIC USES

The major uses of this preparation are:1. As disinfectant for water and utensils-1 in 100 solution.2. As a cleansing application to ulcers and abscesses-1 in 1,000 solution.3. As mouthwash (in gingivitis and steatites), gargles (Condyl's gargles), for washing

wounds and for vaginal irrigation-1 in 4,000 solution.4. Sitz's baths given in hemorrhoids, piles and fissures.5. As gastric lavage in the treatment of morphine, opium, strychnine, aconitine and other

alkaloid poisonings (but not for cocaine and atropine because they are not easily oxidisedby potassium permanganate)-1 in 5,000 solution is employed as applications for weepingskin lesions and for urethral irrigation-1 in 5,000 and 1 in 10,000 solutions.

6. Treatment of snake bite (effective only if the venom is on the skin). It oxidize venom(within 1-2 minutes of bite).


ADVERSE EFFECTS

• The crystals and concentrated solutions of KMnO4 are caustic and can cause corrosiveburns.

• Higher concentration can cause skin irritation, edema and mucous membrane turnsbrown.

• There can be staining of clothes• Do not disinfect surgical instruments, rusting can happen.

Exercise 4: To prepare and dispense one dose of oral rehydration powder for 1000 ml oforal rehydration solution (ORS)

ORS is a simple, cheap and effective treatment for diarrhea-related dehydration, e.g. choleraor rotavirus. It consists of a solution of salts and other substances such as glucose, sucrose,citrates or molasses, which is administered orally. It is used around the world, but is mostimportant in the Third World, where it saves millions of children from diarrhea, still theirleading cause of death.

WHO FORMULA (FOR 1 LITRE ORS)

Sodium chloride 3.5 gmSodium citrate 2.9 gmPotassium chloride 1.5 gmGlucose anhydrous 20.0 gm

OBJECTIVE OF ORS

• To prevent dehydration• To reduce mortality.

PROCEDURE

• Weigh the required quantities of sodium chloride,sodium citrate, potassium chloride and glucose.

• Mix them on a paper placed over pill tile by usingpowder spatula.

• Put the powder in a packet (Fig. 4.1).• Label the packet and dispense. Fig. 4.1: Folding of packet for powder


Name Akash Age/Sex 20 MAddress 132, BRS Nagar, LudhianaDirections: Dissolve the contents of powder in 1000 ml of freshy

boiled and cooled water and take frequent sips.Sign and Regd No. of

24-05-2007 Pharmacist

Pharmacy, ABC Ludhiana

The frequency of sips will depend on level of dehydration.


In diarrhea loss of water and electrolytes leads to dehydration. Hence, both water andelectrolytes are given for treatment of dehydration. If water alone is given it will dilute thesalts present in body and aggravates the condition.

WHO ORS (for 1 litre) provides following salts as mEq/L:Na+ 90.0K+ 20.0

–3HCO 30.0

Glucose 111.0Cl-80.0Osmolarity of 311 mOsm/l215 calories

PHARMACOLOGICAL ACTION OF SALTS

Sodium chloride

As you know, sodium is the main ion involved in various processes in the body, e.g. actionpotential generation. It helps to maintain muscle tone. Symptoms associated with hyponatremiaare fatigue, muscle weakness, abdominal cramps, confusion, hypotension, weak pulse,cyanosis, oliguria, tachycardia, loss of skin elasticity and dryness of mucous membranes.

Glucose

Glucose is the source of energy. Apart from that it helps in absorption of sodium. Molarratio of glucose is more than sodium in ORS. Sodium is absorbed through facilitated diffusionor cotransport with the help of glucose.

Other contents provide sufficient amount of potassium, chloride and bicarbonate lost indiarrhea. Sodium citrate is the source of HCO3

– and also provides stability to the solution.Potassium chloride influences the muscle action and ameliorates the cramps. Chloride helpsto maintain the fluid balance and production of gastric acid.


THERAPEUTIC USES

1. DiarrhoeaOral rehydration therapy is widely considered to be the best method for combating thedehydration caused by diarrhea and/or vomiting. Rehydration does not stop diarrhea,but keeps the body hydrated and healthy until the diarrhea passes. ORS is recommendedin mild to moderate cases of diarrhea. Intravenous fluids are required in severe casesof dehydration.

The amount of rehydration that is needed depends on the size of the individual andthe degree of dehydration. Rehydration is generally adequate when the person nolonger feels thirsty and has a normal urine output. A rough guide to the amount of ORSsolution needed in the first 4-6 hours of treatment for a mildly dehydrated person is:

• Up to 5 kg (11 lb): 200-400 ml• 5-10 kg (11-22 lb): 400-600 ml• 10-15 kg (22-33 lb): 600-800 ml• 15-20 kg (33-44 lb): 800-1000 ml• 20-30 kg (44-66 lb): 1000-1500 ml• 30-40 kg (66-88 lb): 1500-2000 ml• 40 plus kg (88 lb): 2000-4000 mlThe degree of dehydration can be assessed by following parameters:— Pulse in dehydration has low volume and is thready.— No tears, dry mouth in case of moderate to severe dehydration.— Urine output is decreased in dehydration.

2. Heat stroke.3. In patients of burns/surgery to maintain hydration.4. Change from parenetral to enteral therapy.5. High grade fever.

HOME MADE ORS

In a glassful of water, add I teaspoonful of sugar and a pinch of salt. You can also add half alemon.

Rice water and dal water can also be used.orAn inexpensive home-made solution consists of 8 level teaspoons of sugar and 1 level

teaspoon of table salt mixed in 1 liter of water. A half cup of orange juice or half of a mashedbanana can be added to each liter both to add potassium and to improve taste.

SUPER-ORS

In this amino acids are added, e.g. alanine and glycine.


NEW WHO ORS

Because of the improved effectiveness of reduced osmolarity ORS solution, especially forchildren with acute, non-cholera diarrhoea, WHO and UNICEF now recommend thatcountries use and manufacture the following formulation in place of the previouslyrecommended ORS solution.

REDUCED OSMOLARITY ORS

Ingredient (grams/litre) ion (mmol/litre)Sodium chloride (2.6) Sodium (75)Glucose, anhydrous (13.5) Glucose, anhydrous (75)Potassium chloride (1.5) Chloride (65)/Potassium (20)Trisodium citrate, dihydrate (2.9) Citrate (10)Total Osmolarity = 245. In the human body, the plasma osmolality is about 285 mOsm/l.

PRECAUTIONS

• Hot water should not be used as it may lead to breakdown of bicarbonate and alterationin flavor

• Do not use if the solution is coloured.• Always use freshly prepared solution.• The solution made should not be used 24 hours after its preparation.• Use clean utensils to make solution.

Today, the total production is around 500 million ORS sachets per year, with the children'srights agency UNICEF distributing them to children in around 60 developing countries. ORSrepresents a cheap and effective way of reducing the millions of deaths caused each year bydiarrhea.

OBJECTIVES

At the end of this session a student shall be able to:1. Understand how preparations are made in hospital pharmacy.2. Various parts of a label on hospital pharmacy preparations.

Various dosage forms of drugs are used in therapy. Before discussing dosage forms let's seewhat are the various sources of drugs.

SOURCES OF DRUGS

Plants: One third of allopathic drugs are still derived from plants. Problem associated witha plant drug are: identification of plant, conditions of storage, standardization of activeprinciple, purity and maintenance of supply line, e.g. morphine, codeine

Animals: Some drugs are still obtained from animals due to expensive and cumbersomesynthesis, e.g. gonadotropins, heparin

Microorganisms: Antimicrobials are obtained, e.g. penicillin, erythromycin

Minerals: Some minerals are important for body and given prophylactically or for treatmentof deficiency, e.g. Zinc

Synthetic: Most of the drugs in use today are synthetic in origin. These drugs are chemicallypour and it is easy to maintain their supply, e.g. oral antidiabetics

Semisynthetic: Changes are made after synthesis, e.g. insulin

Biosynthetic: Recombinant technology is used to produce drugs, e.g. recombinant insulinDrugs need to be presented in a form that can be administered to an organism. Formulation

is a recipe by which a drug is prepared. Drug formulation can allow specific tissue sites to beselectively targeted or systemic absorption of the drug to be avoided. Formulation is notonly about a small amount of a drug that needs to be encapsulated or bottled for easydelivery but it is also about how to present a drug for administration so that it is guaranteedto reach the target area. The administration of drugs is one of the most important andexacting duties performed in caring for sick and injured patients. The appropriate druggiven in the correct dosage will very often hasten a patient's recovery. On the other hand, aninappropriate drug or dosage may worsen a patient's condition or even result in his death.

C H A P T E R

Common Dosage Forms andRoutes of Administration-I

5

Common Dosage Forms and Routes of Administration-I 31

To discuss formulation we will discuss route of administration of drugs, dosage formsused and their advantages and disadvantages.

Various routes of drug administration are:A. For systemic effects

1. Enterable-oral, sublingual, etc.2. Parenteral (which bypasses GIT)-i.v, i.m. etc.

B. For local effects3. Local, e.g. topical application

C. Special preparations, e.g. controlled releaseRemember that there are six "rights" in the administration of drugs:

1. Right patient2. Right drug3. Right dose4. Right route5. Right time6. Right documentation

ORAL

The drug is given through mouth. It is the commonest and most acceptable method of drugadministration.

ADVANTAGES

1. Most convenient and cheapest2. Non-invasive, painless and no assistance is required.3. Aseptic precautions are not required.4. Both, solid and liquid dosage forms can be given

• Solid preparations are: tablets, capsules, moulded tablets, powders, spansules,etc.

• Liquid preparations are: syrups, mixtures, elixirs, emulsions, etc.

ORAL-TABLETS

A tablet is a disc, containing one or more medications, preparedby compressing a granulated powder (Fig. 5.1). As most drugsare presented in small quantities (sometimes less than amilligram), other materials (excipients) must be added to makethem easy to handle, to be seen and to compress. Tablets musthave property to disintegrate in the gastrointestinal tract. Fig. 5.1: Tablets


Capsules and tablets should be swallowed with a glass of water with the patient in uprightposture either sitting or standing, as this enhances the passage into the stomach and permitsrapid dissolution. Giving drugs orally to a recumbent patient should be avoided if possible,especially in the case of drugs which can damage the esophageal mucosa, e.g. doxycyline,iron salts, etc. Oesophagitis induced by these drugs is very difficult to treat. Tablets may bescored i.e. a line demarcation is there to divide tablet into two equal parts (Fig. 5.2).

DISADVANTAGES

1. Action is slow so it is not suitable for emergency2. Unpalatable drugs (e.g. paraldehyde) are difficult to administer3. It may cause gastrointestinal adverse effects e.g. nausea and vomiting (e.g. emetine)4. It can not be used for non cooperative/unconscious/vomiting patients5. Certain drugs are not absorbed if given by this route (e.g. streptomycin)6. Certain drugs are destroyed by gastric juices (penicillin G, insulin) or extensively

metabolized during first pass in the liver or GIT (e.g. nitroglycerine, testosterone,lidocaine).

ORAL-CAPSULES

They can be of two types:1. Hard gelatin type: It contains the drug as solid. It can be opened. Capsules can come in

many colors for easy identification. Hard capsule consists of 2 cylinders which fit intoone another (Fig. 5.3), e.g. amoxycillin capsules.

2. Soft gelatine type: It contains the drug in liquid or semi-liquid form. They are completelysealed (Fig. 5.4). They are useful for liquid drugs and for drugs which are water insoluble,e.g. nifedipine

Gelatin is heterogenous mixture of water soluble proteins of high molecular weight.Pearls are transparent or translucent capsules that contain liquid or semisolid drugs,e.g. vitamin A capsules.

Fig. 5.3: CapsulesFig. 5.2: Tablets Fig. 5.4: Soft Capsules


ADVANTAGES

1. Masks the bad smell and taste of drugs.2. Avoids destruction by gastric juice and avoids gastric irritation.

DISADVANTAGE

More expensive than tablets.ORAL-Pills means round or ovoid body, usual coated with sugar or even silver or gold

paint, e.g. oral contraceptives.Tablets, capsules and pills are packed in the plastic coated paper or aluminum strips or in

blister packing (Fig. 5.5).ORAL-powder: Powder is a solid form of drugs, which is finely divided and intimately

mixed (Fig. 5.6). They are mainly of three types. (i) Simple powders: contain one ingredientonly, e.g. glucose powder. (ii) Compound powders: contain more than one ingredients, e.g.ORS powder. Simple powder - ORS and (iii) Effervescent powder, e.g. Antacid effervescentpowder, Seidlitz. Powders are packed in sachets.

ADVANTAGES

1. They are flexible in compounding.2. Powders have a good chemical stability.

DISADVANTAGES

1. Needs proper instruction for preparing.2. Time consuming to prepare.3. It is not suitable for dispensing bitter drugs.

For effective use of this dosage form, required amount of powder to be dissolved inrequired amount of water prior to administration and then to be taken orally.

Fig. 5.6: PowderFig. 5.5: Packed tablets, capsules


ORAL-LIQUIDS

Liquid oral formulations include syrups, mixtures, solutions, reconstituted oral solutions,elixirs and gels (Fig. 5.7).

These two preparations (suspension and emulsion) have tendency to separate and requiresa thorough mixing before administration. Liquids for oral use are usually dispensed in plasticor glass bottles.

ADVANTAGES OF LIQUID PREPARATIONS

1. They are more quickly acting than pills or tablets, which require previous disintegrationbefore absorption.

2. Certain substances can only be given in the liquid form, e.g. liquid paraffin.3. Certain chemical substances, e.g. potassium chloride can cause gastric irritation if taken

in the form of powder or tablet.4. Patients are sometimes prone to doubt the efficacy of the treatment they are receiving

unless it includes something in the bottle (e.g. placebo effect).5. Usefulness of some substances are largely dependent upon administration of diffusible

form, e.g. magnesium sulphate in the form of suspension.Syrups: They are liquid oral preparations in which the vehicle is concentrated aqueous

solution of sucrose or other sugar.

ADVANTAGES

1. They are sweet in taste so masking the bad taste of drugs, especially suitable for children.2. Quicker effect than tablets which require previous disintegration.

DISADVANTAGES

1. Maintenance not easy.2. They are costlier than tablets.

PRECAUTION

Close the bottle properly after use.Elixir: Some drugs are insoluble in water, they are dissolved

in alcohol. These preparations are termed elixirs. They are clearliquid oral preparations containing hydroalcoholic vehicle, e.g.bromhexine, promethazine.

ADVANTAGE

Potent or nauseous drugs are pleasantly flavored and usuallyattractively coloured so patient compliance is better. Fig. 5.7: Syrup


DISADVANTAGES

1. Maintenance not easy.2. They are costlier than tablets.

PRECAUTION

Close the bottle properly after use.Suspension: A liquid preparation that is made from a drug in solid form but not dissolved

in alcohol is refers to as a suspension. It is a liquid medicament containing insoluble (diffusibleor indiffusible) solid substances which are homogeneously distributed throughout the vehiclewith or without the help of a suspending agent (Fig. 5.8).

ADVANTAGES

1. They are chemically more stable than the syrup.2. Mask the unpleasant taste and odor of the drugs.3. Insoluble solids can be given in liquid form.

DISADVANTAGES

1. A suitable preservative is required to avoid microbial contamination.2. For effective use of this dosage form, shake the bottle well before use.

Emulsions: They are liquid medicaments containing two immiscible liquids, one of whichis broken into minute globules, each globule being surrounded by a thin film of emulsifyingagent and then dispersed throughout the other liquid, e.g. liquid paraffin emulsion.

ADVANTAGES

1. Oily drugs can be given in this form2. Oil in finely dispersed state is quickly absorbed.3. Emulsifying agents mask the unpleasant taste and smell of the drugs.

DISADVANTAGES

1. A suitable preservative is required to avoid microbialcontamination.

2. For effective use of this dosage form, shake the bottle wellbefore use.

Factors affecting oral route of administration:1. Drug characteristics2. Luminal pH along the GI tract3. Destruction in GIT4. Surface area per luminal volume5. Blood perfusion6. The presence of bile and mucus Fig. 5.8: Suspension


7. The nature of epithelial membranes8. Presence of food9. Gut motility

10. First pass metabolism

DRUG CHARACTERISTICS

1. Unionised drugs are lipid soluble, hence absorption is better.2. Most of the drugs are absorbed from small intestine due to large surface area, longer

contact time and rich vascular supply.3. Presence of food usually delays absorption.4. Some drugs are destroyed by gastric juices e.g. insulin, so these can not be given by

oral route.5. First pass metabolism decreases bioavailability of drugs by oral route e.g. propranolol.6. Gut motility and gastric emptying time also affect absorption of orally administered

drugs.

ORAL- SPECIAL PREPARATIONS

Coated preparations

Sometimes a drug needs to be disintegrated not in the stomach but in the intestine. Thetablets are coated with material which does not disintegrate in the acidic conditions of thestomach but only in the alkaline conditions of the intestine, e.g. enteric coated aspirin toavoid local toxicity in stomach.

• Coated tablets: Tablets may be sugar-coated or film-coated to disguise bad-tastingdrugs, e.g. Chloroquine tablet.

• Dispersible tablets: Tablets may be dispersible to avoid loss of disintegration in stomachor to avoid local toxicity in oesophagus, e.g. doxycyline. These dispersible tablets areto be dissolved in water prior to administration

• Chewable tablets: When chewed it disintegrates due to its creamy base, e.g. antacidtablets, antihelminthic tablets and vitamin C tablets. It is useful tochildren who have difficulty in swallowing and to the adults whodislike swallowing, but tablet is expensive.

• Effervescent tablets: Prepared by compressing granular effervescentsalts. It disintegrates fast when added to water and acts by releasingcarbon dioxide (Fig. 5.9). Effervescence masks the bad taste of drug.It may give psychological effect to patient, e.g. alkaline tablet,antacid tablet, aspirin tablet. The tablet is very sensitive to moistureand expensive also. The tablet to be dissolved in a glass of waterand the same to be taken orally while effervescence is present.Take in upright posture either standing or sitting.

Fig. 5.9: Effervescenttablets


• Lozenges: These are disc shaped solid dosage forms, e.g. menthol, dextromethorphan.They have local action in oral cavity. There is slow and continuous effect of the drug

on the mucous membrane of the throat.

SUSTAINED RELEASE (SR) PREPARATIONS

Drug is enclosed within device in such a waythat the rate of drug release is controlledby its permeation through a membrane wall(Fig. 5.10). These preparations release drugslowly providing longer duration of action,e.g. diclofenac sodium SR.

These are also known as retard orcontrolled release preparations, e.g.pilocarpine-releasing ocular insert for 4-daycontinuous glaucoma treatment.

ADVANTAGES

1. It modifies the rate of release of drug into the gastrointestinal tract.2. It prolongs the effect of drug and also reduces the frequency of administration.3. Patient compliance is better.

DISADVANTAGES

1. It is expensive as compared to uncoated tablets.2. Dose dumping at one site producing local toxicity/systemic and loss of control release

mechanism.Sustained release preparations can be formed by various techniques as follows:

1. Membrane system—drug enclosed in polymers from where it is released slowly.2. Matrix system—drug is incorporated in a porous matrix.3. Coated granules—drug molecules are coated, which release drug at different rates

(Fig. 5.11).

RECTAL

Drugs in the form of suppositories are inserted into the anal canal, e.g. diazepam in childrensuffering from status epilepticus. Rectum has rich vascular supply, so absorption is quick.

ADVANTAGES

1. Unconscious, vomiting patient2. Swallowing problems3. In case of a difficulty to find the vein for intravenous injection4. Uncooperative children5. Unpleasant drugs

Fig. 5.10: SR


DISADVANTAGES

1. Anal or rectal irritation.2. Inconvenient, aesthetic considerations.3. Absorption slow, irregular and unpredictable.4. They are made to melt at body temperature, so needs to be kept refrigerated. They can

even melt on the hand before insertion.The patients need to be educated about the best position for insertion and also to remove

the plastic cover.

OBJECTIVES

At the end of this session a student shall be able to:• Write down the name dosage form of the drug displayed at the various stations.• Give instructions to patients on the proper usage of each dosage form.• Write two important advantages of the dosage form.• Write two important disadvantages of the dosage form.

Exercises for this session can be arranged in stations. Each station has various dosageforms. The stations can have the above mentioned dosage forms like:

Tablets–dispersible, sustained release, controlled release, enteric coated, sublingualtablets, pills

Capsules–soft/hard gelatine capsules, pearls, spansulesLiquid oral formulations (mixtures)–syrups, mixtures, solutions, reconstituted oral

solutions, elixirs, suspensions, etc.

Fig. 5.11: Delivery systems and drug release

Any method of drug administration that avoids the gastrointestinal tract is termed parenteraladministration. Parenteral is derived from combination of 2 words:

Par = beyond Enteral = intestinalTransdermal, intranasal, rectal are, therefore, parenteral methods. However, the usual

term parenteral is reserved for drug injections.

ADVANTAGES

1. They can be employed in an unconscious or an uncooperative patient.2. They can be employed in cases of vomiting and diarrhoea and in the patients unable to

swallow.3. Drugs which might irritate the stomach or which are not absorbed orally can be

administered, e.g. aminoglycosides.4. They avoid drug modification by the alimentary juices and liver enzymes e.g. Insulin,

nitroglycerine.5. Rapid action and accuracy of dose are ensured.

DISADVANTAGES

1. Less safe, once given the action of given drug will become irreversible2. More expensive3. Inconvenient for use, self-medication being difficult4. Liable to cause infection if proper care is not exercised5. Likely to injure important structures such as nerves and arteries if not given properly.

Strict aseptic precaution should be taken while giving injection in order to preventinfections due to HIV and Hepatitis B virus. Disposable syringe and needle should beused and should be purchased from an authentic source. Needle should be brokendown and syringe should be discarded after use.

Injections: An injection is a method of putting liquid into the body with a hollow needleand a syringe which is pierced through the skin long enough for the material to be forcedinto the body. Preparations meant for parenteral administration must be sterile. Depending

C H A P T E R

Common Dosage Forms andRoutes of Administration-II

6


upon the volume, they are supplied in sealed glass ampoules, e.g. streptomycin or rubbercapped multi-dose vials, e.g. multivitamins or large infusion bottles, e.g. 5% dextrose or inpolypropylene pouches, e.g. metronidazole.

DOSAGE FORMS FOR INJECTIONS

i. Aqueous or clear solution for subcutaneous/intramuscular/intravenous use.ii. Suspension for intramuscular/intravenous use.

iii. Emulsion for intravenous use. Oily solution for intramuscular use long-acting forms ofsubcutaneous/intramuscular injections are available for various drugs; these are calleddepot injections.

iv. Powder to be reconstituted for intramuscular/intravenous use. Powder has to bedissolved or suspended in colloidal form before injecting by adding an adequate quantityof a suitable solvent (e.g. streptomycin) because reconstitution of drug reduces theshelf life and stability.

PARENTERAL

Intravenous injections (IV)

An intravenous infusion is a liquid administered directly into the bloodstream via a vein.Drug is given in one of the superficial veins.Drug is either given as:

1. Bolus IV injection, e.g. adenosine in PSVT (immediate action is required), furosemide inacute pulmonary edema.

2. Slow IV injections over 5-10 minutes, e.g. calcium gluconate in arrhythmias (to avoidtoxicity of calcium on heart).

3. Slow IV infusion, e.g. oxytocin in induction of labour (slow and sustained action isrequired) (Fig. 6.1). This is done by dissolving drug in 50-100 ml of isotonic glucose orsaline.

4. Rapid IV infusion is sometimes used, e.g. fluids in shock.Drug is usually in aqueous form (Fig. 6.2). It should be nonirritant to vascular endothelium.

Fig. 6.2: IV fluidFig. 6.2: IV infusion

Common Dosage Forms and Routes of Administration-II 41

ADVANTAGES

1. 100% bioavailability2. Immediate onset of action, so it can be used in emergencies3. Titration of dose can be done4. First pass metabolism bypassed5. GIT adverse effects not present6. Can be used in unconscious, uncooperative and vomiting patients.

DISADVANTAGES

1. Aseptic precautions are mandatory2. Vital organs are exposed to high concentration of drug3. Thrombophlebitis4. Expensive5. Invasive6. Painful7. Trained person is required8. If the drug extravasates there may be necrosis and sloughing, e.g. with pentothal sodium,

quinine.Before learning technique of IV injection it is important to learn to fill the syringe with

drug. Drug can be available as liquid or powder form. It can be present in single doseampoule or multidose vial.Exercise: How to aspirate drug from ampoule into syringe?

REQUIREMENTS

Syringe of appropriate size, ampoule with required drug or solution, needle of right size,disinfectant, gauze (Fig. 6.3).

TECHNIQUE

1. Wash your hands properly with soap and water.2. Take out syringe and needle from disposable pack taking care not to touch naked end

of syringe.3. Put the needle on the syringe.4. Remove the liquid from the neck of the ampoule by flicking or tapping it or swinging it

fast in a downward spiralling movement.5. File around the neck of the ampoule.6. Carefully break off the top of the ampoule. Protect your fingers with gauze if ampoule

is made of glass.7. For a plastic ampoule twist the top.8. Remove cover from needle.


9. Aspirate the fluid from the ampoule.10. Remove any air from the syringe.11. Clean up, dispose of working needle safely and wash your hands.

Exercise: How to aspirate drug from vial into syringe?

REQUIREMENTS

Vial, syringe of the appropriate size, needle of right size, disinfectant, gauze.

TECHNIQUE


of syringe. Use a syringe with a volume of twice the required amount of drug or solution.3. Put the needle on the syringe.4. Remove protective covering from vial cap. Disinfect the top of the vial with a cotton

swab soaked in disinfectant (Fig. 6.3).5. Remove cover from needle.6. Suck up as much air as the amount of solution needed to aspirate.7. Insert needle into vial through rubber cap and push down and then mix.8. Pump air into vial (creating pressure).9. Aspirate the required amount of solution and 0.1 ml extra. Make sure the tip of the

needle is below the fluid surface (Fig. 6.4).10. Pull the needle out of the vial.11. Remove the air from the syringe.12. Clean up, dispose of waste safely and wash your hands.

Fig. 6.3: Ampoule Fig. 6.4: Aspiration


Exercise: How to dissolve dry medicine in vial and aspirate drug solution into syringe?

Antibiotic drugs such as penicillins, streptomycin and the tetracyclines often are manufacturedand supplied to you in the form of a sterile powder in a vial which must be reconstitutedwith sterile water for injection, normal saline solution, or other suitable diluent (solvent)

REQUIREMENTS

Vial with dry medicine to be dissolved, syringe of the appropriate size, needle of right size,disinfectant, gauze.

TECHNIQUE


of syringe.3. Put the needle on the syringe.4. Aspirate solvent into syringe from the ampoule.5. Remove protective covering from cap of vial. Disinfect the rubber cap (top) of the vial

containing the dry/powdered medicine.6. Insert the needle into the vial, hold the whole unit upright.7. Suck up as much air as the amount of solvent already in the syringe.8. Inject only the fluid into the vial, not the air.9. Shake well.

10. Turn the vial upside-down.11. Inject the air into the vial (creating the pressure).12. Aspirate the total amount of solution.13. Remove any air from the syringe.14. Clean up, dispose of waste safely and wash hands.

It is recommended that all antibiotics that are reconstituted and are to be used later,should be labeled in the following way (see example):

1. Hour and date reconstituted.2. Strength of reconstituted antibiotic.3. Initials of the preparer.

Exercise: How to inject by Intravenous route?

REQUIREMENTS

Syringe, drug, needle 20G, liquid disinfectant, cotton wool, adhesive tape and tourniquet.

PROCEDURE

1. Wash your hands properly with soap and water2. Reassure the patient and explain the procedure3. Uncover arm completely

1400 hrs 9 Mar 07 50,000 units/ml


4. Have the patient relax and support his arm below the vein to be used5. Apply tourniquet, tell patient to clinch fist and look for a suitable vein6. Wait for the vein to swell. Disinfect skin7. Stabilize the vein by pulling the skin taut in the longitudinal direction of the vein. Do

this with the hand you are not going to use for inserting the needle.8. Insert the needle at an angle of around 35° (Fig. 6.5)9. Puncture the skin and move the needle slightly into the vein (3-5 mm)

10. Hold the syringe and needle steady11. If blood appears hold the syringe steady, you are in the vein. If it does not come, try

again12. Loosen tourniquet. Withdraw needle swiftly. Check for pain, hematoma13. Press sterile cotton wool onto the opening. Secure with adhesive tape14. Check the patient's reactions and give additional reassurance, if necessary15. Clean up, dispose of waste safely and wash your hands.

Exercise: Model for IV injections for students in laboratory

REQUIREMENTS

A simple model for IV administration can be used to teach the students about the process ofIV injection. Model of hand with vein (made of latex glove stuffed with mattress foam and arubber tube filled with red ink placed under the latex glove on top of the cotton), IV infusionsets, butterfly needles, IV fluid bottles.

Follow same procedure as described forIV injection.

GENERAL PRINCIPLES

Apart from the specific technique of injecting, there are a few general rules that you shouldbe kept in mind.

1. Expiry dates: Check the expiry dates of each item including the drug. If you makehousecalls and keep stock of injections, check the drugs in your medical bag regularlyto make sure that they have not passed the expiry date.

2. Drug: Make sure that the vial or ampoule contains the right drug in the right strength.3. Sterility: During the whole preparation procedure, material should be kept sterile. Wash

your hands before starting to prepare the injection. Disinfect the skin over the injectionsite.

4. Prudence: Once the protective cover of theneedle is removed extra care is needed. Donot touch anything with the unprotectedneedle. Once the injection has been given takecare not to prick yourself or somebody else.

6. Waste: Make sure that contaminated waste isdisposed of safely. Fig. 6.5: IV injection


7. Do not use plastic tubing for glyceryl trinitrate, paraldehyde.8. Protect nitroprusside from light by covering infusion set with brown paper.

PARENTERAL-IM

Intramuscular injections

Drug is injected in one of the large skeletal muscles of the body, i.e. deltoid, gluteus and ininfants in anterolateral region of the thigh in middle third region. Skeletal muscle is highlyvascular and its capillaries contain small pores which enable substances of small molecularweight to pass through into the bloodstream. Several muscles of the body have considerablemass and can be injected with quantities of up to several millilitres of fluid without inducingdiscomfort to the patient. Generally, intramuscular injections are not self-administered, butrather by a trained medical professional, e.g. many vaccines, antibiotics, and long-termpsychoactive agents.

Aqueous solutions better absorbed than oily solutions. Depot preparations in oil can begiven to prolong duration of action. The degree of tissue perfusion and condition of theinjection site will influence the rate of drug absorption.

ADVANTAGES

1. Rate of absorption is reasonably uniform.2. Less painful.3. Onset of action-fairly rapid.4. Depot preparations can be given.5. In addition to soluble substances, mild irritants, suspensions and colloids can be injected

by this route.

DISADVANTAGES

1. Aseptic precautions are mandatory.2. Danger of injecting into blood stream.3. Intramuscular absorption is not always faster than oral absorption.4. The volume of injection should not be more than 10 ml.5. Pain at the site of injection, irritation, abscess formation or

tissue and nerve damage may occur. Rapid absorption maycause even death.

PRECAUTIONS

1. Do not inject in gluteal region in a child until child startswalking. Inject into lateral part of thigh.

2. Heparin should not be given IM (hematoma).3. Injury to nerves leading to paresis of muscles can occur. Never

give IM injection to child with suspected poliomyelitis.

Fig. 6.6:Sites for IM

injection in adults


4. A healthy well developed person can tolerate 3.0 ml in large muscles, this does NOTinclude the deltoid. For elderly, thin clients or children the total amount should notexceed 2.0 ml. No more than 1.0 ml should be given to young children and older infants.

Exercise: How to inject drug by intramuscular route?

REQUIREMENTS

Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant,cotton wool, adhesive tape.

PROCEDURE

1. Wash your hands properly with soap and water2. Reassure the patient and explain the procedure3. Uncover the area to be injected (lateral upper quadrant major muscle lateral side of

upper leg, deltoid muscle Fig. 6.6)4. Disinfect the skin and tell the patient to relax the muscle5. Insert needle swiftly at the angle of 90° (watch depth)6. Aspirate briefly, if blood appears withdraw needle. Replace it.7. Inject slowly (less painful)8. Withdraw needle swiftly9. Press sterile cotton wool onto the opening. Fix with adhesive tape Check the patient's

reaction and give additional reassurance, if necessary10. Clean up, dispose of waste safely and wash your hands.Exercise: How to inject drug by intramuscular route in an orange model?

REQUIREMENTS

Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant,cotton wool, adhesive tape, Orange.

Orange peel gives resistance and feeling of injecting through skin. When needle entersinside orange it gives feeling of injecting in muscle.

PROCEDURE

Same as above.

PARENTERAL-SC

A subcutaneous injection is administered into the subcutis, the layer ofskin directly below the dermis and epidermis, collectively referred to asthe cutis. Subcutaneous injections are highly effective in administeringsuch medications as insulin, morphine, diacetylmorphine or goserelin(Fig. 6.7). Drug is injected into loose subcutaneous tissue. Hyaluronidasecan increase absorption, which breaks down intracellular matrix. A person Fig. 6.7: SC injection


with type I diabetes mellitus typically injects insulin subcutaneously. Places on the bodywhere people can inject insulin most easily are:

• The outer area of the upper arm• Just above and below the waist, except the area right around the navel (a 2-inch circle)• The upper area of the buttock, just behind the hip bone• The front of the thigh, midway to the outer side, 4 inches below the top of the thigh to

4 inches above the knee.Subcutaneous—the volume to be administer is 1.0 ml or less.

ADVANTAGES

1. Self-administration possible.2. Drugs in oil or implants can be given.3. Action of the drug is sustained and uniform (Fig. 6.8).

Fig. 6.8: ROA and concentration time curve

DISADVANTAGES

1. Painful2. Onset of action-slower3. Only non-irritant substances can be injected by this route.

Subcutaneous drug implants can act as depot therapy, e.g. Medroxyprogesterone.

Exercise: How to inject drugs subcutaneously?


REQUIREMENTS

Syringe with the drug to be administered (without air), needle 25G, liquid disinfectant,cotton wool, adhesive tape.

PROCEDURE

1. Wash hands with soap and water.2. Reassure the patient and explain the procedure.3. Uncover the area to be injected (upper arm, upper thigh, abdomen).4. Disinfect skin, "Pinch" fold of the skin.5. Insert needle in the base of the skin-fold at an angle of 20 to 30°.6. Release skin.7. Aspirate briefly, if blood appears: withdraw needle, replace it with a new one, if possible,

and start again from point 4.8. Inject slowly (0.5-2 minutes).9. Withdraw needle quickly.

10. Press sterile cotton wool onto the opening. Fix with adhesive tape.11. Check the patient's reaction and give additional reassurance, if necessary.12. Clean up, dispose of waste safely and wash hands.

Insulin is administered only using an insulin syringe. Most insulin vials contain 100 units/ml. Insulin may be administered subcutaneously, intramuscularly (rarely used) andintravenously. Regular insulin is the only type that may be given IV since it does not containany additives to prolong the action. Regular insulin is clear. If the vial is cloudy, it has beencontaminated and should be discarded. Longer acting insulin is cloudy and may have aprecipitate on the bottom of the vial. Be sure to mix the vial well by rotating it between thehands.

PARENTERAL-INTRADERMAL INJECTION

Drug or substance is injected into the dermis using a fine needle. The absorption is very slowand only small quantities of the drug can be given by this route. This route is used forspecific purpose only. Intradermal—the volume to be administered is 0.1 ml or less, e.g.BCG vaccine.

Other less commonly used injectable routes are:

Intra-thecal injectons are made into the cerebrospinal fluid. This drug are given to getdrugs directly into the central nervous system by avoiding the blood brain barrier commonlyused for spinal anesthesia and chemotherapy.

Epidural injections is just like intrathecal but the drug is deposited above the dura andnot in the cerebrospinal fluid. Local anesthetics are often given this way during surgicalprocedures, specially for procedures involving the pelvic and inferior regions, to block.

Intra-arterial injections: To deliver high concentration of anticancer drugs in malignancy,e.g. vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatmentof embolism.


Intra-articular injections: are used to inject drugs directly into joint. But strict asepticprecautions are a must (Fig. 6.9).

PARENTERAL- SUBLINGUAL

Highly lipid soluble drugs can be absorbed from sublingual and buccal mucosa, e.g.Nitroglycerin, a potent vasodilator, used in angina.

ADVANTAGES

• This form of administration avoids the mixing of drug with food and/or gastric juiceswhich may impede absorption.

• Immediate action, can be used in emergency.• Action can be terminated by spitting the remaining drug.• Bypasses hepatic first pass metabolism (Fig. 6.10).

Fig. 6.9: Intraarticular injection Fig. 6.10: Circulation

DISADVANTAGES

1. Drug taste must be pleasant.2. Irritant drugs cannot be given.

Can produce ulcers in mouth.

PARENTERAL-TRANSDERMAL

The skin is relatively more impermeable to drugs than otherstratified epithelia. The skin is useful to administer drugs whichare very lipophilic and active in very small amounts. Drug is presentin patches (Fig. 6.11) which release drug at constant and predictablerate. No peaks or troughs of drug concentration are seen. Site usedare-chest, abdomen, upper arm, buttocks. Transdermal drugdelivery avoids problems such as gastrointestinal irritation, Fig. 6.11: Patch


metabolism, variations in delivery rates and interference due to the presence of food. It isalso suitable for unconscious patients. The technique is generally non-invasive and aestheticallyacceptable and can be used to provide local delivery over several days.

Examples are:

• Nicotine patches-help stop smoking.• Oestradiol-prevent menopausal symptoms.• Fentanyl cytrate-prevent severe pain.• Nitrate patches-for angina.

Transdermal delivery system (patches) can be of various types (Fig. 6.12) as follows:1. Membrane controlled

The drug in solution or bound to polymer is held in a reservoir between an occlusivebacking film and a rate controlling micropore membrane. The drug is absorbed intosystemic circulation by diffusion.

2. Matrix controlledThe drug is homogeneously mixed with rate controlling polymer and rate of release iscontrolled by its diffusion through polymer matrix.

3. Sandwich typeCombination of membrane and matrix type. Matrix is coated with a rate controllingpolymer membrane.Rate of absorption depends on:

Fig. 6.12: Transdermal delivery


• Degree of hydration.• Keratinisation.• Rate of blood flow through skin.

ADVANTAGES

1. Bypasses first pass metabolism.2. Maintains constant plasma levels for a longer period.3. Less side effects.4. Easy to discontinue if toxicity appears.5. No GIT side effects.6. Convenient to use, compliance improves.

DISADVANTAGES

1. Local irritation, erythema.2. Onset of action-slower.3. Can not achieve high concentration in plasma.4. Can not deliver drugs in a pulsatile manner.5. Development of tolerance.6. Expensive.

Methods to increase permeation

• Physical, e.g. iontophoresis.• Chemical, e.g. sorption promoters.• Biological, e.g. skin metabolism inhibitors.

Instructions for correct use of this dosage form:

1. Do not apply over bruised or damaged skin.2. Do not wear over skin folds or under tight clothing and change spots regularly.3. Apply with clean, dry hands.4. Clean and dry the area of application completely.5. Remove patch from package, do not touch 'drug' side.6. Place on skin and press firmly. Rub the edges to seal.7. Remove and replace according to instructions.

OBJECTIVES

At the end of this session a student shall be able to:• Write down the dosage form of the drug displayed at the various stations.• Administer the drug properly by required method.


• Understand and describe precautions required during use of each dosage form.• Write two important advantages of the given dosage form.• Write two important disadvantages of the given dosage form.

Exercises for this session can be arranged in stations. Each station has various dosageforms. The stations can have the above mentioned dosage forms like:

Ampoules, vials, IV set, syringes, needles, patches.

DEMONSTRATE

1. How you will aspirate drug from an ampoule/vial?2. How you will make solution of dry drug for injection?3. How you will inject drug through IV route/ IM route?

Exercise 1:

Inject 0.1 ml of saline intravenously into the model provided.

Check-list

1. Wipes area with spirit from centre to periphery.2. Waits for the spirit to dry.3. Positions needle with bevel facing upwards.4. Holds syringe in correct manner (without touching needle).5. Inserts needle into skin first.6. Withdraws to check whether in vein.7. Pushes plunger smoothly and completely.8. Withdraws and wipes area with cotton.9. Disposes needle (without recapping) and syringe correctly.

10. Completes procedure smoothly without disruption.

Exercise 2:

Give clear instructions on the proper use of a transdermal nitroglycerine patch to this patient.

Check-list

1. Greets the patient.2. Offers a seat.3. Opens pack.4. Right side has to be on skin.5. Over the lateral chest wall.6. Change every day.7. Do not place on exactly same site.8. If irritation or redness - come to doctor.


9. Not more than two patches in a day.10. Check whether it is there after bath.

Exercise 3:

You have decided to put this 24 years female going to get married, on oral contraceptivesafter having taken a history and done a physical examination. Give instructions on the use ofthis packet of contraceptive pills which contain low dose combination pills.

Check-list

1. Explains that she will be on a contraceptive.2. To start on fifth day of menstrual cycle.3. To start a new packet at end of this without gap.4. If pill is missed to take it next day.5. If more than 2 pills are missed additional contraceptive cover.6. Additional methods for first cycle.7. Explains withdrawal bleeding.8. Explains breakthrough bleeding.9. To take at same time each night.

10. When to return - next visit.

LOCAL

This refers to the application of a drug to an area of the body for direct treatment. Usuallythere is inefficient absorption (1-15%). High local tissue levels nevertheless achievable, oftenhigher than by systemic route. Toxicity usually not a problem.

DROPS

Eye and nose drops are made isotonic to avoid pain or discomfort. Ear drops are formulatedas oily solutions to coat and adhere to the aural cavity.

EYE DROPS

They are aqueous or oily solutions for instilling into conjunctival sac (Fig. 7.1). They are usedas anesthetics, anti infective or anti inflammatory agents, miotics, mydriatics and artificialtears.

For example atropine sulphate (mydriatic), pilocarpine nitrate (miotic), timolol maleate.

ADVANTAGES

1. Local effect at required place.2. Easy to apply.3. Drug interactions can be avoided.

DISADVANTAGES

1. It requires repeated application.2. Systemic effects can occur following absorption.3. May cause irritation.4. Once seal is broken, should be used within 1 month.

PROCEDURE

1. Wash your hands.2. Do not touch the dropper opening.3. Look upward. Fig. 7.1: Eye drops

C H A P T E R

Common Dosage Forms andRoutes of Administration-III

7

Common Dosage Forms and Routes of Administration-III 55

4. Pull the lower eyelid down to make a 'gutter' or pouch.5. Bring the dropper as close to the 'gutter' as possible without touching it or the eye.6. Instill the prescribed number of drops (usually 1 or 2) in the 'gutter'.7. Close the eye for about two minutes. Do not shut the eye too tight.8. Excess fluid can be removed with a tissue. Do not rub.9. If more than one kind of eye drop is used wait at least five minutes before instilling the

next drops.Eye-drops may cause a burning feeling but this should not last for more than a few

minutes. If it does last longer, consult a doctor or pharmacist.

EYE OINTMENT

They are semisolid preparations with a greasy base, to be applied in the eye, e.g. neomycineye ointment, chloramphenicol eye ointment, tetracycline eye ointment.

ADVANTAGE

They have longer duration of action.

DISADVANTAGE

Due to greasy base eyes may become sticky.

PROCEDURE

1. Wash your hands.2. Do not touch anything with the tip of the tube.3. Tilt the head backwards a little.4. Take the tube in one hand and pull down the lower eyelid with the other hand, to make

a 'gutter'.5. Bring the tip of the tube as close to the "gutter" as possible.6. Apply the amount (usually 1 cm length) of ointment.7. Close the eye for two minutes.8. Remove excess ointment with a tissue.9. Clean the tip of the tube with other tissue.

EAR DROPS

They are aqueous or oily solutions instilled in the ear, e.g. wax softeners, sodium bicarbonate.

ADVANTAGE

Avoid systemic side effect due to its local action.

DISADVANTAGE

Local irritation can occur.


PROCEDURE

1. Lie on one side with the ear upward.2. Gently pull the lobe to expose the ear canal.3. Instill the amount (usually 4-5) of drops.4. Wait for five minutes before turning to the other ear.5. Use cotton wool to close the ear canal after applying the drops only if the manufacturer

explicitly recommends this.6. Ear drops should not burn or sting longer than a few minutes (Fig. 7.2).

NASAL DROPS

They are aqueous solutions of drugs instilled into the nose with a dropper, e.g. Xylometazoline,ephedrine, etc.

ADVANTAGE

Local and quick action.

DISADVANTAGES

1. Absorption can occur producing systemic effect.2. May cause local irritation.

PROCEDURE

1. Blow the nose.2. Sit down and tilt head backward strongly or lie down with a pillow under the shoulders;

keep head straight.3. Insert the dropper one centimeter into the nostril.4. Instill the number of drops prescribed (usually 3-4 drops).5. Sit up after a few seconds, the drops will then drip into the pharynx.6. Repeat the producer for the other nostril, if necessary.7. Rinse the dropper with boiled water.

NASAL SPRAYS

These are drugs or combinations of drugs (Fig. 7.3) which by virtue of their high vaporpressure, can be carried by an air current into nasal passage and exert their effect, e.g.Beclomethasone, calcitonin, vasopressin, etc.

ADVANTAGES

1. Easy to use.2. It covers large surface area so quick absorption.

DISADVANTAGE

Explosion may occur in hot environment as the contents are under pressure.


PROCEDURE

1. Blow the nose.2. Sit with the head slightly tilted forward.3. Shake the spray. Insert the tip in one nostril.4. Close the other nostril and mouth.5. Spray by squeezing the vial (flask, container) and sniff slowly.6. Remove the tip form the nose and bend the head forward strongly (head between the

knees).7. Sit up after a few seconds; the spray will drip down the pharynx.8. Breath through the mouth.9. Repeat the procedure for the other nostril, if necessary.

10. Rinse the tip with boiled water.

SUPPOSITORIES

A suppository (Fig. 7.4) is a drug delivery system that is inserted either into the rectum(rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where itdissolves. They are used to deliver both systemically acting and locally acting medications.They are solid, uniformly medicated masses of medicaments, e.g. glycerin, bisacodyl.

ADVANTAGES

1. Local application for systemic as well as local effect2. Especially helpful for unconscious or in a patient who can not take orally.

DISADVANTAGES

1. Inconvenient and some times irritant2. Aesthetic concerns3. Local irritation.

Fig. 7.3: Nasal spray Fig. 7.4: SuppositoryFig. 7.2: Ear drops


PROCEDURE

1. Wash your hands.2. Remove the covering (unless too soft).3. If the suppository is too soft let it harden first by cooling it (fridge or hold under cold

running water, still packed) then remove covering.4. Remove possible sharp rims by warming in the hand.5. Moisten the suppository with cold water.6. Lie on your side and pull up your knees.7. Hold the suppository by the non pointed end and insert the tip into the anal opening.8. Now just gradually push, keep pushing (it may be further than you imagine) and at

some point the suppository will be pulled into the rectum by the anal sphincter. Remainlying down for several minutes.

9. Try not to have a bowel movement during the first hour.

VAGINAL PESSARIES

It is the term applied to suppository shaped medications for vaginal administration. This isa topical treatment and it is important that the drug coats all the vagina mucosa. Vaginalmedications whether in pessaries or cream come with applicators which are designed toreach the upper parts of the vaginal canal. Vaginal preparations which are left in situ are bestused at night because the vagina has no means of retention like sphincters and the medicationcan run out.

Vaginal tablet (Pessary) with applicator

They are vaginal suppositories intended for introduction into vagina, e.g. nystatin,metronidazole.

ADVANTAGES

1. Local application2. Avoid systemic effect.

DISADVANTAGES

It may cause staining and irritation.

PROCEDURE

1. Wash your hands.2. Remove the wrapper from the tablet.3. Place the tablet into the open end of the applicator.4. Lie on your back, draw your knees up a little and spread them apart.5. Gently insert the applicator with the tablet in front into the vagina as far as possible, do

not use force.


6. Depress the plunger so that the tablet is released.7. Withdraw the applicator.8. Discard the applicator (if disposable).9. Clean both parts of the applicator thoroughly with soap and boiled lukewarm water (if

not disposable).

Without applicator

1. Wash your hands.2. Remove the wrapper from the tablet.3. Dip the tablet in lukewarm water just to moisten it.4. Lie on your back, draw your knees up and spread them apart.5. Gently insert the tablet into the vagina as high as possible, do not use force.

OINTMENTS

These are lipid-based. They have a greasy appearance and feel. The drug is trapped underthe dressing and, the layer of the skin is soften from sweating, enabling the drug to penetratedeeply into the tissues. Eye ointments are formulated to melt quickly so that vision is notimpaired.

PASTES

They have a very high powder content. They are useful in protecting areas of skin frommoisture, being water repellent.

GEL AND LOTIONS

They are used on the hairy areas of the body. Alcoholic gels or lotion are less messy thanointments or creams, but the evaporation of carrier is rapid, therefore, there is little penetrationof the drug (Fig. 7.5).

JELLIES

For urethral application.

DUSTING POWDER

They are free flowing very fine powders having particle size < 150 µm for external use. Theyare used to treat superficial skin conditions.They are sterilized by dry heat and supplied inairtight glass or plastic jars with reclosableperforated lid or sprinkler holes at top.Commonly used dusting powders are purifiedtalc, magnesium sulphide powder, neomycinpowder, sulphacetamide sodium, sulphadiazinepowder. Fig. 7.5: Gel


ADVANTAGES

1. Systemic side effects of drugs are avoided because of local application.2. It provides greater stability.

DISADVANTAGE

It requires repeated application.

LOTIONS

They are liquid preparations meant for local application to the skin or mucous membranewithout rubbing for providing soothing or antiseptic effects. These medications are preferablysupplied in amber or blue coloured bottles to protect them from sunlight, e.g. potassiumpermanganate lotion (0.1%), cetrimide lotion (1%), calamine lotion.

ADVANTAGE

Systemic side effects of drugs are avoided because of local application.

DISADVANTAGE

Patient may experience a gritty feeling.

PROCEDURE

1. Shake the bottle well before use2. Apply without rubbing, on the affected part with the help of cotton swab.

LINIMENTS

They are liquid or semiliquid preparations intended for external application by rubbing andmay contain substances possessing analgesic, rubefacient, soothing or stimulating properties.They may be either emulsions or solutions, e.g. liniment turpentine.

ADVANTAGE

Systemic side effects of drugs are avoided because of local application.

DISADVANTAGE

Patient may experience a burning sensation.

PROCEDURE

Apply with rubbing on the affected part.

OINTMENTS

They are semisolid preparations in a greasy base used for external application by inunction.They are of such consistency that they soften but not necessarily melt when applied to theskin, e.g. Whitfield's, salicylic acid, calamine ointment.


ADVANTAGES

1. They increase the hydration of the skin.2. The duration of action is prolonged due to occlusive dressing.

DISADVANTAGES

1. They stain the clothes.2. Inconvenient to the patient due to greasy base.

PROCEDURE

To be applied on the affected part with inunction.

CREAMS

They are semi solid preparations consisting of opaque emulsions for external use (Fig. 7.6).The term cream is most frequently applied to a soft cosmetic type of preparation. Creams

are used in treatment of skin conditions like eczema, pruritis as astringent, emollient, andantiseptics. They are dispensed in collapsible metal or plastic tubes, glass or plastic pots.

ADVANTAGE

They are cosmetically more acceptable due to their less greasy nature.

DISADVANTAGE

They are easily washed out so requires repetitive application.

SPRAYS

They are preparations of drugs in aqueous, alcoholic or glycerin containing media, e.g.adhesive sprays.

ADVANTAGE

Easy to use and cover a larger surface area.

DISADVANTAGE

Explosion may occur in hot environment as the contents are under pressure.

PAINTS

They are simple solutions containing medicaments in semisolid solvents like liquid paraffinor glycerin, e.g. povidone iodine.

Fig. 7.6: Cream


ADVANTAGE

Retain the medicament in situ for longer period.

DISADVANTAGE

May cause staining and irritation.

LOCAL-inhalation

Drug administered by nasal or oral respiratory route. Action is either on bronchial tree orsystemic due to absorption through lungs, e.g. salbutamol and beclomethasone in bronchialasthma. Drugs are delivered to bronchial musculature in asthma. Aerosols are formed asdrug solution or microionised drug powder is converted into mist/dust respectively.

Particle size which is absorbed in between 3 to 5 µm. If size < 3 µm-particles are notretained, they come out with expiration. If size > 5 µm particles are not absorbed. Preparationsused for inhalation route are:

1. Dry powder inhalers.2. Metered dose aerosol-drug is delivered through pressurized canister equipped with a

valve through which only metered dose is discharged. Medication is most commonlystored in solution in a pressurized canister. The canister is attached to a plastic, hand-operated pump. The standard metered dose inhaler (MDI) on activating releases afixed dose of medicine in aerosol form (Fig. 7.7).

3. Nebuliser—In children and other patients who can not inspire forcefully whilecoordinating with inhaler opening, nebulisers are used (Fig. 7.8). The air pressurerequired for aerosol formation is generated by an electric pump. A nebuliser, or"breathing machine," is another way to take inhaled medicines. A nebuliser treatment isgiven with an air compressor machine. Pressurized room air is used to create a mist ofthe medicine solution, which is inhaled for approximately 5-10 minutes.

4. Rotahalers—The device is loaded with rotacapsules and then drug is inhales with forcefulinspiration. Only capsules specifically made for rotahalers are used with rotahalers(Fig. 7.9).

Fig. 7.7: MDI Fig. 7.8: Nebuliser Fig. 7.9: Rotahaler


Only a small portion of drug (10%) reaches respiratory tract a small fraction of thisamount penetrates mucosa.

ADVANTAGES

1. Systemic effects including toxicity is less, e.g. steroids in asthma2. Targeted delivery of drug3. Easy to use4. Less amount of drug is needed5. Onset of action is fast.

DISADVANTAGES

1. Reflex bronchospasm2. Candida growth in oral cavity3. Patient has to learn the technique.

PROCEDURE FOR CORRECT USE (FOR MDI) (FIGS 7.10 AND 7.11)

1. Cough up as much sputum as possible.2. Shake the inhaler before use.3. Hold the inhaler as indicated in the manufacturer's instructions (this is held usually

upside down).4. Fully exhale.5. Place the lips tightly around the mouthpiece.6. Tilt the head backward slightly.7. Breathe in deeply and activate the inhaler (press the metallic bottle), keeping the tongue

down. The co-ordination between activating the inhaler and breathing in is critical foreffective delivery of the drug into the lungs.

8. The aerosolized medicine is drawn into thelungs by continuing to inhale deeply beforeholding the breath for 10 seconds to allowabsorption into the bronchial walls.

Fig. 7.10: Absorption through lungs Fig. 7.11: Use of Inhaler (MDI)


9. Hold the breath for ten to fifteen seconds.10. Breathe out through the nose.11. Rinse the mouth with warm water.

PROCEDURE (FOR ROTAHALER)

1. Check the mouthpiece for foreign objects.2. Twist the barrel in either direction until it stops.3. Take a capsule (designed for rotahaler) and insert the clear (thinner/white) end into

the raised hole of rotahaler. Push the new capsule in until it is level with the top of thehole (Fig. 7.12).

4. Hold the Rotahaler vertically, turn the lower end as far as it will go in the oppositedirection. This will open the capsule.

5. Cough up as much sputum as possible and gently breathe out.6. Place the lips tightly around the mouthpiece.7. Tilt the head backward slightly.8. Breathe in through your mouth as quickly and deeply as possible. Continue to take a

full, deep breath.9. Hold your breath for upto ten seconds. This allows the medication time to deposit in

the airway.10. Resume normal breathing.11. After each use, pull the two halves of the rotahaler apart and throw away the loose

capsule shell.12. Reassemble the rotahaler. Repeat steps 1-7 when more than one rotacap is prescribed.

CARE OF FOR THE ROTAHALER

Clean the rotahaler once every two weeks or soonerif needed. Regular cleaning will prevent powderaccumulation inside the rotahaler.

1. Remove the empty capsule shell beforewashing the rotahaler.

2. Rinse the two halves of your rotahaler in warmwater.

3. Shake off any excess water.

LOCAL-ORAL

Gargles and Mouthwashes

They are aqueous solutions used for throatinfections and hygienic purpose, e.g. saline gargles,potassium permanganate solution, povidoneiodine, betahexidine. Fig. 7.12: Parts of rotahaler


ADVANTAGE

Local soothing and antiseptic action.

DISADVANTAGE

May cause staining and irritation.

PROCEDURE

1. Use with proper instruction that is written on the label. Swish mouthwash around inthe mouth for at least 30 seconds and then spit it out. Do not swallow it.

2. Keep away from children.

NEW TECHNIQUES FOR DRUG DELIVERY

Conventional Drug Delivery Systems

Tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectables.

New drug delivery systems (NDDS)

Most of the marketed drugs these days are new delivery systems of older drugs only,hence, you will find a lot of OD, CR, SR and patches in the market. The reason is that an olddrug can be given a new life by putting it into new delivery system, it is less expensive andtime consuming as compared to discovering a new molecule. The profits are almost similar.There is now a growing realisation that innovative delivery of drugs would not only increasesafety and efficacy levels but also improve the overall performance of the drug.

WHY NDDS?

• These days a consumer (patient) demands more efficacious, safe, convenient and lowcost drugs, e.g. cipro-OD, intranasal insulin.

• The provider spends less money in new drug delivery system as compared to newdrug. New drug development takes approximately $800 million and 12 years. NDDSdevelopment takes only 20% cost of new drug and only 6-8 years.

Advances in drug delivery systems are also expected to offer a host of additionaladvantages such as ease of administration, increased patient compliance, decreased sideeffects and cost reduction. Multiple injections required per week or day could be replacedby once a month dosages or even longer intervals, which would stabilise blood levels of themedication, thereby enhancing treatment outcomes and patient compliance.

New delivery systems are usually offer following advantages

1. Targeted drug delivery.2. Maximum efficacy/minimum adverse effects.3. Maintain steady state plasma conc.4. Longer duration and patient compliance.


NDDS-ORAL

• Programmed drug delivery• Sustained release and controlled release (SR/CR), e.g. theophylline SR, Indomethacin

CR• Prodrugs• Cyclodextrins.

PRODRUGS

Also known as "Smart Drugs", these compounds are designed to work only when activatedby certain components in the body. For example, a smart drug designed to be activated by acertain enzyme will be activated only in tissues that produces that specific enzyme. Theseare drugs which are inactive outside body and get activated through metabolism in thebody, e.g. Enalapril. So these drugs have.

• Inactive precursors• Have active metabolites.

ADVANTAGES

1. Better bioavailability2. Increased stability3. Less side effects4. Targeted delivery, e.g. Cyclophosphamide, Levodopa, Zidovudine.

SUSTAINED VS. CONTROLLED RELEASE

Sustained release, a pharmaceutical dosage form formulated to retard the release of atherapeutic agent such that its appearance in the systemic circulation is delayed or prolongedand its plasma profile is sustained in duration. These forms also limit fluctuation in plasmadrug concentration, providing a more uniform therapeutic effect. Absorption rate is slowedby coating drug particles with wax or other water-insoluble material, by embedding thedrug in a matrix that releases it slowly during transit through the GI tract, or by complexingthe drug with ion-exchange resins. Most absorption of these forms occurs in the large bowel.Crushing or otherwise disturbing a controlled-release pill can often be dangerous. Alcoholcan also disturb this delivery system, leading to dose dumping at one point only.

Controlled release, goes beyond the scope of sustained drug action. Implies apredictability and reproducibility in drug release kinetics.

NDDS-OTHERS

• Transdermal therapeutic systems• Inhalation route• Coated implantable devices• Antibody tagging


• Non viral vectors for gene therapy• Special forms of subcutaneous route

DemotedPellet implantationSialistic and biodegradable implants

• Tissue specific drug delivery systemsBone specificColon specificLung and liver specific

• Biomolecular engineering, protein drugs• Gene gun, gene pills• Nanotechnology• Microfabrication• Oral vaccines ( in banana)• Liposomal delivery.

OBJECTIVES

At the end of this session a student shall be able to:• Write down the dosage form of the drug displayed at the various stations.• Administer the drug properly by required method• Understand and describe precautions required during use of each dosage form• Write two important advantages of the given dosage form• Write two important disadvantages of the given dosage form

Exercises for this session can be arranged in stations. Each station has various dosageforms. The stations can have the above mentioned dosage forms (Flow Chart 7.1) like:

Eye drops, ear drops, eye ointments, vaginal pessaries, inhalers, nasal sprays,suppositories, prodrugs.

DEMONSTRATE

Explain the use of inhaler to a patient.

CHECK-LIST

1. Greets the patient.2. Offers a seat.3. Open the mouthpiece.4. Breath normally thrice.5. Start inhaling mid inspiration.


6. Hold breath for 20 secs.7. Wipe mouthpiece.

• What precautions you will give to patients to take drug through nebulisers• What precautions you will give to patients to take drug using rotahalers• What precautions you will give to patients to take drug vaginaly/rectally

PRECAUTIONS FOR STORAGE OF DOSAGE FORMS (FIG. 7.13)

• Most of the commercial preparations are labeled with expiry dates.• The longevity of a medicament is governed by its shelf-life. Shelf-life of a drug is the

duration from the time the product is manufactured till thepotency of the drug has been reduced by 10%.

• This limit is usually considered acceptable in practice; morestringent standard is required if the degradation products aremore toxic or irritative than the parent drugs. This can happenwith tetracycline antibiotics.

• Products with a shelf-life of more than 3 years are consideredto be stable as these are expected to sold and used within hisperiod.

• Products with a shorter half-life should be labeled withexpiration date.

Flow Chart 7.1: Depicting various dosage forms

Fig. 7.13: Storage of drugs


• As a guide to good pharmaceutical practice it is suggested that mixtures recommendedto be 'freshly prepared' should be prepared not more than 24 hours before issue to thepatient.

• Mixtures recommended to be 'recently prepared' should be stored in unopened bottlesin the dispensary for not more than 3 months.

• Should there be any doubt, the pharmacist should be consulted.

ENVIRONMENTAL FACTORS AFFECTING DOSAGE FORM

• pH: Affect rate of chemical reaction and hence, longevity of a drug.• Temperature: An increase in temperature usually increases the rate of chemical reaction.

Storage of a medicine in a cool place (below 15°C) will prolong the shelf-life. Refrigerationmay prolong shelf-life of a medicament that is unstable in room temperature but solidparticles may grow and precipitate in a suspension. The temperatures suitable for storageof topical drugs lies in the range of 15-25°C.

• Environmental factors affecting dosage form.• Oxygen: Many drugs show slow oxidation in the presence of atmospheric oxygen, e.g.

adrenaline, glyceryl nitrate is so prone to oxidation, the shelf-life is only about 3 monthsafter the bottle has been opened.

• Light: Can induce photochemical degradation. This can be reduced by the use of light-resistant containers or more effectively, by storage in the dark. Sodium nitroprussidevery light sensitive, must be kept in darkened glass ampoules, wrapped in black plastic.

• Humidity: Low humidity may be responsible for the powdering of granular solidscontaining effervescent salts and for the 'drying out' of creams. High humidity bringsabout the deterioration of effervescent tablets and solid preparations that containhygroscopic materials. The adverse effects of humidity can be avoided by the use ofmoisture-proof containers. Aspirin hydrolyses readily to acetic acid and salicylic acidin the presence of moisture (most people store medicine and their aspirin tablet inbathrooms).

Section 2Experimental Pharmacology

Today's pharmacology teaching is much different from yesterday's teaching of MateriaMedica. For better healthcare and to provide more effective, safe and affordable medicationsresearch is continuously being carried on new chemicals. This continuous search for new andbetter drugs starts from animal experimentation, i.e. preclinical testing before clinical testingin human subjects. There is enormous change in research methodology due to new high-techinstruments and methods available to us.

Just as medicine cannot be taught or learnt without going towards and clinics, similarlypharmacology cannot be taught without experimentation. But animals should not besacrificed just to gain skills about exact methodology and the techniques of animal experiments.Animals are not easily available nowadays due to animal welfare regulations and ethics.Animal experiments are expensive, time consuming and tedious. Thus with the changingscenario alternative methods of teaching pharmacology experiments have been developedalong with the advances in computer technology. Animal experiments can be substituted bydemonstrations using computer simulated learning programs. Students can be taught to usethese programs. Give them exercises to analyse the results obtained from experiments,interpret them and apply them in different clinical situations. To analyse the results of anyexperiment or drug trial and draw conclusions is good learning experience for developingclinical judgement skills.

A number of animal experiments can be demonstrated to students, but important onesare:

1. Effects of various drugs on the Rabbit Eye2. Effects of various drugs on the Frog Heart3. Effect of various drugs on Rabbit Intestine4. Effects of various drugs on the Dog Blood Pressure.

These experiments can be carried out on animals (Fig. 8.1) orthese can be demonstrated with computer simulation models.Wherever animals are sacrificed, those experiments can be demons-trated with computer simulation models. In those experiments whereanimals are not sacrificed or tortured and if animals are available inthe institute, then animals can be used in experiments.

C H A P T E R

Introduction to ExperimentalPharmacology

8

Fig. 8.1: Albino rat


Various softwares are available for computer simulation demonstrations. Exercises inthe form of graphs, tables obtained from various animal experiments can be used to teachstudents. They will analyse and interpret them applying different methods, formulae andstatistics whenever necessary. After the discussions they will draw conclusions, correlatethem clinically and answer the various questions given with graphs, tables and other exercises.

Exact simulation of real animal experiments on a computer is not easy because thebiological responses are very complex. Many factors come control an organ or a system.Hence, the results obtained with these simulated models may not be very accurate. Butremember that the aim of the software is to teach the students about major facts that havepractical utility in their future life.

The purpose of demonstration of these models by a teacher would be of great help tostudents to understand the experimental procedure and the theory behind it. These programsmay be used for self-learning later on.

Understanding of autonomic nervous system pharmacology is essential for planningrational drug therapy of diseases like asthma, hypertension, parkinsonism, glaucoma, etc.Theoretical discussion alone may not suffice for the same, while discussion of experimentalexercises may provide a sound background for enhancing the understanding. This will giveto the students a general idea about how experiments are conducted, how results areinterpreted and applied clinically.

INTRODUCTION

The Iris is composed of two types of muscle fibres, the circular and the radial muscles. Thecircular fibres are supplied by parasympathetic nerve fibres (cholinergic) and the radialones are innervated by sympathetic nerve fibres (adrenergic). The stimulation of sympatheticand parasympathetic nerves produces mydriasis and miosis respectively and their paralysisproduces opposite effects. Drugs which simulate the effects of autonomic nervous systemcan produce the above mentioned effects. This experiment uses a few such drugs on therabbit eye (Figs 9.1 and 9.2).

Fig. 9.2: Muscle fibres of eye

Dilator Pupillae(Radial Muscle Fibres)Sympathetic (adrenergic receptors-α1)

Sphincter Pupillae(Circular Muscle Fibers)Muscarinic (cholinergic receptors-M3)

Fig. 9.1: Structure of eye

C H A P T E R

Effects of Drugs on Rabbit Eye9


Fig. 9.3: Instillation

REQUIREMENTS

1. Rabbit2. Scissors3. Measuring scale4. Droppers5. Torch6. Cotton wool.

DRUGS AND SOLUTIONS

A. Normal salineB. Mydriatic drugs:

Active Passive

Phenylephrine 20% Atropine sulphate 1.0%C. Miotic drugs:

Active Passive

Pilocarpine 4.0% Phentolamine (not used)D. Local anaesthetic:

Lignocaine hydrochloride 1-2%

PROCEDURE

• Handle rabbit with care.• Clip off eyelashes of both the eyes• Use pouch method to instill drugs into eye. Pinch lower eyelid to make a small pouch.

Instill 1-2 drops of saline/drug in it using dropper. Pull the lower eyelid upwards andkeep it in contact with conjunctiva for 1-2 minutes

• You can also press medial canthus for 5 seconds after instillation of drug• Keep one eye (either right or left eye) as control and the other as test• Apply saline in the control eye and a drug in the test eye.

Following parameters are measured at 5-15 minutes after instillation of drug (Fig. 9.3):1. Size of pupil 2. Light reflex3. Touch reflex (Corneal reflex)1. Size of Pupil

Measure the diameter of both the pupils. This can be measuredwith a pupilometer made up of cardboard or hard paper. Takea hard paper, cut it approximately equal to a 6 inch ruler.Then cut holes in it having increasing order of diameter inmillimeters. You can start with 1mm then mark upto 10 mm.You can also measure with the help of a simple scale. It willlook like this:

Effects of Drugs on Rabbit Eye 77

It is difficult to force open eyes of rabbit. Hence, with pupilometer it becomes easy tomeasure diameter. Keep pupilometer close to eye through which you can see pupil, matchthe hole in pupiolometer with size of pupil and note down the size in mm written on thematched hole.

2. Light Reflex

Light reflex is checked with a torch. A pencil torch is best suited for this purpose. Alwaysput the light from side (back) and bring it to the front. Do not put the light from the frontside of the rabbit. Observe the changes in the diameter of pupil when light is put intoeye. Note any decrease or increase in pupillary diameter. Take 3 readings.

3. Corneal Reflex

It is tested with a fine cotton wool wick. Wick is made in such a manner that there is noprotruding part of cotton. Touch peripheral part of cornea with tip of cotton wick. Alwaysbring forward the cotton wool from the side (back). Rabbit should not be able to seecotton wool or your hand. Blinking represents presence of corneal reflex. Do not forgetto note down the 3 readings.Precaution: Do not touch central part of cornea it can cause corneal ulcers/opacities.

This can lead to blindness as central part of cornea is the main part of cornea used forvisibility.

Computer Simulation Model (CSM) Procedure: The teacher will show the students thevarious instruments used for this experiment. Then he/she will describe the procedure andsteps in setting up the experiment. Then the whole batch for a particular day is shown theexperiment using LCD projector. Students are told about the various options available andhow to operate the software. Then the batch is divided into groups and each group isprovided with a computer which has been pre-loaded with software. Then demonstrator/instructor will then guide students to operate the software and students are allowed towork on their own. An instructor/demonstartor is always there to help the students. Studentsare expected to write down the procedure and effect of drugs and tabulate findings givingreasons for the changes in heart rate, respiration or increase or decrease in BP. They have todraw the graph obtained and find out the nature of the unknown drug given in the program(Table 9.1).


Table 9.1. Effect of drugs on rabbit eye

DRUGS LIGHT REFLEX CORNEAL REFLEX PUPIL SIZE mmRight Left Right Left Right Left

Phenylephrine +++ +++ +++ +++ 4 8Atropine +++ --- +++ +++ 4 8Pilocarpine +++ + +++ +++ 4 1.4Physostigmine +++ + +++ +++ 4 1Lignocaine +++ +++ +++ --- 4 4

ADDITIONAL INFORMATION

Active and passive miotics and mydriasis (Table 9.2)

When miosis occurs as a result of active contraction of the sphincter pupillae (circular muscleof the iris), it is known as active miosis. This usually occurs as a result of action ofcholinomimetics. When miosis occurs as a result of (passive) relaxation of the dilator pupillae(radial muscle of the iris), it is known as passive miosis. It usually results from action ofadrenergic blockers. Similarly with mydriatics also, there is active and passive mydriasisdue to active contraction of the dilator pupillae or relaxation of sphincter pupillae.

Table 9.2. Classification of miotics and mydriatics

Drugs Active PassiveMiotics Cholinomimetics: Adrenergic blockers

Pilocarpine PhentolamineCarbacholAnticholinesterasesPhysostigmineNeostigmine

Mydriatics Sympathomimtics Anticholinergics1Phenylephrine Atropine

HomatropineCyclopentolateTropicamide

Centrally acting Morphine

Indications of Miotics

1. Cataract2. Anterior chamber surgery3. Wide angle glaucoma4. To break adhesions between lens and iris

Effects of Drugs on Rabbit Eye 79

5. Reversal of mydriatic effects of anticholinergics6. Xerostomia.

Indications of mydriatics

1. Fundoscopy for visualisation of the periphery of retina.2. Retinoscopy in those who are unable to relax their eyes, e.g. children, very old patients.3. To break and prevent adhesions between iris and lens in iridocyclitis (alternate miotics

and mydriatics)4. Chronic simple glaucoma5. Corneal ulcer/uveitis6. Preoperative: Cataract surgery/Vitrectomy/Retinal surgery7. Fluorescent fundus or Indocyamine green angiography.

LOCAL ANAESTHETICS (LAs)

LAs reversibly block impulse conduction along nerve axons and other excitable membranesthat utilises the Na+ Channels as primary means of action potential generation.

Procaine is not a surface anaesthetic (Poor penetration). Cocaine is not used because ofcorneal sloughing (protoplasmic poison). LAs block corneal reflex in the rabbit eye.

OBJECTIVES

At the end of the practical class the student shall be able to:1. Explain effect of drug A on rabbit eye.2. Identify the nature of unknown drug B instilled into rabbit eye.3. Name three miotics/mydriatics used clinically and their important uses and

contraindications.4. Explain difference between active and passive miosis/mydriasis.

Demonstrate on animals

1. Instill drugs carefully into the rabbit's eye by making pouch without injuring thecornea.

2. Study the effect of given drug on the rabbit's eye.3. Record, analyze and interpret the observations obtained during this experiment.

Exercise in examination

These days LCD projectors are available in which you can project only a part of computerscreen. This type of projector it is very easy to use these softwares for examination purpose.On your projector screen everything is visible including name of drugs, but you can projectonly eye in which drug is instilled.

Many drugs act on the heart. Adrenergic and cholinergic drugs produce opposite effects onit. These drugs act through their respective receptors. Some drugs act directly on the heart.This experiment demonstrates the effects of drugs and ions (agonists, antagonists, calciumand potassium) on the frog heart.

C H A P T E R

Effect of Drugs on Frog Heart10

Fig. 10.1: Starling heart lever

Requirements

1. A medium sized frog, frog board andfrog tray.

2. Starling's heart lever (Fig. 10.1).3. Venous cannula attached through drip

set to a reservoir containing ringerperfusion fluid.

4. A kymograph with drum and smokedpaper or physiograph with chartrecorder.

5. A pithing needle, 2 pairs of scissors, 2pairs of forceps, 1cc syringe with aneedle, scale and pencil.

Procedure

A frog is pithed and dissected to expose theheart (Fig. 10.2). Pericardium is removed.Heart is lifted up. Sinus venosus is cannulatedusing a glass cannula (Syme's cannula) andsecured with thread. Then the heart isperfused with Ringer solution through thesinus venosus. Perfusion rate is adjusted at30-40 drops/minute. A curved needle isinserted in the apex and attached to a heartlever for recording contractions on the

Fig. 10.2: Dissected frog

smoked paper pasted over the drum of akymograph. Starling heart lever is used. Ithas a spring to record fast contractions.

Effect of Drugs on Frog Heart 81

Lever should be horizontal. Normal contractions are recorded followed by effect ofdrugs (Table 10.1). Students are demonstrated this experiment in batches of 5-6 studentsand then they are supposed to conduct the same experiment themselves in batches of 5-6students.

[Instead of heart lever, drum and kymograph, a physiograph can be used (Fig. 10.3).Transducer replaces the heart lever and is connected to the heart. Chart paper and pens areused for recording].CSM Procedure: The teacher will show the students the apparatus and other instrumentsused for this experiment. Then he/she will describe the procedure and steps in setting upthe experiment. Then the whole batch for a particular day is shown the experiment usingLCD projector. Students are told about the various options available and how to operate thesoftware. Then the batch is divided into groups and each group is provided with a computerwhich has been pre-loaded with software. Then demonstrator/instructor will guidestudents to operate the software and students are allowed to work on their own. Aninstructor/demonstartor is always there to help the students. Students are expected to writedown the procedure and effect of drugs and tabulate findings giving reasons for the changesin heart rate, respiration or increase or decrease in BP. On screen is seen graph recordingcontractions. You can choose drugs from a drop down menu. You can also select dose of thedrug. Then press inject button and observe changes in graph. There is also provision of useof blockers to find out nature of action of drug, i.e. whether it is direct acting or indirectacting.

The students have to draw the graph obtained and find out the nature of the unknowndrug given in the program.

Fig. 10.3: Physiograph

Facts About Frog Heart!

• Heart is three chambered—there are twoatria, but only one ventricle.

• Ventricle contains mixed blood.• Superior and inferior venae cava open

into sinus venosus. Venous blood flowsfrom sinus venosus to right atrium andfrom right atrium to ventricle. Arterialblood comes from left atrium into theventricle. Ventricle pumps mixed bloodto bulbous aorta. Bulbous aorta havespiral valve that directs arterial bloodto body and venous blood to lungsthrough pulmonary arteries.

• There is no specialised conducting tissuein the heart. There is muscular continuityin all the chambers of the heart andthere is NO VALVES in the heart.

• There is NO CORONARY CIRCULATIONto the heart. Heart derives its energyfrom atmospheric oxygen and directlyfrom the blood contained in it.

• Heart rate is 20-80 beats /minute.


Table 10.1: Drugs and solutions used in frog heart experiment

Drugs Dose Concentration(µg) (µg/ml)

1. Epinephrine 2 10(Adrenaline)

2. Norepinephrine 2 10(Noradrenaline)

3. Isoprenaline 2 10

4. Propranolol 200 1 mg/ml

5. Acetylcholine 2 10

6. Atropine sulphate 20 100

7. Calcium Chloride 2000 10 mg/ml

8. Potassium Chloride 2000 10 mg/mlµg = micrograms

9. Frog Ringer solution

Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is notthere increase dose to 0.2 ml and so on.

Procedure

Inject drugs one by one. Observe the following parameters before and after drugadministration:

a. Force of contraction–amplitude (normal, increased or decreased)b. Tone (normal, increased or decreased)c. Heart rate (beats per minute).

Parameter (a) and (b) are assessed by observing the recording (Figs 10.4 and 10.5). Tables10.2 and 10.3 shows the effect of various drugs on frog’s heart (recording 1 and recording 2respectively). The amplitude of contractions reflect the force. Shift in the mid point of systolicand diastolic contractions indicate the change in tone. Heart rate is assessed by countingmovements of lever or directly by observing the heart.

Fig. 10.4: Effect of various agonists of frog heart contractions (Recording 1)


Fig. 10.5: Effect of various agonists in presence of antagonists on frog heart contractions (Recording 2)

The above parameters must be recorded in a sheet or record book. Tabulate the data.Interpret the data and record your conclusions.

Precautions

a. Give sufficient time for the heart to recover between drug administrations.b. Always note the parameter readings before and after giving drugs.c. Record heart rate when there is maximum effect of drug.

Table 10.2. Effect of drugs on frog heart (Recording 1)

S.NO. DRUG HEART RATE AMPLITUDE TONE

1 Control 87 Normal Normal2 Epinephrine 92 Increased Increased3 Norepinephrine 83 Increased No change4 Isoprenaline 115 Increased Increased5 CaCl2 1 Decreased Increased6 Acetylcholine 67 Decreased No change7 KCl2 1 Decreased Decreased

Procedure to Inject Drugs

Inject 0.2 ml of drugs 1-4 in succession (cardiac stimulants) in the tube through which theheart is being perfused and record the responses. A control reading (without addition ofany drug) should be taken before and after each drug response. All the parameters mentionedabove should be recorded during the control and drug responses respectively. The heartrate, drug name and the dose should be mentioned in the recording during the control anddrug responses. The next drug response should be recorded only after the heart rate hasreturned to the approximate original value. Inject stimulants and depressants. In case theheart stops because of systolic or diastolic arrest restart only when the heart is contracting.In case adequate response is not observed use a higher dose.

Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whether


its effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedurewith 0.4 ml propranolol.

Inject calcium chloride immediately after adrenaline effect has been blocked and notewhether its effect has been blocked or not. In case the typical increase in rate and/orsystolic arrest is not observed use higher dose.

Inject 0.2 ml of cardiac depressants, i.e. acetylcholine and potassium chloride after takingcontrol readings in between drug responses. Note also the condition of the heart duringdiastolic arrest. Diastolic arrest is due to hyperpolarisation.

Inject 0.2 ml of atropine and note its response. Normally no response is seen because it isan in vitro preparation and moreover atropine has no intrinsic activity of its own. Stop thedrum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and notewhether effect is completely blocked. In case sufficient blockade is not obtained, repeat thesame procedure with 0.4 ml of atropine.

Table 10.3. Effect of drugs on frog heart (Recording 2)

S. NO. DRUG HEART RATE AMPLITUDE TONE

1 Control 86 Normal Normal2 Propranolol 76 Decreased Decreased

followed byEpinephrine 76 No change No change

3 Propranolol 72 Decreased Decreasedfollowed byNorepinephrine 72 No change No change

4 Propranolol 69 Decreased Decreasedfollowed byIsoprenaline 69 No change No change

5 Propranolol 72 Decreased Decreasedfollowed byCaCl2 1 Decreased Increased

6 Control 85 Normal Normal7 Atropine 89 No change No change

followed byAcetylcholine 89 No change No change

8 Atropine 85 No change No changefollowed byKCl 1 Decreased Decreased


Finally inject potassium chloride after the effect of acetylcholine has been blocked byatropine and note whether the effect is blocked. There should be no blockade of KCl effect.

OBJECTIVES

At the end of the practical class the student shall be able to:

CSM

1. Interpret effect of various drugs on heart rate, amplitude and tone2. Describe mechanism of action of various drugs3. Comment on nature of unknown drugs given.

Exercise in Examination

These days LCD projectors are available in which you can project only a part of computerscreen. With this type of projector it is very easy to use these softwares for examinationpurpose. On your computer screen everything is visible including name of drugs, but youcan project only recording showing effect.

Many drugs act on the intestine. Adrenergic and cholinergic drugs produce opposite effectson it. These drugs act through their respective receptors. Some drugs act directly on theintestine. This experiment demonstrates the effects of various drugs on the rabbit intestine.

Requirements

1. A medium sized rabbit.2. Frontal writing lever. It does not stick to writing paper on drum and gives straight

lineas compared to simple lever (Figs 11.1 and 11.2).3. A water bath having temperature control unit, organ bath with aeration tube.4. A kymograph with drum and smoked paper or Physiograph with chart recorder.5. 2 pairs of scissors, 2 pairs of forceps, 1cc syringe with a needle, scale and

pencil.

Procedure

A rabbit is sacrificed and dissected to expose the intestines. A part of ileum is taken 10 cmaway from ileocaecal valve. An optimal length of tissue (5-6 cm) is cut and a thread is tied toantimesenteric border on both sides. Then one end is tied to a fixed point inside organ bathand other point is attached to the lever for recording contractions on the smoked paperpasted over the drum of a kymograph (Fig. 11.3). Lever should be horizontal. Normalcontractions are recorded followed by effect of drugs. Students are demonstrated thisexperiment in batches of 5-6 students and then they are supposed to conduct the sameexperiment themselves in batches of 5-6 students.

C H A P T E R

Effect of Drugs on Rabbit Intestine11

Fig. 11.1: Frontal writing lever Fig. 11.2: Simple lever

Effect of Drugs on Rabbit Intestine 87

told about the various options available and how to operate the software. Then the batch isdivided into groups and each group is provided with a computer which has been pre-loaded with software. Then demonstrator/instructor will guide students to operate thesoftware and students are allowed to work on their own. An instructor/demonstartor isalways there to help the students. Students are expected to write down the procedure andeffect of drugs and tabulate findings giving reasons for the changes amplitude, tone andfrequency of intestinal movements. You can choose drugs from a drop down menu. You canalso select dose of the drug. Then press inject button and observe changes in graph. There isalso provision of use of blockers to find out nature of action of drug, i.e. whether it is directacting or indirect acting.

The students have to draw the graph obtained and find out the nature of the unknowndrug given in the program.

Table 11.1. Drugs and solutions used in rabbit intestine experiment

Drugs Dose Concentration(µg) (µg/ml)

1. Epinephrine 2 10(Adrenaline)

2. Propranolol 200 1 mg/ml

3. Acetylcholine 2 10

4. Atropine sulphate 20 100

5. Barium chloride 2000 10 mg/ml

6. Kreb’s solution

Volume of above solutions to be injected into organ bath = start with 0.1 ml, if sufficientresponse is not there increase dose to 0.2 ml and so on.

Fig. 11.3: Organ bath with intestine attached to lever

[Instead of heart lever, drum andkymograph, a physiograph can be used. Forcetransducer replaces the heart lever and isconnected to the heart. Chart paper and pensare used for recording].

CSM Procedure: The teacher will showthe students the apparatus and otherinstruments used for this experiment. Thenhe/she will describe the procedure and stepsin setting up the experiment. Then the wholebatch for a particular day is shown theexperiment using LCD projector. Students are


Procedure

Inject drugs one by one (Table 11.1). Observe the following parameters before and afterdrug administration:

a. Force of contraction—amplitude (normal, increased or decreased)b. Tone (normal, increased or decreased)c. Frequency of contractions (per minute).

Parameters (a) and (b) are assessed by observing the recording. The amplitude ofcontractions reflect the force. Shift in the mid point of contractions indicate the change intone. Rate is assessed by counting movements of lever.

The above parameters must be recorded in a sheet or record book. Tabulate the data(Table 11.2). Interpret the data and record your conclusions.

Precautions

a. Give sufficient time for the intestine to recover between drug administrations.b. Always note the parameter readings before and after giving drugs.c. Record frequency of contraction when there is maximum effect of drug.

Table 11.2. Effect of drugs on rabbit intestine

S. NO. Drug Frequency Amplitude Tone1 Control Normal Normal Normal2 Epinephrine Decreased Decreased Decreased3 Acetylcholine Increased Increased Increased4 Atropine Decreased Decreased Decreased5 BaCl2 Increased Increased Increased6 Ephedrine Decreased Decreased Decreased

Procedure to Inject Drugs

Inject 0.1 ml of drugs 1-4 in succession (spasmogenic) in the organ bath and record theresponses. A control reading (without addition of any drug) should be taken before andafter each drug response. All the parameters mentioned above should be recorded duringthe control and drug responses respectively. The drug name and the dose should bementioned in the recording during the control and drug responses. The next drug responseshould be recorded only after the rate and amplitude have returned to the approximateoriginal value. Inject spasmogenics and spasmolytics. In case adequate response is notobserved use a higher dose.

Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whetherits effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedurewith 0.4 ml propranolol.

Effect of Drugs on Rabbit Intestine 89

Inject barium chloride immediately after adrenaline effect has been blocked, and notewhether its effect has been blocked or not.

Inject 0.1 ml of atropine and note its response. Atropine produces relaxation. Stop thedrum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and notewhether effect is completely blocked. In case sufficient blockade is not obtained, repeat thesame procedure with 0.4 ml of atropine.

Finally inject ephedrine after the effect of acetylcholine has been blocked by atropineand note whether the effect is blocked. There should be no blockade of ephedrine effect.

OBJECTIVES


CSM

1. Interpret effect of various drugs on rabbit intestine.2. Describe mechanism of action of various drugs.3. Comment on nature of unknown drugs given.

This experiment should be demonstrated using computer simulation model only. Experimentson large animals require permission from subcommittee of CPCSEA.

ProcedureA dog is anesthetized with pentobarbital 3% intravenously (30 mg/kg). Trachea and carotidarteries are exposed. A ‘Y’ shaped tracheal cannula is put in cut trachea. Through one limbartificial respiration can be given with a respiratory pump if required or secretions can becleaned. Other limb can be attached to a tube to record respiratory movements. Carotidartery on one side is cannulated. The cannula prefilled with sodium citrate solution is attachedto a mercury manometer to record blood pressure. A butterfly cannula is inserted into legvein to inject drugs. Drugs (Table 12.1) are injected and there effect is recorded on a smokingdrum. The arterial cannula may be connected to a mercury manometer or to a pressuretransducer, which is connected to a polyrite or physiograph (Fig. 12.1). Heart rate is recordedby observing movements of lever.

C H A P T E R

Effect of Drugs on DogBlood Pressure

12

Fig. 12.1: Dog BP and respiration recording

Effect of Drugs on Dog Blood Pressure 91

Table 12.1. Drugs and solutions used in dog BP experiment

Drugs Dose Concentration(µg/kg) (µg/ml)

1. Epinephrine 1-8 10(Adrenaline)

2. Norepinephrine 1-8 10(Noradrenaline)

3. Isoprenaline 2 10

4. Propranolol 1mg 1 mg/ml

5. Acetylcholine 1-5 10

6. Atropine sulphate 0.5 mg 1 mg/ml

7. Dopamine 1-5 10

8. Histamine 0.2-5 1-10

9. CaCl2 0.1 1%

10. KCl 0.1 1%µg = micrograms

Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is not thereincrease dose to 0.2 ml and so on.

CSM

The model usually have an on screen recording. You can choose drugs and record theireffect (Table 12.2).

The recordings will look like as:Actual dog experiment (Fig. 12.2).

Fig. 12.2: Dog BP recording with agonists


CSM (FIG. 12.3)

Table 12.2. Effect of drugs on dog BP

S. NO. DRUG HEART RATE BP1. Control 62 Normal2. Epinephrine 71 Increased3. Norepinephrine 57 Increased4. Isoprenaline 91 Increased5. CaCl2 1 Decreased6. Acetylcholine 37 Decreased7. KCl2 1 Decreased8. Dopamine 35 Decreased9. Histamine 40 Decreased

Epinephrine (Fig. 12.4): Produces biphasic response because of its actions on alladrenergic receptors. Initially there is α1 stimulation leading to increase in BP, this followedby β2 action leading to decrease in BP. It is followed by β1 action leading to increaser in BP,after this there is compensatory decrease in BP.

Norephinephrine: Produces greater rise in BP as compared to equivalent dose ofadrenaline. This is because there is no vasodilatory component (β2).

Isoprenaline: Decreases BP, as it has predominant β2 action.

Fig. 12.3: Dog BP recording

Fig. 12.4: Biphasic response with adrenaline

Effect of Drugs on Dog Blood Pressure 93

Dopamine: There is decrease in BP with 1-5 µg dose, but BP increase with 5-20 µg dose.Histamine (Fig. 12.5): Produces fall in BP.Acetylcholine (Fig. 12.5): Produces fall in BP.

Blockers can also be used to identify nature of unknown.

OBJECTIVES


CSM

1. Interpret effect of various drugs on dog BP and heart rate2. Describe mechanism of action of various drugs.3. Comment on nature of unknown drugs given.

Exercise in examination

These days LCD projectors are available in which you can project only a part of computerscreen. With this type of projector it is very easy to use these softwares for examinationpurpose. On your computer screen everything is visible including name of drugs, but youcan project only recording showing effect.

Fig. 12.5: Effect of depressors on Dog BP

These experiments are demonstrated to students so that they get an idea of how efficacyand safety of drugs is tested in animals. The following experiments can be shown to students

1. Evaluate analgesic effect of drugs on rats2. Evaluate antidepressant effect of drugs on mice3. Evaluate adverse effects of drugs on mice4. Evaluate Antianxiety effect of drugs.

DEMONSTRATION I

Evaluate analgesic effect of drugs on rats using Tail flick method

Pain is an unpleasant sensation localized to a part of the body. Tail flick method is used toevaluate analgesic activity of narcotic analgesics. Tail flick method evaluates sharply localizedpain and measures the threshold for an escape response.

C H A P T E R

Short Experiments forEfficacy and Safety

13

Fig. 13.1: Analgesiometer

Procedure

In this method radiant heat is used. A wireheated upto 55°C is used for radiant heat.The apparatus used is analgesiometer(Fig. 13.1). The animal is put in rat restrainer.The tail is cleaned. The tail is placed on a levelsurface, a radiant heat is applied to the tailand the latency of the mouse to remove itstail from the heat is recorded. To avoid theheating of surrounding metallic parts due toradiant heat, cold water is circulated throughhollow metallic portion of the apparatussurrounding the hot wire.

Animal are screened on the apparatus andcut off time is 5 seconds. If an animal doesnot flick tail after > 5 seconds, the animal isexcluded from the experiment.

Wistar rats can be used for thisexperiment. After screening 8 animals areselected for this experiment. There aredivided into 2 groups. Four animals are givennormal saline (group A) by intraperitoneal

Short Experiments for Efficacy and Safety 95

route (i.p.) other 4 are given test drug (e.g. morphine 2 mg/kg i.p.-group B). Tail flick is doneat 30 minutes, 1 hour and 2 hours after the drug administration. Everytime 3 readings aretaken.

Mean of group is taken for calculations (Table 13.1).

Calculations

% antinociception = Test latency – control latencyCut off time – control latency

× 100

orThe maximum possible analgesia (MPA) can be calculated as:

MPA =

Test reaction time – Saline reaction time15 – Saline reaction time

ExerciseWhat is the % antinociception or MPA of the given drug using analgesiometer?

Table 13.1. To record your findings

Mean tail flick time

30 minutes 1 hour 2 hoursGroup AGroup BP value

DEMONSTRATION II

Evaluate antidepressant effect of drugs on mice using despair behaviour test

Depression involves decreased self-esteem of the person. It is usually caused by reaction tosome exogenous stimuli or may be due to an endogenous emotional cause.

Fig. 13.2: Mouse swimming

Procedure

In this method mice are put in a glass jar containing water.The dimensions of glass jar can be 40 cm height and 18 cmdiameter. Water can be upto 15 cm. This is an inexpensivemethods, you need not buy any expensive instrument.

Animals are trained for swimming for 15 minutes.Mice when left in water start swimming (Fig. 13.2). Whendepression sets in, they stop swimming. This is countedas immobility period. In this period mouse does effortonly to keep the head above the water. There is no activeswimming. Test is conducted 24 hours after training.


After training 8 animals are selected for this experiment. There are divided into 2 groups.Four animals are given normal saline (group A) by intraperitoneal route (i.p.) route 4 aregiven test drug (e.g. imipramine 10mg/kg i.p.-group B). Total immobility period is notedfor each mice.

Mean of group is taken for calculations (Table 13.2). Statistical test can be applied to seeany difference in score.

Exercise: Evaluate the effect of the given drug on despair behaviour test.

Table 13.2. For your recordings

Total immobility period (mean)

Group AGroup BP value

DEMONSTRATION III

Evaluate adverse effects of drugs on mice using Rota Rod apparatus (Fig. 13.3)

This experiment is a measure of strength and coordinated movements of the animal. Theapparatus is known as rota rod treadmill. It consists of a rotating rod (diameter 3 cm). Rodis suitably machined to provide grip for animals. Five flanges divide the rod into 4 partitionsand 4 animals can be placed simultaneously. The rod is rotated by a electric motor at 6-10rpm. There is digital display at bottom of each partition. It shows time the animals spendson the rod. It is run by solid state clock running at one second interval. When a animal fallsoff the rod on to the plate below, it trips the corresponding circuit for that partition. Theclock stops and you can note the reading of endurance time of animal on rod.

Fig. 13.3: Rota rod

Procedure

Wistar rats or albino mice can be used for thisexperiment. Animal are trained on rota rod. Theanimals are placed on rod and made to walk.Each time animals falls down, keep it again onthe rod. Training for an animal ended when ananimal remained on rod continuously for 180seconds or completed 20 trials, whichever isearlier. If the animal failed, it was excluded.

Test is conducted 24 hours after training.After training 8 animals are selected for thisexperiment. There are divided into 2 groups.Four animals are given normal saline(group A) by intraperitoneal route (i.p.) route 4

are given test drug (e.g. diazepam 3mg/kg i.p.-group B). The time spent on rod(endurance time) by each animal is noted.

Short Experiments for Efficacy and Safety 97

Mean of group is taken for calculations (Table 13.3). Statistical test can be applied to seeany difference in score.

Exercise: Evaluate the effect of given drug on motor functions using rota rod.

Table 13.3. For your recording

Mean endurance time


DEMONSTRATION IV

Evaluate antianxiety effect of drugs on rats using hole board test (Fig. 13.4)

This experiment is a measure of anxiolytic activity of a drug. The apparatus is an inexpensivewooden platform. Its dimensions are 0.5 × 0.5 m and it has 16 holes of 3 cm diameter each.Holes are large enough for animal to dip their head into holes. Head dip is calculated as oneif it dips till eyes. Head dips are counted by a counter for 30 minutes.

Procedure

Fig. 13.4: Hole board test

Wistar rats can be used for this experiment. Eightanimals are selected for this experiment. There aredivided into 2 groups. Four animals are given normalsaline (group A) by ip route 4 are given test drug (e.g.diazepam 3mg/kg ip-group B). The head dip countwas noted for each animal after 30 minutes of drugadministration.

Mean of group is taken for calculations (Table13.4). Statistical test can be applied to see any differencein score.

Exercise

Evaluate the effect of given drug using hole board test.

Table 13.4. For your recordings

Mean head dip count


Ethics is whatever you do when no one is observing you. These days it is very important tounderstand ethical issues when we are dealing with research on animals and humans. Thefour principles of ethics are:

• Autonomy: Right to decide• Beneficence: One must remember that whatever we do should be done for benefit of

patients.• Do no harm.• Justice: Best treatment and justice to all as far as possible.

The guidelines for performing experiments on animals are given by CPCSEA ( committeefor purpose of control and supervision on experiments on animals). The guidelines regardingmaintenance of animal house are also given by CPCSEA (http://medind.nic.in/ibi/t03/i4/ibit03i4p257.pdf).

Animals are used in pharmacology in:

1. Undergraduate teaching to show effects of various drugs.2. Postgraduate teaching to show effects of various drugs, to find out the nature of unknown

drug and for bioassay.3. Research to conduct screening for drugs, bioassay and for preclinical testing.

For all new drugs, it is mandatory to do toxicity studies in animals.

C H A P T E R

Ethics and Animals14

ANIMAL TOXICITY STUDIES

These are done before drug can be tested in human beings.The toxicity studies are divided into three stages:

1. Acute toxicity studies (single dose studies): Acutetoxicity studies should be carried out in at least twospecies, usually mice and rats using 2 routes ofadministration. One of the routes should be same asintended for humans. The effect of drug is observedfor 24 hours. Fig. 14.1: Rat in cage, ethical!

Ethics and Animals 99

2. Subacute toxicity studies (repeated dose studies): These studies last for 3 weeks-3 months.Three doses and 2 species are used.

3. Chronic toxicity studies (long term studies): Long-term toxicity studies should be carriedout in at least two mammalian species, of which one should be a non-rodent. Thesestudies can continue upto the life time of animal (1-2 years). Effects of drugs are studieseven in next generation.

SPECIAL TOXICITY STUDIES

1. Fertility studies2. Teratogenicity studies3. Carcinogenicity studies.

Rodents (rats, mice) and non-rodents (rabbits) are used in these studies.

There is a lot of unnecessary pain and trauma to animals during these experiments, hence toreduce this the following principle of 3Rs is recommended:

1. Refinement: Refine experimental methods to decrease unnecessary pain and trauma toanimals.

2. Reduction: Reduce the number of animals used in these experiments.3. Replacement: Replace the animal experiments with appropriate alternative methods,

e.g. computer simulation models, in-vitro methods, cell culture techniques.Whenever you think of animal experiments, critically analyse following:

1. Is the animal, the best experimental system for the problem (Fig. 14.1)?2. Can the pain and discomfort be lessened?3. Is the problem under review is worth solving?

Debate on use of animals in teaching and research:

Full class is divided in two batches.(If you get class in batches for practical, you can use one theory lecture for this activity)

One batch speaks for the use of animals and other against the use of animals in teachingand research. Each batch is given fifteen minutes to discuss the issue in their respective batchand then choose a group leader to speak on behalf of group. The speaker gets 10 minutestime to speak. Ten minutes are allowed for questioning and comments. This if followed byconcluding remarks by a faculty member.

Visit to animal house: central animal house as well as departmental animal house:

This can be done on day of practical by dividing students into small batches.This is done after debate to avoid any enthusiastic, biased reaction of students to use of

animals. This is done because first time they are exposed to animal experiments as well asanimal house, most of them might feel too concerned about animals by looking at cute lookinganimals (especially guinea pigs, rabbits).


Depending upon facilities available in animal house, the following points can be discussedduring the to animal house:

1. Maintenance of stock, types of animals kept2. Why they are required (name of experiments)3. Breeding of animals4. Separation of pregnant, just delivered pups5. Maintaining room temperature, humidity, air flow, light-dark cycle6. Feeding practice (pellets, greens, etc.)7. Care of sick animals8. Disposal of animal waste.

OBJECTIVES

At the end of the session the student shall be able to:1. Understand principles of ethics.2. Realize the importance of ethics when using animals for experiments.3. Justify the need for adhering to proper standards of maintenance and care in the use of

animals for research and teaching.

Section 3Clinical Pharmacology

Clinical pharmacology is study of drugs in clinical material, i.e. human beings. Clinicalpharmacology is also the science of prescribing the correct drug at the correct dose at theright price to the right patient, i.e. rational drug utilisation. It includes clinical trials of drugs,postmarketing surveillance, pharmacokinetics, pharmacodynamics, toxicity, drug interactions,etc. The focus of pharmacology teaching has shifted more to clinical pharmacology. In clinicalpharmacology, a student is expected to know the appropriate indication, dose, route ofadministration, frequency adverse effects, contraindications, potential drug interactions, howto reported adverse effects and above all explain these salient features to patient. Prescribingand therapeutics are important areas of clinical pharmacology. It is proposed that teachingof clinical pharmacology should be extensive for undergraduates. They should be taughtmore about clinical pharmacology of drugs. There should be a problem based approach toteach clinical pharmacology. Learning through curiosity, the exploitation of knowledge andcritical evaluation of evidence should be encouraged. To learn this aspect of pharmacology,it is essential to learn some basic principles of pharmacology. A sound knowledge of basicprinciples of clinical pharmacology allows students to take a logical approach to learningabout any of the drugs they are likely to encounter during the course. This section dealswith the above mentioned issues. This branch of pharmacology is most demanding thesedays. With the shift of a number of clinical trials of new drugs to India, the training anddemand has increased tremendously in this area.

Most of the aims of clinical pharmacology are general requirements for the safe andeffective use of dugs in most areas of clinical practice. Inculcate the attitude and behaviourrequired by a professional competent doctor. Prescription load can be decreased by usingessential drug list. A student who is able to effectively learn these aspects of clinicalpharmacology, should be able to cope safely and effectively with most of the prescribingchallenges that he/she is likely to face in early postgraduation or practice.

Clinical Pharmacology learning should produce graduates who are competent to prescribesafely and effectively. They should learn to assimilate information about new drugdevelopments that will occur throughout a professional carrier.

C H A P T E R

Introduction toClinical Pharmacology

15

Pharmacokinetics is what the body does to the drug. The knowledge of kinetics is veryimportant for budding doctors to understand how dosage schedules are formed for variouspatients and diseases.

Basically the process of pharmacokinetics involves 4 steps, i.e. ADME as follows:Step 1: Absorption of drugs from various route of administrationStep 2: Distribution of drugs into bodyStep 3: Metabolism of drugs into bodyStep 4: Elimination of drugs or their products from body.

The ADME process can be depicted as (Fig 16.1):

Various body fluids and organs involved in ADME are (Fig. 16.2):The knowledge about pharmacokinetic principles and their clinical significance is very

important for doctors to generate dosage schedules, to monitor therapy, to modify schedulesin case of diseases, etc. Clinical pharmacokinetics is the name assigned to science disciplinedealing with the application of pharmacokinetics to the safe and effective therapeuticmanagement of the individual. Let us discuss important pharmacokinetic parameters.

C H A P T E R

Pharmacokinetic Parametersand Calculations

16

BIOAVAILABILITY

Bioavailability refers to the extent and rate atwhich the active moiety (drug or metabolite)enters systemic circulation, thereby accessing thesite of action. It is denoted as "f". Bioavailabilityis the amount of the administered drug that isavailable to have an effect. Bioavailability of adrug is largely determined by the properties ofthe dosage form (which depend partly on itsdesign and manufacture), rather than by thedrug's physicochemical properties. Fig. 16.1: Plasma concentration time curve

Pharmacokinetic Parameters and Calculations 105

SALIENT FEATURES

1. Drugs given intravenously may be considered to be 100% bioavailable as they areadministered directly into the circulation.

2. Administration of highly lipid soluble drugs by oral route means that some of the drugmolecules will be lost due to first pass metabolism and thus bioavailability is reduced.For calculating bioavailability (f) drug is give by IV route and by intended route ofadministration.Plasma concentration curves are plotted and area under plasma concentration curve(AUC) is measured for each mode of administration (Fig. 16.3).

Fig. 16.2: Various organs, tissues involved in pharmacokinetics

f = AUC oral × 100

AUC IV

For new preparations of the same drug, bioavaila-bility can be compared to see their bioequivalence.Bioequivalence is whether both preparations givesame bioavailability in the body or not.

Clinical significance:

1. Oral dose is more as compared to IV Dose.2. Marked interindividual variation in first pass

metabolism, hence dose required.3. Hepatic diseases affect first pass metabolism,

hence concentration achieved will be high. Fig. 16.3: AUC


4. Drug interactions can occur when 2 drugs compete for same pathway of first passmetabolism.

AUC

It is area under plasma concentration-time curve. It tells about total amount of drug presentin the body. The most commonly method used to calculate AUC is trapezoidal rule.

AUC is a measure of quantity of drugs in the body.

From AUC one can determine bioavailability (f) of a drug and the relative bioavailability.

AUC can be calculated by the following methods:

1. Square counting method2. Cutting and weighing method3. Planimetery4. Trapezoidal rule: This is considered to be the best method. A blood concentration,

time curve can be described by a series of trapezoids that are determined by eachconcentration time point. In Figure 16.4, A is triangle and B-F are trapezoids. Calculatearea of all and add up. This will give you AUC0-6.

AUCt-α = KelLast observed concentration

AUC0-α = AUC0-6 + AUCt-α

Relative bioavailability (Bioequivalence) =

Other formulae for AUC:

AUC =

AUC =

Fig. 16.4: Trapezoids

AUC =

CL = Clearance, Vd = Volume of distributionKel = Elimination rate constant.

VOLUME OF DISTRIBUTION (VD)

It is defined as "apparent or hypothetical volumeof body fluids that can accommodate the totalamount of drug administered so that the con-centration achieved is equal to concentration inthe plasma.


If total amount of administered drug = 1000 mgAnd plasma conc. achieved = 50 mg/lThen Vd will be calculated as given in Figure 16.5.

Vd gives an idea about distribution of drug as given in Tables 16.1 and 16.2.

Table 16.1. Vd as related to drug present in body

If vd is Drug is present in Example10-20 L Plasma and extracellular Streptomycin

fluid Lipid insoluble20-40 L Intracellular fluid Phenytoin

Lipid soluble> 40 L Concentrated in tissues Chloroquine

Highly lipid soluble

Table 16.2. Vd of common drugs

Drug Vd (L/Kg)WARFARIN 0.1LIGNOCAINE 1.5DIGOXIN 7NORTRIPTYLINE 20

Vd depends on the following factors:• Blood flow rate in different tissue• Lipid solubility of drug• Partition coefficient of drug and different types of tissues• pH• Binding to biological material.

Vd is often proportional to body weight.In obesity Vd is lower than expected from the body weight.In edema, Vd is larger than expected for the body weight.

Fig. 16.5: Vd calculation


Other formulae for Vd

Vd =

CL =

Vd =

Vd =

Clinical significance

1. Hemodialysis in drug poisoning:Drugs with low Vd can be easily removed by hemodialysis, e.g. Salicylates

2. Calculation of loading dose (LD)LD = Vd × CL (IV Route) CL = clearance

LD = f = bioavailability.

HALF-LIFE

The half-life (t½) is the time taken for the circulating plasma concentration of a drug to fall to50% of original/peak concentration.

t½ = Kel = elimination rate constant

Kel = so t½ =

For example: Aspirin 15 minutesPhenobarbital 2-6 days.

Salient features

1. Half-life is a derived parameter that changes as a function of both clearance and volumeof distribution. Half-life is constant in first order kinetics. Half-life increase with increasein concentration in zero order kinetics

2. Plasma protein binding increase half-life3. Drug widely distributed and sequestrated in tissues got longer half-life, e.g. amiodarone4. Approximately 4-5 half-lives are required for complete elimination of drug from the

body:


one t½ = 50% drug is eliminatedtwo t½ = 75% (50 + 25) drug is eliminated

three t½ = 87.5% (75 + 12.5) drug is eliminatedfour t½ = 93.75% (87.5 + 6.25) drug is eliminated.


1. Half-life determines frequency of administration or dosing interval of drug, e.g. If t½is 12 hours, then drug is given twice a day.

2. When rate of absorption equals rate of elimination steady state is said to be achieved.3. The clinician usually wants to maintain steady-state concentrations of a drug within a

known therapeutic range (gl), assuming complete bioavailability.4. Approximately 4-5 half-lives are required to reach steady state (Fig. 16.6).5. In most clinical situations, drugs are administered in a series of repetitive doses or as a

continuous infusion in order to maintain a steady-state concentration of drug in plasmawithin a given therapeutic range. At steady state the rate of drug administration isequal to drug elimination and the mean concentration remains constant.

CLEARANCE

Clearance is the most important concept to be considered when a rational regimen for long-term drug administration is to be designed.

Clearance is defined as the volume of the plasma cleared of the drug in a unit time. It isexpresses as ml/minute. If given clearance is 5 ml/minute, it means that 5 ml of plasma iscleared of the drug.

Most of the drugs follow first order kinetics for clearance.Total body clearance is:

CL = CLrenal + CLhepatic + CLother

Other formulae for clearance

CL = Vd * Kel

CL =

CL = Cp = Plasma concentration

Salient features

1. If a drug is only excreted by glomerularfiltration, CLrenal can not exceed GFR(120 ml/min), e.g. Aminoglycoside anti-microbials. Fig. 16.6: Steady state


2. If a drug is completely removed by tubular secretion, CLrenal can not exceed renalplasma flow (700 ml/min), e.g. Penicillin.

3. Reabsorption can decrease CLrenal to as low as 1ml/min.4. Clearances is constant in zero order kinetics. Zero order kinetics are saturable kinetics,

e.g. Phenytoin. It is also known as non-saturable kinetics. Most of the drugs follow firstorder kinetics.

5. Clearance increase with increase in concentration in first order kinetics.


1. Most of the drugs got unsaturable enzyme system for their hepatic biotransformation,hence most of the drugs are metabolised in liver. In this instance, the concentration ofdrug in the blood leaving the liver will be low (Cv = 0). Extraction ratio (ER) willapproach unity

2. The rate limiting step will become hepatic blood flow. These drugs are known as highextraction ratio (HER) drugs, e.g. Lidocaine imipramine (Fig. 16.7).

3. In contrast, changes in intrinsic clearance and protein binding will affect.4. The clearance of drugs with low extraction ratios, but changes in blood flow should

have little effect.5. Maintenance dose is calculated with the help of CL

MD = CL × Cp.

LOADING DOSE

The "loading dose" is one or a series of quickly repeated doses that may be given at the onsetof therapy with the aim of achieving the target concentration rapidly (Fig. 16.8). Theappropriate magnitude for the loading dose is:

LD = , e.g. 20L*20 mg/L = 200 mg, Cp = plasma concentration required

• Loading dose depends on extent ofdistribution. If a drug is widelydistributed in the body a large loadingdose is required to fill the distributionsites.

• A loading dose may be desirable if thetime required to attain steady state bythe administration of drug at a constantrate (four elimination half-lives) is longrelative to the temporal demands of thecondition being treated. Fig. 16.7: Hepatic extraction

Example: The half-life of lidocaine, anantiarrhythmic, is usually more than 1 hour.One cannot wait for 4 to 6 hours to achieve a


OBJECTIVES

At the end of this session a student shall be able to:1. Define the various pharmacokinetic parameters2. Calculate various pharmacokinetic parameters from given data3. Explain clinical significance of these parameters.

therapeutic concentration, arrhythmiasencountered may be life threatening, hence,a loading dose of lidocaine is used.

Maintenance dose

To maintain steady state a maintenance doseis required.

MD =

Maintenance dose depends on clearance.Whatever dose is lost in clearance is replacedby maintenance dose. Fig. 16.8: Loading dose

A prescription is a written order by a physician to a pharmacist to dispense a therapeuticagent to a patient. This therapeutic transaction is the sum of the physician's evaluation of theproblem (the history, physical examination, diagnostic tests, decision on treatment, andprognosis). On this single sheet of paper are the final results of the physician's education,experience, and diagnostic acumen.

Prescriptions are typically handwritten on preprinted prescription forms that areassembled into pads, or alternatively printed onto similar forms using a computer printer.Preprinted on the form is text that identifies the document as a prescription, the name andaddress of the prescribing provider and any other legal requirement such as a registrationnumber. The word "prescription" can be decomposed into "pre" and "script" and literallymeans, "to write before" a drug can be prepared.

It is estimated that 3 billion prescriptions were written in the United States in 2002. Thisnumber has grown from 1.5 billion in 1989 and is expected to continue to grow. Drugsshould be prescribed only when they are necessary for treatments following clear diagnosis/indication. Not all patients or conditions need prescriptions for drug. In certain conditionssimple advice and non-drug treatment may be more suitable.

All written prescriptions should contain

• Patient's full name and address• Prescriber's full name, address, telephone number and registration number• Date of issuance• Signature of prescriber• Drug name, dose, dosage form, amount• Directions for use• Refill instructions.

A prescription has various parts. Predating modern legal definitions of a prescription, aprescription traditionally is composed of four parts: a "superscription", "inscription","subscription" and "signature".

C H A P T E R

Prescription Writing ThroughProblem Based Learning(Rational Prescribing)

17

C H A P T E R

Prescription Writing Through Problem Based Learning (Rational Prescribing) 113

Superscription: it has

• Name and address of doctor.• Name, age, sex and address of patient (age is desirable for safety purposes) and date.• The symbol "L" separates the superscription from the inscriptions sections. L is a

traditional esoteric symbol, for the word recipe 'take thou' (Latin "recipe") the imperativeform of "recipere", "to take". It should not be interpreted as instructions to the patientto "take thou" as patient instructions are in a later section. Some the literal exhortationto the pharmacist is "take thou this recipe".

Significance of superscription is to expedite the handling of the prescription and toavoid confusion with the medications intended for some one else. It is also the duty ofpharmacist to verify the patient's name and age to monitor the prescribed dose.

Inscription: The inscription section defines what the medication is.It has name of drug, its dose, frequency, duration, route of administration

• Choice of drug name: best is to use generic names or non-proprietary or official namesrather than using brand names. This eliminates necessity for memorising multiple drugnames.

• The name, strength of drug and its inert additives should be mentioned, both for thesingle ingredient drug and fixed dose drug combinations (FDCs). This helps in rapididentification of drug and a quick estimate of the amount consumed and can help in theinitiation of appropriate therapy in case of adverse drug reactions (ADRs) or accidentalor deliberate over dosage.

• Frequency and duration of administration.• One should avoid using abbreviations since it frequently leads to errors.• For decimals a zero should precede the decimal point where there is no other value,

e.g. 0.5 ml not .5 ml.• Do not abbreviate microgram, nanogram• Prescription orders should always be written in metric system. Home/domestic

measures or convenient kitchen utensils should not be used to measure as they are notuniform and accurate to indicate the metric unit of weight or volume desired for liquiddrugs. Instead a calibrated dropper, moulded plastic cylinders, measuring oral syringe,and graduated caps have been designed for administering liquid medications.

Subscription: It has dispensing directions to the pharmacist, e.g. send such number ofcapsules/send such number of tablets.

Importance of subscription is to reduce the communication gap between patient andphysician and direct the pharmacist to detect any overdose of potent drugs for safety ofpatient and educate the patient about compliance and how to take medication.

Transcription or signature: The "signature" section contains directions to the patient andis often abbreviated "Sig." or "Signa". It also obviously contains the signature of the prescribingdoctor though the word "signature" has two distinct meanings here and the abbreviationsare sometimes used to avoid confusion. It has instruction or direction to the patient regarding


the use of medications prescribed. Here brevity, clarity and accuracy are especially important.This is required to improve patient's compliance and to explain the patient about his or herillness and how the prescribed medication will alter the disease process. Only the registeredmedical practitioner can prescribe the drug.

Prescribe drug therapy for a male patient age 55 years, suffering from myasthenia gravis

Dr Rakesh KumarAn example of prescription: MBBS, MD

115, Civil Lines, Ludhiana Phone: 0161-5030987

Name: Amit Sharma Age/Sex: 55 MaleAddress: H.No 445, Model town, Ludhiana Tel: 5058677Unit No. C-238567 Date. 27-6-2007L

Tab. Pyridostigmine 30 mgTab. Prednisone 60 mg

InscriptionDispense 45 tablets of PyridostigmineDispense 15 tablets of Prednisone

SubscriptionTake 1 tab. of pyridostigmine 3 times a day for 15 daysTake 1 tab. of prednisone once a day for 15 days

Transcription Revisit after 15 days

SignatureRegd.No 24456 (Punjab Medical Council) Name Dr Ankur Sharma, MD

In conventional curriculum, practice of prescription writing becomes mechanical. Mostof the times the students copy the prescribing behavior of their seniors or teachers on existingstandard treatment guidelines, without explanation as to why certain treatments are chosenand prescribed. The need of improvement with supplementing sufficient backgroundinformation and proper orientation is felt. Prescription writing through problem-basedpharmacotherapy teaching is one such way, which can help the students appreciate therelevance of acquired information for appropriate or rational prescribing in a better way. Itprovides step by step guidance to the process of rational prescribing.

Su

perscrip

tion


To develop self-learning and thinking process in the medical students early in theircareer while learning pharmacology is the best way to inculcate these habit of rationalprescribing. The students will be learning how to prescribe effectively and judiciously forany given situation and also the skill of choosing and prescribing drugs logically and rationally.For this we can use the WHO concept of "P" drug.

WHO has introduced the concept of "P" drugs. As a doctor you may see 50 patients perday or more, many of whom need treatment with a drug. How do you manage to choose theright drug for each patient in a relatively short time? This can be achieved by using "P"drugconcept. "P"drugs or personal drugs are the drugs you have chosen to prescribe regularlyand with which you have become familiar. They are your priority choice for given indications.They will differ from country to country and between doctors. In general, the list of drugsregistered for use in the country and the national list of essential drugs contain many moredrugs than you are likely to use regularly. Most doctors use only 40-60 drugs routinely. It is,therefore, useful to make your own selection from these lists and to make this selection in arational way. In fact, in doing so you are preparing your own essential drugs list. The P-drug concept is more than just the name of a pharmacological substance, it also includes thedosage form, dosage schedule and duration of treatment. Students will be taught to makean inventory of possible treatments of any common disorder resulting in a set of first choicedrugs called P (personal) drugs on the basis of their efficacy, safety, suitability and cost.

Steps in choosing a P-drug:

Step i: Define the diagnosisStep ii: Specify the therapeutic objectiveStep iii: Make an inventory of effective groups of drugsStep iv: Choose an effective group according to criteriaStep v: Choose a P-drug(i) Define diagnosis:

When selecting a P-drug, it is important to remember that you are choosing a drug offirst choice for a common disorder. Knowledge about pathophysiology of the diseasewill help you to choose drug of first choice. Treating symptoms without really treatingthe underlying disease/pathology is known as symptomatic treatment.

(ii) Specify the therapeutic objective:It is very useful to define exactly what you want to achieve with a drug. For example,to control the blood pressure to a certain level, to cure an infectious disease or preventoccurrence of hepatitis. If you are sure about therapeutic objective, it becomes easier toselect P drug.

(iii) Make an inventory of effective drugs:In this step you link the therapeutic objective to various available drugs. Efficacy is thefirst criterion for selection of drugs. Initially, you should look at groups of drugs ratherthan individual drugs. There are tens of thousands of different drugs, but only about70 pharmacological groups.


(iv) Choose an effective group:There are two ways to identify effective groups of drugs. The first is to look at formulariesor guidelines or standard treatment guidelines that exist in your institution/state/country, or at international guidelines, such as the WHO treatment guidelines for certaincommon disease groups, or the WHO model list of essential drugs. You can also takehelp from the index of a good pharmacology reference book and determine whichgroups are listed for your diagnosis or therapeutic objective. In most cases you willfind only 2-5 groups of drugs which are effective.

(v) Choose a P-drug:Out of these shortlisted drugs choose a P-drug for a common condition.

After choosing a P drug this concept can be extended to rationally treat patients. There are6 steps:(i) Define patient's problem:

Make right diagnosis based on clinical history, sign symptoms as well as investigationsPatient's complaints are mostly linked to his/her symptoms. A symptom is not a diagnosisin itself, although it will usually lead to it, e.g. all patients with symptoms of sore throatwill not need the same treatment even when they have same diagnosis.

(ii) Define therapeutic objective:Before choosing a treatment it is essential to specify your therapeutic objective. Whatdo you want to achieve with the treatment?

(iii) Verify the suitability of your P-drugs:You have chosen a P drug as first drug of choice for common condition. You cannotassume that 'first-choice' treatment will always be suitable for everyone. You mustverify whether your P-drug is suitable for this individual patient or not.

It is to be remembered here that P drug for a condition may not always be the mostappropriate drug for every patient. A number of patient specific factors like extremesof age, pregnancy and lactation, concurrent medications, existing diseases (hepatic orrenal disease) may require a different P drug for a particular patient.

The process of "personal drug" selection is centered around the drug and indication.But for patient treatment, even if the disease is same, the patient related factors becomeimportant and need to be considered. There might be some factors or characteristicspeculiar to the patient that renders the personal drug unsuitable for him/her.

(iv) Write a prescription:Write legibly and completely as described in various parts of prescription.

(v) Give information, instructions and warnings:It has been seen that, 50% of patients do not take prescribed drugs correctly, take themirregularly or not at all. The most common reasons cited are that symptoms have ceased,side effects have occurred, the drug is not perceived as effective or the dosage scheduleis complicated for patients, particularly the elderly. Hence, it is very important to talkto your patients. Explain them about treatment, specific instructions and warnings aboutmedications.


(vi) Monitor and/or stop the treatment:After rational treatment of your patient, you would be interested to know what happenedto patient's condition. For that you can monitor of follow up the patient. You can decidewhether treatment is effective or not.

P-DRUGS AND P-TREATMENT

There is a difference between P-drugs and P-treatment. The key point is that not all diseasesneed to be treated with a drug. Not every P-treatment includes a P-drug!

Electronic prescriptions

Softwares are available to write prescriptions. But more and more, doctors are writingprescriptions electronically in developed countries, but it is not so popular in our countrydue to various reasons.

OBJECTIVES

At the end of this practical, a student shall be able to:

1. Acquire cognitive, motor and communication skills that are necessary throughout aclinical career for rational therapeutics.

2. Choose an appropriate drug from P-drug list, deciding what information or instructionis (or not) to be given and to monitor the result of treatment.

3. Write appropriate prescription for a given case.

Exercises in class

Anil Verma, 42 years old male is found to be diabetic during routine medical examination.He does not experience any symptoms related to increased blood glucose (PPBS 160 mg/dl).Physical examination reveals- his BP 160/130 mm of Hg, weight 76 kg, height 5 ft. 10 inches.No other abnormality is found.

Exercise:Q1. What is the patient's problem?Q2. What is the goal of treatment in this patient?Q3. Prepare a list of effective groups of drugs for the given condition/s.Q4. Choose the effective group/groups of your choice for the given condition/s giving

justification.Q5. Choose the most appropriate drug/drugs from your chosen group/s of drugs based

on efficacy, safety, suitability and cost, for this patient.Q6. Write the prescription with suitable instructions and follow up plan for this patient.


Examples of prescriptions for common diseases:

1. Anemia (microcytic hypochromic)

Dr Rakesh Kumar MBBS, MD


Name: Amit Sharma Age/Sex: 55 MaleAddress: H. No 445, Model Town, Ludhiana Tel: 5058677

Unit No. C-238567 Date 07-07-2007L

• Tab. Ferrous sulphate (60 mg elemental iron) 1od × 1 month

• Tab. Albendazole 400 mg statDirection: Dispense 30 such tablets of ferrous sulphate and 1 tablet of albendazoleSig: Take one tablet of ferrous sulphate every day before food for 1 month. Take onetablet of albendazole. Revisit after 1 month for hemoglobin estimation.

Name: Dr Ankur Sharma, MDRegd. No 24456 (Punjab Medical Council)


2. Angina pectoris



Name: Amit Sharma Age/Sex: 55 MaleAddress: H. No 445, Model Town, Ludhiana Tel: 5058677Unit No. C-238567 Date 07-07-2007

L

• Tab. Isosorbide dinitrate 5 mg sublingually as and when required• Tab. Isosorbide mononitrate 50 mgSR 1od × 15 days• Tab. Atenolol 50 mg 1 od × 15 days• Tab. Aspirin 100 mg 1 od × 15 days

Direction: Dispense 10 tablets of isosorbide dinitrate, 15 tablets of isosorbidemononitrate, atenolol and aspirin.Sig: Take these tablets after breakfast


Other measures:

• Life style change is recommended, e.g. work stress, smoking, etc.• Stop working and sit down at the earliest indication of pain in chest• Avoid tea, coffee, nasal decongestant drops• Atenolol contraindicated in asthmatics• Do not take aspirin empty stomach• Revisit after 2 weeks or earlier in case of any distress or breathlessness, fainting or

palpitations.


3. Acute asthma




L

• Salbutamol MDI2 puffs (100 µg/puff) SOS

Direction: Dispense one MDI of SalbutamolSig: Use inhaler whenever needed as described in attached pictorial diagram.



4. Acute severe asthma




L

• Oxygen inhalation• Inj. Hydrocortisone hemisuccinate

100 mg iv stat, repeat 100 mg every 6 hourly• Nebuliser salbutamol

2 ml diluted to 5 ml with normal saline over 30 minutes• Inj. Terbutaline - 5mg/ml

1 ampoule SC immediately• Review the patient every 2 hourly

Direction: Dispense 10 vials of hydrocortisone, nebuliser salbutamol and 5ampoules of terbutaline.


Other measures:

• Hospitalise the patient• If patient is not in hospital, give salbutamol inhaler (100 ug/puff) 2 puffs every 10

minutes till patient reaches hospital• Admit and keep the patient in propped up position.


5. Hypertension (Essential hypertension with no associated disease)




L

• Salt restriction• Exercise/meditation to relief stress• Tab. Atenolol 50 mg 1 od × 15 days• Revisit after 15 days.

Direction: Dispense 15 such tabletsSig: Take one tablet every day, regularly do aerobic exercises, restrict salt intake.


Other measures/additional information:

• Dose of atenolol may be increased upto 100 mg/day• The choice of drug may vary depending on age and associated diseases. Alternative

drugs are: enalapril (hypertension with CHF or diabetes), thiazide diuretics,amlodipine (hypertension with asthma).

• Combination therapy with more than one agent can be used if the patient does notrespond to single drug therapy.

• Advice to reduce/eliminate smoking/alcohol intake.


6. Status epilepticus

Dr Rakesh KumarMBBS, MD

115, Civil Lines, LudhianaPhone: 0161-5030987


L

• Inj Lorazepam 0.1 mg/kg at rate of 2 mg/ml ivCan be repeated after 10 min (max 3 doses)If seizures persist then give

• Inj Phenytoin 15-20 mg/kg slow iv infusion• Review the situation every 15 minutes


Additional measures:

• Admit the patient in casualty• Maintain patent airway, breathing, circulation• Phenytoin can be repeated at 5-10 mg/kg (max 30 mg/kg)• If seizure still persist then give Inj. Phenobarbitone 20 mg/kg iv at 50-100 mg/min. It

can be repeated. If seizures are not controlled then give midazolam or propofol.


7. Peptic ulcer




L

• Tab. Omeprazole 20 mg I od



• Test for H pylori, if positive then prescribe for H pylori eradication.• Avoid alcohol, smoking, stress, caffeinated drinks, chillies and drugs like steroids,

NSAIDs.


8. NIDDM




L

• Tab. Glibenclamide 5 mg ½ tablet every day before breakfast



• Dose can be titrated up based on blood glucose levels.• Advice diet modification and exercise.


9. Acute abdomen



Name: Amit Sharma Age/Sex: 55 MaleAddress: H. No 445, Model town, Ludhiana Tel: 5058677Unit No. C-238567 Date 07-07-2007

L

• Inj. Dicyclomine HCl 10 mg IM stat• Tab. Dicyclomine HCl 10 mg 1 sos

Direction: Dispense 1 ampoule of dicyclomine and 4 tablets of dicyclomineSig: Take one tablet whenever needed



• Narcotics may be given in severe pain• If pain due to soft tissue trauma give NSAIDs• Advise semisolid diet.


10. Dysmenorrhoea



Name: Ritu Sharma Age/Sex: 35 FemaleAddress: H. No 445, Model Town, Ludhiana Tel: 5058677Unit No. C-238567 Date 07-07-2007

L

• Tab. Mefenamic acid 250 mg tds × 3 days• Tab. Dicyclomine HCl 10 mg tds × 3 days

Direction: Dispense 9 tablets of mefenamic acid and dicyclomine



11. Acute attack of migraine




L

• Tab. Aspirin 650 mg stat, repeat after 4 hours if needed• Tab. Ergotamine (1mg) + caffeine (100 mg) 2 tab stat

Then 1 tablet half hourly (max 6 in a day)If nausea/vomiting

• Tab. Metoclopramide 10 mg stat and sosDirection: Dispense 4 tablets of aspirin, 6 tablets of ergotamine + caffeine and 6 tabletsof metoclopramideSig: Take tablet of aspirin immediately. Take ergotamine + caffeine 2 tab, then take 1tablet half hourly. Take metoclopramide immediately and then whenever required.



• Alternative to tablet aspirin are paracetamol and ibuprofen.


12. Allergic Conjunctivitis




L

• Betamethasone eye drops (0.1%)• Ketorolac eye drops (0.5%) q6h till symptoms subside

Direction: Dispense 1 vial of betamethasone and 1 vial of ketorolac



13. Herpes zoster




L

• Tab. Acyclovir 800 mg 5 times a day × 7 days• Tab. Ibuprofen 400 mg tds till symptoms subside

Direction to pharmacist: Please dispense 35 tabs of tablets of acyclovir and 10 tablets ofibuprofen.



14. Oral candidiasis (Thrush)




L

• Tab. Fluconazole 100 mg 1 od × 14 daysor

• Clotrimazole mouth paint 1% 2-3 times/day × 7 daysDirection: Dispense 14 tabs of fluconazole



15. Vaginal candidiasis (Vulvovaginitis)



Name: Ritu Sharma Age/Sex: 35 FemaleAddress: H. No 445, Model Town, Ludhiana Tel: 5058677Unit No. C-238567 Date 07-07-2007

L

• Tab. Fluconazole 150 mg statDirection: Dispense 1 tab of fluconazole



16. Hepatic amoebiasis




L

• Tab. Tinidazole 300 mg 2 bd × 7 days• Tab. Chloroquine 250 mg 2 bd × 1day then 1 bd × 19 days

Direction: Dispense 14 tabs of tinidazole and 42 tabs of chloroquine.Sig: Take 2 tablets of tinidazole two times in a day. Take 2 tablets of chloroquine two

times in the day on day 1 then 1 tablet two times in a day.



• Metronidazole can be given in place of tinidazole• If severe, give metronidazole IV


17. Intestinal amoebiasis




L

• Tab. Tinidazole 500 mg bd × 3 days• Tab. Diloxanide furate 500 mg tds × 10 days

Direction: Dispense 6 tabs of tinidazole and 30 tabs of diloxanide furate



• Tinidazole can be taken as 2 g single dose• In place of tinidazole secnidazole 2 g single dose can also be taken.


18. Primary syphilis




L

• Inj. Benzathine penicillin G.2.4 M Units IM stat AST (1.2 M Units in eachbuttock)

Direction: Dispense 1 vial of inj. benzathine penicillin



• AST-after sensitivity test• If patient allergic to penicillin give tab. Doxycycline 100 mg bd × 10 days.


19. Typhoid




L

• Tab. Ciprofloxacin 500 mg 1 bd × 14 days• Tab. Paracetamol 500 mg tds × 5 days

Direction: Dispense 28 tabs of ciprofloxacin and 15 tablets of paracetamol


Additional information:

• Dose of ciprofloxacin is 750 mg if weight of patient > 50 kg• Paracetamol is for headache and fever, but if there is any bleeding episode stop

paracetamol• If patient is hospitalized start with inj. ciprofloxacin 200 mg IV bd• If no response within 5 days or condition worsens earlier shift to following therapy:

Inj. Ceftriaxone or Inj. Ofloxacin or combination of both.


20. Acute gouty arthritis




L

• Tab. Aspirin 300 mg 2 q4h• Tab. Colchicine 0.6 mg 1 q4h till pain is there

After that• Tab Allopurinol 100 mg tds × 7 days• Low purine diet

Direction: Dispense 24 tabs aspirin, 12 tablets of colchicines and 21 tablets of allopurinolSig: Take 2 tablets of aspirin 4 hourly and 1 tablet of colchicines 4 hourly till pain subsides.

After that take 1 tablet of allopurinol three times in a day for 7 days.



21. Multibacillary leprosy




L

Day 1- Tab. Clofazimine 300 mg once in month supervisedTab. Rifampicin 600 mg once a month supervisedTab. Dapsone 100 mg 1od × 1 month

Then 2-28 daysTab. Clofazimine 50 mg 1od × 1 monthTab. Dapsone 100 mg 1od × 1 month

Direction: Dispense 1 tab of rifampicin, 30 tabs of dapsone and 36 tab of clofazimine(50 mg).

Sig. Tablets on day 1 to be taken under supervision of doctor.Special instruction: Regular follow up every month. Repeat the same treatment every

month and continue the treatment for 2 years. To report immediately in case of skin reaction.There might be red hypopigmented patches on skin due to clofazimine. There may beorange discolouration of body secretions due to rifampicin.



22. Paucibacillary leprosy




L

Day 1-Tab. Rifampicin 600 mg once a month supervisedTab. Dapsone 100 mg 1od × 1 monthThen 2-28 days

Tab. Dapsone 100 mg 1od × 1 monthDirection: Dispense 1 tab of rifampicin, 30 tabs of dapsone.Special instruction: Regular follow up every month. Repeat the same treatment every

month and continue the treatment for 6 months. To report immediately in case of skin reaction.There may be orange discolouration of body secretions due to rifampicin.



23. Tuberculosis




L

• Tab. Isoniazid (300 mg) 1 od × 30 days• Tab. Rifampicin (600 mg) 1 od × 30 days• Tab. Pyrazinamide (750 mg) 1bd × 30 days• Tab. Pyridoxine (10 mg) 1 od × 30 days• Tab. Ethambutol (1000 mg) 1 od × 30 days

Direction: Please dispense 30 tablets of isoniazid, rifampicin, ethambutol, pyridoxineand 60 tabs of pyrazinamide

Sig: Take tab. Rifampicin once daily empty stomach for 30 days. Take tab. Pyrazinamidetwo tab. once daily for 30 days. Take tab. Ethambutol and pyridoxine once daily for 30 days

Special instruction: Regular follow up every month on the same day. To undergo sputumsmear examination at the end of 2 months of treatment. To undergo ophthalmic examinationprior to starting tab ethambutol. The colour of body secretions may turn orange with intakeof tab. rifampicin.



• If sputum is negative after 2 months, start continuation phaseTab. Isoniazid 300 mgTab. Rifampicin 600 mgTab. Pyridoxine 10 mg all 1 od × 4 months

• The drugs can be given 3 times in a week, but dose is more.


24. Chloroquine sensitive malaria




L

• Tab. Chloroquine (250 mg) 4 stat then 2 after 8, 24 and 48 hours• Tab. Primaquine 45 mg stat*

Direction to pharmacist: Please dispense 10 tablets of chloroquine phosphate and 1 tabletof primaquine.

Sig. Take 4 tablets at once, then 2 tablets after 8, 24 and 48 hours. Take single table ofprimaquine.



• Dose of chloroquine is 10 mg/kg followed by 5mg/kg• 1 tablet of 250 mg chloroquine phosphate contains chloroquine base 150 mg, hence

above dose of chloroquine is 600 mg stat followed by 300 mg after 8, 24 and 48 hours• Each 5 ml of suspension contains 50 mg base• *For Falciparum malaria• For vivax/mixed malaria tab primaquine 15 mg 1 od for 5 days is given.


25. Chloroquine resistant malaria




L

• Tab. Mefloquine (250 mg) 3 tab stat then 2 tab after 8 hours• Tab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat

Direction: Dispense 5 tab. of tab. of mefloquine and 7 tab. primaquineDirection to patient: Take 3 tabs of mefloquine 250 mg at once followed by 2 tabs after 8

hrs. Take 3 tab of pyri + sufa together.


Other measure:

• To conduct test to assess the G-6 PD status before starting tab. primaquine.• Other alternative drugs are:

Tab. Quinine sulfate (600 mg) tds × 7days plusTab. Doxycycline (100 mg) 1od × 7days

orTab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat

orTab Mefloquine + Tab. Artesunate 80 mg 2 tab-day1, 1 tab od × 5 days.


26. Cerebral malaria




L

• Inj. Quinine sulphate (600 mg in 1 ml) 10 mg/kg iv q8h• Inj. 5% Dextrose (100 ml)

Direction to pharmacist: Please dispense such 24 ampoules of Inj. quinine and 24 Infusionsof 5% dextrose.

Sig. Inj. Quinine (20 mg/kg) loading dose to be mixed in 5% dextrose (20 ml) and givenslowly over 20 minutes. Then inj. Quinine (10 mg/kg) mixed in 5% dextrose every 8 hours.


Additional information

• Infusion should continue for 4 hours• Once the patient attains consciousness start tab. quinine (10 mg/kg) to make total duration

of therapy 7 days.


27. Upper respiratory tract infection




L

• Tab. Paracetamol 500 mg 1 tds × 3 days• Tab. Cetrizine 10 mg 1 od hs × 3 days

Direction: Please dispense such 15 tablets of paracetamol and 3 tablets of cetrizineSig. Take cetrizine at bedtime, avoid driving and operating heavy machinery.



28. CHF




L

• Tab. Enalapril 2.5 mg 1od × 7 days• Tab. Chlorthiazide 250 mg 1 od om × 7 days• Salt restriction

Direction: Please dispense such 7 tablets of enalapril and chlorthiazideSig. Take chlorthiazide in the morning.

Name: Dr Ankur Sharma, MDRegd.No 24456 (Punjab Medical Council)


• In severe cases add Inj. furosemide 40 mg iv stat and repeat if required after 2-3 hours• Digoxin can be given if associated with atrial fibrillation.


29. Generalised tonic clonic and partial seizures



Name: Amit Sharma Age/Sex: 55 MaleAddress: H. No 445, Model Town, Ludhiana Tel: 5058677Unit No. C-238567 Date. 27-6-2007

L

• Tab. Carbamazepine 200 mg tablets 1tds × 1 monthDispense 90 tabletsRevisit after 30 days



• Dose of carbamazepine to be increased to 800-1200 mg/day gradually• Alternative to carbamazepine are phenytoin and sodium valproate.


30. Depression




L

• Cap. Fluoxetine 10 mg bd × 1 monthDirection: Dispense 30 capsuleRevisit after 30 days



31. Bipolar disorder




L

• Tab. Lithium carbonate 300 mg 1tds x15 daysDirection: Dispense such 45 tabletsRevisit after 15 days



32. Parkinsonism




L

• Tab. Levodopa (100 mg) + Carbidopa (10 mg) 1tds × 15 daysDispense 45 tabletsSig: Take tablets after mealsRevisit after 15 days



• Dose of L-dopa to be increased gradually to 2-3 g/day.


33. Myasthenia gravis




L

• Tab. Pyridostigmine 60 mg 1tds × 15 days• Tab. Prednisone 30 mg 1 od × 15 day

Direction: Dispense 45 tablets of pyridostigmine and 15 tablets of prednisoneSig: Take prednisolone early in the morningRevisit after 15 days



34. Insomnia




L

• Tab. Zolpidem 10 mg tablets 1od hsDirection: Dispense such 15 tabletsRevisit after 15 daysSig: Do not take more dose than recommended



• Advise nonpharmacological methods for sleep• Do not take medication in more than recommended doses and beyond the prescribed

duration• Alternative drugs are-Tab. diazepam or alprazolam.


35. Erectile dysfunction




L

• Tab. Sildenafil 25 mg 1 tablet I hour before intercourseDirection: Dispense such 10 tablets



• Check CVS status of patient• Check which other drugs are being taken.


36. Chronic simple glaucoma




L

• Pilocarpine (2%) eye drops tds × 1month• Timolol (0.5%) eye drops bd × 1month• Tab. Acetazolamide 250 mg bd × 1month

Revisit after 1 monthDirection: Dispense 1 eye drops of timolol and pilocarpine and 30 tablets of acetazolamide.



• Revisit earlier if any deterioration in vision or persistent headache is there.


37. Aphthous ulcer




L

• Tab. Vitamin B-complex 1 bd × 1 month• Tab Ferrous sulphate (60 mg elemental iron) 1 tds × 1 month• Tab Albendazole 400 mg single dose• Metronidazole cream for local application × 7days• Lignocaine (2%) viscous for local application × 7days

Direction to Pharmacist: Please dispense 60 tab. Vit B-complex, 90 tablets of ferroussulphate, 1 tab of albendazole 250 mg, one metronidazole cream and 1 lignocaine.



Exercises in class:

After going through solved examples of prescription for common diseases, students areadvised to solve the following:

Choose a P drug and write appropriate prescription in the following conditions:1. A 55-year-old farmer (Kulwant Singh), was admitted in emergency department with

irritation and watering of eyes, increased salivation, sweating, blurring of vision andabdominal pain. History revealed accidental exposure to heavy amount of an insecticide.

2. Tonometric examination of a 48-year-old Ram Singh patient showed raised intraocularpressure (55 mm of Hg). He was complaining of severe pain, redness in eye and nausea/vomiting and headache.

3. A female aged 38 years (Kamlesh Kaur) came with complains of easy fatigability,weakness, dizziness and soreness of the tongue. Investigations reported reducedhemoglobin level (6.5 gm/dl) and blood film reported megaloblastic cells.

4. A 26 years pregnant female (Nisha Agarwal) patient complained of headache andvisual disturbances in 2nd trimester. On examination edema of feet was present. HerBP was 160/130 mm of Hg. Urine examination reported albuminuria.

5. A 55 years Arun Kumar was brought to ICU with persistent severe chest pain for lastone hours. The pain persists at rest and was radiating to left shoulder. Pain is associatedwith vomiting and profuse sweating.

6. Ashok Kumar, 48-year-old male, complained of dyspnoea, cough, easy fatigability andswelling over lower limbs. His BP was 170/130 mm of Hg.

7. A 22-year-old, Anushka a medical student reported loss of sleep due to examinationstress for last two days.

8. Buta Singh, 55-year-old male, developed tremor, rigidity and disturbed gait followinghaloperidol therapy for last 1 month.

9. Anita Rani, 56-year-old female, complained of joint pain (small joints of fingers andtoes) and joint stiffness. He reported that stiffness was more in the early morning. Painincreases on movement of affected joint.

10. Kanta, a 45 years, fair, fatty female complained of sudden onset of pain in epigastricregion lasting for about 3 hours and some times upto 6 hours. A plain abdominalultrasonograph reported presence of gall stones.

11. A 35-year-old Rajesh Singh complained of purulent urethral discharge, dysuria andmeatal erythema. His blood smear showed leukocytosis and urethral swab culturereported neisseria gonococci.

12. A 28-year-old Kanta Kumari, complained of fever with chills, burning micturition,increased and frequency of urination. Microscopic examination of urine reported plentyof pus cells and epithelial cells.

13. A 20-year-old Sharad Gupta, complained of malaise, decreased appetite, itching allover body, abdominal discomfort and diarrhoea with mucus and blood for the last oneweek. Investigations revelaed high eosinophil count and stool examination reported,occult blood positive and presence of ova of both roundworm and hookworm.


14. A 20-year-old female (Sunayna), is known to vomit during journey. She approachedyou for help. She wants to travel for about 4 hours in bus from Chandigarh to Shimla.

15. A 35-year-old Amar Kaur, presented with history of palpitation, weight loss, increasedappetite and swelling of the thyroid region for past 2 months. On clinical examinationthere were tremors in hands and investigations revealed raised serum T3 and T4 levels.

16. A 23-year-old female Charu, is recently getting married. She has come to you to takeadvice for contraception.

Irrational prescribing is seen every where (developing and developed countries), at all levels(senior consultants and junior students) and in all categories (specialists, superspecialists).As drug treatment is the essence of therapeutics, it become extremely important to auditprescriptions. Wrong prescriptions can be fatal. With consumer protection Act (CPA) inforce, you need to be careful when writing prescriptions.

Common errors in prescription writing

• Dosage form: Tab, cap, inj missing, hence difficult to dispense. Sometimes pharmacist/patient decides on their own what can be the dosage form. Suppose patient is prescribedan injection for an spreading infection, but he takes only tablets or a patient is prescribedtablet to decrease his BP, but he takes injection.

• Quantity: This is very common. You reach a pharmacist/chemist, give him prescription,but he asks which one you want 250 mg or 500 mg. Missing quantity can play havocwith lives of patients. Similarly error in dose when prescribing to children can lead toserious adverse effects. Sometimes you will find a prescription for an amount thatdoesn't exist. Do not assume anything, always write on prescription.

• Length of therapy: This is a common error with most of the prescriptions. The result isthat most of patients decide on their own when to stop or when to restart. This leads toirrational use especially with antimicrobials. With antimicrobials you need to be veryspecific about duration.

• Patient allergies: Usually a missing part on prescriptions.• Date: Very important to track back when medication was started, how much time has

passed and to refill prescription.• Signature: Missing on prescriptions. This mistake is now increasing, may be because of

CPA.• Registration number: Again a serious omission.• Directions: A busy physician will not explain or explain in such a hurry that the patient

does not understand or understand in incorrect way, e.g. a lady took methotrexatedaily which was to be taken weekly. She died because of severe bone marrowsuppression.

C H A P T E R

Critical Evaluation of Prescription(Audit of Prescriptions)18


• An error in reading the prescription by the pharmacist so that the wrong drug or doseis dispensed, e.g. cotrimoxazole-cotrimazole.

• Substitution: Usually physician does not write substitution in case drug is not available.It is only when you go back ant tell them that a particular drug is not available then he/she will write substitution.

• Bad handwriting leading to confusion of drug name, e.g. similar names, e.g.Acetazolamide and acetohexamide

• Drugs may be administered incorrectly, especially in institutions. A drug may be givento the wrong patient, at the wrong time or by the wrong route. Certain drugs must begiven slowly when given IV, and some drugs cannot be given simultaneously.

• Use of expired/outdated drugs is common. For some drugs (e.g. aspirin, tetracycline)risk of harm is great when outdated drug is used.

• Most commonly, drug error results from a patient's confusion about how to take drugs.

Tips for avoiding prescribing errors

a) Keep all blank prescription pads in a safe placeb) Minimizing the number of prescription pads in usec) Write in inkd) Write out the amount prescribed in addition to the numerical numbere) Avoid large quantitiesf) Only use prescription pads for prescriptionsg) Don't sign prescriptions in advanceh) Put only one prescription on a blank prescription form.

Precautions for controlled or unscheduled medications, e.g. morphine

a) Put the patient's diagnosis or the purpose of therapy on the prescriptionb) Printc) Include the patient's age and weight if relevant on the prescriptiond) Use the metric system unless dealing with unitse) Avoid uncommon abbreviationsf) Be consistentg) Sign your own prescriptionsh) Inform patient about medicationsi) Never leave a decimal point naked.

Prescription audit is part of medical audit. Medical audit is an objective and systematicway of evaluating the quality of care provided by physicians. It is conducted mainly in thehospitals, assesses only the technical aspects of medical care, and often falls short in itsobjectives.

Critical Evaluation of Prescription (Audit of Prescriptions) 159

Parameters of Prescription Audit :

1. Format of the prescription: Superscription, Inscription, Subscription, Transcription-complete/incomplete.

2. Whether the diagnosis is recorded? Final or provisional.3. Number of drugs prescribed.4. Whether drugs prescribed are by official/pharmacological or brand names.5. Choice of drugs for the given condition.

First choice/Second choice/Third choice/Placebo.6. Unnecessary/Irrational/Hazardous drugs.

Unnecessary drug or injection: means a category of drugs or formulations notrecommended for that particular condition in the standard text books. However, rationalalternatives should not be considered unnecessary.

Irrational drug or drug combinations, i.e. a drug or drug combination notrecommended in the standard text books of pharmacology or other reputed scientificmedical literature.Hazardous drugs: Drugs listed under the heading 'Banned and bannable drugs'.

7. Dose regime: Dosage form, dose, frequency and duration of treatment.8. Prescription cost is calculated using the prevailing prices of drugs given in the latest

volumes of Indian Drug Review, MIMS, CIMS or Drug Index.9. Status of the prescription: Rational/Semirational/Irrational.

10. Date.11. Signature of doctor, registration number.12. Patient's particulars are right.

Tips for writing a good prescription

1. Write or print the prescription legibly. If the physician has poor writing, preprinted ortyped prescriptions may help.

2. Spell the name(s) of the drug(s) correctly, especially in view of the number of "look-alikes" and "sound-alikes." Get in the habit of writing both the trade and generic names.

3. Write the prescription in proper English grammar. Latin abbreviations such as qid maybe interpreted as qd or od and are no longer recommended. Avoid phrases such as "asdirected" or "as needed." Specify exact times to be taken: daytime hours, around theclock and relationship to meals.

4. Careful use of decimal points to avoid ambiguity:a. Avoid unnecessary decimal points: 5 ml instead of 5.0 ml to avoid possible

misinterpretation of 5.0 = 50b. Always zero prefix decimals: For example 0.5 instead of .5 to avoid

misinterpretation with .5 = 5


c. Never have trailing zeros on decimals: For example use 0.5 instead of .50 to avoidmisinterpretation with .50 = 50

d. Avoid decimals altogether by changing the units: 0.5 g = 500 mg.5. Directions should be written out in full in English.6. Quantities can be given directly or implied by the frequency and duration of the

directions.7. Where the directions are "as needed" the quantity should always be specified8. Where possible, usage directions should specify times (7 am, 3 pm, 11 pm) rather than

simply frequency (3 times a day) and especially relationship to meals for orally consumedmedication

9. Avoid unspecified or "as needed" instructions-limits and indicators should be provided,e.g. "every 3 hours pain"

10. For refills, minimum duration between repeats and number of repeats should bespecified

11. Provide the indication for all prescriptions even when obvious to the prescriber so thatthe pharmacist may identify possible errors

12. Avoid non-standardized units such as "teaspoons" or "tablespoons"13. Write out numbers as words and numerals ("dispense #30 (thirty)") as in a bank draft or

cheque.

Exercises:

Critically analyse following prescription and rewrite the correct prescription.

Example 1:

L

• Injection L-Dopa l0 mg IV Stat• Tab B complex 1 tab twice daily• Tab Benzhexol hydrochloride 2-5 mg. initially and then dose increased to 300

mg daily in divided doses.Dr ABC

Reg No. 456

Comments:

1. Format of prescription is not proper, i.e. superscription is not given. Further the durationof drugs is not specified.

2. In the Inscription : Route and dose of L-Dopa mentioned is wrong.3. Pyridoxine which is present in B complex tablet is dopa decarboxylase enzyme stimulator,

so that very little amount of dopamine will reach the brain, further deteriorating theclinical condition.

Critical Evaluation of Prescription (Audit of Prescriptions) 161

4. Tab Benzhexol is increased to only 10-50 mg/day and also in divided doses. Such highdoses can lead to toxic anticholinergic side effects.

Example 2: Comment on the following prescription:Date 12/9/88

Name: Mr Kulwant SinghAge: 47Sex: M Occupation: Business executive, Address: Mahim (Bombay)Diagnosis: Status asthmaticus

L Tab Cetrizine 10 mg statInjection pethidine 10 mg LM. 6 hourlyTab salbutamol 20 mg tds.Injection adrenaline hydrochloride 1:1000 IV, sos

Comments: (write your comments)

Drug interactions deserve a special mention because interactions are one of the leadingcauses of the adverse drug effects. It is estimated that drug-drug interactions representfrom 3 to 5% of all in hospital medication errors. Drug interactions are also an importantcause of patient visits to emergency department of hospitals.

Drug interactions are often recognized only when serious toxicity occurs. Sufficientknowledge regarding effective and safe use of drugs is possible only if there is adequateknowledge understanding of pharmacokinetic and pharmacodynamic of drugs. This willenable physicians to select proper drug combinations. A number of drugs have beenwithdrawn from market because of drug interactions. Few important ones are:

• Terfenadine February 1998• Mibefradil June 1998• Astemizole July 1999• Cisapride January 2000.

Hence, drug interactions between drugs represent a major concern for the pharmaceuticalindustry, for drug regulatory agencies and clinically for health care professionals and theirpatients. Drug interactions may be synergistic or antagonistic, desired or undesired, beneficialor harmful.

Drug interaction can occur at 3 levels (Table 19.1):

A. Pharmaceutical: These are interactions before administration of drugs. These interactionscan occur in vitro (IV fluid, syringe, vial-outside the body) due to chemical interaction.Example: Heparin should not be mixed with tetracyclines, penicillins and hydrocortisone

in the same syringe. Inactivation of these drugs may occur.When phenytoin is added to solutions of dextrose, a precipitate can and the phenytoin

falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longeravailable to control convulsions. Amphotericin is still used widely as a urinary bladderperfusion to treat aggressive fungal infections. If it is administered in saline, the drugprecipitates and can erode through the bladder wall if not removed. The clinical presentationof such cases is an acute abdomen due to perforation of the bladder. Lastly, it is recommended

C H A P T E R

Problem Based Drug Interactions19

Problem Based Drug Interactions 163

that aminoglycosides should not be mixed in IV fluids with betalactam antibiotics (penicillins,cephalosporins). This can markedly reduce antibiotic activity.

Table 19.1. Sites of adverse drug interaction

Site MechanismIn vitro Chemical interactionOral Altered bioavailabilityIntestine Altered absorptionPlasma Protein binding displacement reactionsLiver Enzyme induction/inhibitionKidney Reabsorption, secretion, altered pHReceptor Competition/antagonism

B. Pharmacokinetic: Usually the cause of drug interactions is an alteration in pharmacokineticproperties of one drug by another drug. Pharmacokinetic properties can be altered duringabsorption, distribution, metabolism or excretion of drugs.1. AbsorptionDrug interactions can occur during absorption of drugs in the gastrointestinal Tract.Examples:

a) Aluminum-containing medicines such as sucralfate and antacids to reduce theabsorption of expensive and potentially life-saving antibiotics like ciprofloxacinand azithromycin.

b) Women taking iron supplements often do not consider them as medicines andshould be specifically questioned about whether they are taking iron if they areto be prescribed a quinolone or azithromycin.

c) Drugs such as ketoconazole and delavirdine require an acidic environment to bein the unionised form that is preferentially absorbed. Solubility is drasticallyreduced in neutral or basic medications such as omeprazole, lansoprazole or H2-antagonists that raise the stomach pH.

The following drugs/food products, i.e.• Sucralfate, some milk products, antacids and oral iron preparations• Omeprazole, lansoprazole and H2-antagonists• Didanosine (given as a buffered tablet)• Cholestyramine.

CAN

• Block absorption of quinolones, tetracycline and azithromycin• Reduce absorption of ketoconazole, delavirdine• Reduces ketoconazole absorption• Binds raloxifene, thyroid hormone and digoxin respectively.


Distribution

Displacement of highly protein bound drug (warfarin) by another drug (e.g. NSAIDs) couldlead to an increase in the free plasma concentration of first drug and an adverse effect(bleeding tendency). But most of the drug interactions due to plasma protein displacementreactions are not clinically significant, because the displaced drug (free drug) is eliminatedfaster, i.e. more free drug is now available to kidneys for excretion.

Metabolism

Drug interactions involving metabolism are the most important drug interactions clinically.Some important preventable drug interactions are due to their effects on drug metabolizingenzymes, resulting in either inhibition (reduced activity) of the enzyme or induction (increasedactivity) of the enzyme. There are many potential consequences of changes in drug metabolismfor a given drug. It is made more complex by the fact that there are multiple pathways ofmetabolism for many drugs.

The major group of enzymes in the liver that metabolize drugs can be isolated in asubcellular fraction termed the microsomes. The largest and most important of these enzymesare the cytochrome P450(CYP450) family of enzymes, which mediate phase I reactions. SincePhase II reactions generally result in conjugation of a drug to a water-soluble group like asugar, peptide (glutathione) or sulfur group, and because there is a large excess of thesegroups in well nourished cells, these reactions are rarely rate-limiting. Thus, they are rarelyinvolved in drug interactions. In contrast, the Phase I reactions carried out by cytochromeP450 enzymes, flavin monooxygenases and reductases are more frequently rate limiting.These are the target of clinically significant drug interactions, such as the inhibition ofcyclosporine metabolism by erythromycin.

Although there are other enzyme systems that perform similar functions, the cytochromeP450 system is important because it is involved in most clinically relevant metabolic druginteractions. Six CYP450 isoforms are clinically important. These days drug interactions canbe predicted if we know by which isoenzyme it is metabolized. The following Table 19.2 canhelp to predict mechanism of interaction of few important drugs.


Table 19.2: Cytochrome P450 isoenzymes, their substrates, inhibitors and inducers

Isoenzyme Substrates Inhibitors Inducers

3A Most calcium channel blockers Ketoconazole CarbamazepineMost benzodiazepines Fluconazole RifampicinMost HIV protease inhibitors Cimetidine RifabutinStatins Erythromycin RitonavirCyclosporine Troleandomycin St. John's wort

2D6 Codeine SSRIs DexamethasoneMany tricyclic antidepressants Haloperidol Rifampicin

Amiodarone

2C9 Most NSAIDs (including COX-2) Fluconazole RifampicinS-warfarin (the active form) Fluvastatin SecobarbitalPhenytoin Isoniazid

Sulfamethoxazole

2C19 Diazepam Omeprazole CarbamazepinePhenytoin Isoniazid pentobarbitalOmeprazole Ketoconazole Rifampicin

1A2 Theophylline Many Brussel sproutsImipramine fluoroquinolone Char-grilled meatPropranolol antibiotics OmeprazoleClozapine Fluvoxamine Tobacco

INHIBITION (FIG. 19.1)

Warfarin is anticoagulant and cimetidine is used in treatment of peptic ulcers.

Fig. 19.1: Drug interaction by inhibition of metabolism


INDUCTION (FIG. 19.2)

Rifampicin is an antitubercular drug.

Excretion

Drugs can compete for excretion, hence, there can be inhibition of excretion of one of thedrugs. This leads to increased concentration, prolonged action or toxicity.

Examples:• Sulfinpyrazone inhibits excretion of tolbutamide and increases its toxicity.• Probenecid inhibits excretion of penicillins and increases their duration of action.

C. Pharmacodynamic: Pharmacodynamic interaction occurs at site of action.Examples:a) The combined inhibitory effects of propranolol and verapamil or diltiazem on

atrioventricular node represent potential site of an adverse interaction.b) Alteration of compensatory mechanisms could also lead to such interactions. Beta

blockers prolong the recovery from hypoglycemic effects of antidiabetics.c) Drugs with sedative potential can aggravate sedation when given together especially

in the elderly, e.g. tricyclic antidepressants and antiepileptics.

Effects of drug interactions

1. Diminished therapeutic response2. Enhanced side effects3. Relative overdosage toxicity4. Intensified allergic reactions5. Increased secondary effects6. Severe idiosyncratic reactions7. Greater teratogenicity8. Additive addiction potential9. Miscellaneous.

Fig. 19.2: Drug interaction by induction of metabolism


Food-drug interactions

Several drugs are known to interact with foods.a) Reduced absorption of tetracycline when taken with milk products. The chelation of

tetracycline by calcium prevents it from being absorbed from the intestines.b) Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage

requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients shouldbe counseled to maintain a consistent diet during warfarin therapy.

c) Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolismof many drugs. This was first described for felodipine but has now been observedwith several drugs. This interaction can lead to reduced clearance and higher bloodlevels when the drugs are taken simultaneously with grapefruit juice. Grapefruit juice(GFJ) is often taken at breakfast in the western countries when drugs are also oftentaken. GFJ contains bioflavonoids mainly naringin and furacoumarin which causemechanism based inhibition of presystemic elimination of a number of drugs and increasetheir bioavailability and toxicity.

d) Cheese reaction (hyperadrenergic crisis) can occur when a patient on MAO inhibitorsconsumes cheese or cheese containing preparations, e.g. cheese tomato. This is becauseof tyramine present in cheese that leads to release of catecholamines in the body. Sincethe patient is on MAO inhibitors there is already decreased metabolism of catecholaminesin the body, hence, there is exaggerated response.

It is impossible to remember all of the drug interactions that can occur. It is, therefore,important to develop a stepwise approach to prevent drug interactions. First, taking agood medication history is essential. The following stepwise approach can help healthcare practitioners to develop good habits when performing this task.

1. Take a medication history2. Remember high risk patients

a. Any patient taking 2 medicationsb. Anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc.

3. Check pocket reference4. Consult pharmacists/drug info specialists5. Check up-to-date computer program.

OBJECTIVES

At the end of this session, a student shall be able to:1. Identify type of drug interaction in a given problem2. Explain mechanism of drug interaction3. Provide preventive and curative treatment for the interaction.


Exercises in class: Problem based exercises can be designed for this activity. These aregiven in the form of a statement of a case for class exercises. Students are divided intobatches. Each batch has 5-6 students. In examination, these can be given on cards and a shortviva can be conducted. They can also be given this activity with prescription writing as isdone usually. A short viva can be held on the answer written by the student. This can bedone in labs where students are doing experiments.

Examples of problem based drug interactions:1. A 35-year-male was prescribed astemizole and erythromycin together for sore throat.

Next day he was admitted in cardiac casualty with arrhythmias.a) What happened to the patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

2. A 35-year-male on taking MAO inhibitors. He consumed cheese tomato during awedding party of his friend. Next day he was admitted in casualty with a BP of 190/110 mm of Hg.a) Why his BP increased?b) How this can be prevented?c) How this can be treated?


3. A 26-year-female was using oral contraceptive pill for the last 2 years. He wasprescribed antitubercular drugs for the tuberculosis. She became pregnant after 2months.a) Why she became pregnant even when she was on oral contraceptives?b) How this can be prevented?c) Which other drugs can produce similar situation?

4. A 4-year-old child was prescribed iron syrup for anemia (Hb 9.5 gm). To avoid badtaste, his mother used to give milk with iron syrup. After 4 months of iron therapythe Hb was still 9.5 gm.a) Why there was no increase in Hb?b) How this can be prevented?


5. A 30-year-male patient was stable with warfarin therapy. He was prescribed cimetidine.After 1 week he was admitted to hospital with intracranial bleeding.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

6. A 40-year-male epileptic patient was stable with phenytoin. He was prescribedketoconazole. After 1 week he was admitted to hospital with slurred speech anddizziness.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


7. A 50-year-male was taking azathioprine for the last 2 months. He was prescribedallopurinol for gout. After 1 week he was admitted to hospital with bleeding fromgums.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

8. A 30-year-lady was taking oral contraceptives for the last 1 year. She was prescribedampicillin for an infection. She became pregnant after 1 month inspite of taking oralcontraceptives regularly.a) What she became pregnant?b) Which other drugs can lead to similar situation?c) How this can be prevented?


9. A cardiac CHF patient was taking metoprolol. He was prescribed verapamil by anothercardiologist without asking what he was already taking. Next day patient wasadmitted in ICCU with severe bradycardia.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

10. A 45-year-old male hypertensive patient was stable on metoprolol for the last oneyear. He was prescribed diclofenac for joint pains. After 2 months his BP increasedeven when he was taking metoprolol regularly.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


11. A 45-year-old male epileptic patient was stable on carbamazepine for the last oneyear. He was prescribed clarithromycin for throat infection. After 1 month hecomplained of diplopia and ataxia.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

12. A 55-year-old male patient was stable on lithium for the last 6 months. He wasprescribed chlorthiazide for CHF. After 1 month his complained of persistent nausea/vomiting and blurred vision.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


13. A 45-year-old male hypertensive patient was stable on enalapril for the last one year.He was prescribed spironolactone for CHF. After 5 days he complained of palpitationsand restlessness.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

14. A 34-year-old male consumed alcohol during a wedding party. He felt abdominaldiscomfort in the morning and took metronidazole. In the evening he developed arash on the body, throbbing headache and respiratory difficulty and nausea.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


15. A 65-year-old male Parkinsonian patient was stable on L-dopa last one year. He wasprescribed pyridoxine. After 1 month his condition deteriorated.a) What happened to patient?b) How this can be prevented?

16. A 40-year-old male diabetic patient was stable on chlorpropamide for the last oneyear. He was prescribed probenecid. After 1 month he was admitted in ICU with inunconscious state.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


17. A 40-year-old male diabetic patient was stable on gliclazide for the last one year. Hewas prescribed chlorthiazide for hypertension. After one month his fasting bloodsugar increased to 180 mg/dl.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

18. A 45-year-old male diabetic patient was stable on glibenclamide for the last 6 months.He was prescribed propranolol for migraine. After one week he was admitted in ICUwith in unconscious state.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?


19. A 52-year-old male was taking nitrates for angina for the last one year. He wasprescribed sildenafil for erectile dysfunction. On next day, at 11pm he was admittedin ICU with aggravation of angina.a) What happened to patient?b) Which other drugs can lead to similar situation?c) How this can be prevented?

It took many decades before the deleterious effects of aspirin on the gastro-intestinal tractbecame apparent and almost as long before it was recognised that the protracted abuse ofphenacetin could produce renal papillary necrosis; 35 years elapsed before it became clearthat amidopyrine could cause agranulocytosis; and several years before the association ofphocomelia with thalidomide became obvious. The recent withdrawal of a very successfuldrug 'Rofecoxib' highlights the importance of ADR monitoring. Hence, systematic collectionof information on adverse drug reactions is essential to provide much needed informationregarding patients at risk, drug interactions and adverse reactions to new drugs not detectedin studies conducted before marketing of the drug. The ADR monitoring is also known aspharmacovigilance. WHO defines pharmacovigilance as "the science and activities relatingto the detection, assessment, understanding and prevention of ADRs or any other, medicine-related problem". Pharmacovigilance plays a major role in pharmacotherapy decision-making,be it individual, regional, national or international.

What is an adverse drug reaction?

1. Adverse reaction: A response to a drug which is noxious and unintended, and whichoccurs at doses normally used in man for the prophylaxis, diagnosis or therapy ofdisease or modifying a physiological function.

2. Side effects: Any unintended effect of a pharmaceutical product occurring at dosesnormally used in man which is related to pharmacological properties of the drug.

3. Toxic effect: A direct action of the drug, often at high dose damaging cells, e.g. liverdamage from paracetamol overdose.

Types of ADRs:

A. (Augmented)—directly related to pharmacolgical action of drug, e.g. hypokalaemiawith digoxin

B. (Bizarre)—idiosyncratic and genetically determined, e.g. acute intermittent porphyriadue to sulphonamides in patients with G-6 PD deficiency.

C. (Continues use)—associated with long term use of drugs tardive dyskinesia withneuroleptics.

C H A P T E R

Adverse Drug Reaction (ADR)Monitoring

20

Adverse Drug Reaction (ADR) Monitoring 179

D. (Delayed)—Teratogenicity or carcinogenicity, e.g. phenytoin-teratogenicityE. (End of dose)—abrupt stoppage of drug, e.g. beta blockers, corticosteroids.

Severity:

Minor : no treatment/antidote or hospitalization required. Drug is continued.Moderate : change in drug therapy required, specific treatment, increase in

hospitalization by at least for one day.Severe : potentially life threatening, caused permanent damage or require intensive

medical care.Lethal : directly or indirectly contributed to death of the patient.Causality: It is determination that the event is due to drug and that there is no other

alternative explanation for it.The Naranjo algorithm is one means to assign the likelihood of a drug causing an untoward

event. This simple ten-item questionnaire uses specifically assigned numerical values to arriveat an overall total score for probability assignment. Probability is assigned via a score termed:

1. definite2. probable3. possible or4. doubtful.

Advantages of the Naranjo algorithm include its ease and widespread use. However,tests of its reliability as a tool for serious cases of adverse drug reactions have not beenperformed. The Naranjo algorithm can be used to assess the likelihood that a change inclinical status is the result of an ADR rather than the result of other factors such as progressionof disease. Answer each of the ten items in the assessment and enter the value of the answerin the column labeled Score. Sum the scores of the ten items to determine the total score, andapply the interpretation rules that appear at the bottom of the page (available at http://mqa.dhs.state.tx.us/QMWeb/MedSim/Naranjo.htm).

Health professionals are in the best position to report on suspected ADRs observed intheir every day patient care. All healthcare providers (physicians, pharmacists, nurses, dentistsand others) should report ADRs as part of their professional responsibility, even if they aredoubtful about the precise relationship with the given medication. You can reduce the sufferingand save thousands of patients lives by doing this. ADR monitoring is to help ensure thatpatients obtain safe and efficacious products. The results of ADR monitoring have also avery important educational value. The aim is to obtain data of scientific quality for rationaland safe use of drugs.

Several methods used for collection of information on adverse reactions to drugs havebeen reported in literature. The main methods are as follows:


A. Premarketing Clinical trialsBefore marketing of drug, animal studies and human trials (Phase I, II, III and IV) are doneto detect ADRs. Animal studies include acute, subacute, chronic toxicity studies and specializedtoxicity studies. But, it has been proved again and again that tests in animals are insufficientto predict human safety. Clinical trial done in humans to look for ADRs, but number ofpatients is limited and there trials detect ADR with an incidence of 1:200 only. The declaredpurpose of 'pre-marketing' clinical trials is to discover:

• If a drug works and how well• If it has any harmful effects• If there is potential harm how serious is it and how does it weigh against the benefits.

There are concerns about these premarketing studies because of two reasons:1. Before marketing drugs are evaluated for toxicity in animals. These studies produce an

overall picture of toxicology of the drug and indicate organs which are at highest riskof damage. However, it is difficult to draw direct parallels between toxicity in animalmodels and potential risks to man.

2. After animal toxicity studies drug undergoes clinical trials in humans. For a new drugpre-marketing clinical trials are generally carried out in less than 3000 patients. Type Areactions can thus be identified. Subgroups at particular risks are occasionally identified.However, type B reactions with incidence of 1:1000 are generally missed.

By the time of licensing, exposure of less than 5000 human subjects to a drug allows only themore common ADR to be detected. At least 30,000 people need to be treated with a drug tobe sure that you do not miss at least one patient with an ADR which has an incidence of 1 in10,000 exposed individuals. Susceptible population like elderly, children, lactating mothersare unlikely to be included in these studies. However, within a short time after entering themarket, the drug may be administered to several million patients. That means that for drugsthat cause rare toxicity, their toxicity can only be detected after, not before, marketing.

So, the safety profile for new drugs that come into the market is never totally definedbecause new drugs are studied only in relatively small and homogenous patient populations.The complete safety profile of a new drug will be defined only after it has been approvedand is in use in the market.

Clinical trials generally do tell a good deal about how well a drug works for a defineddisease and what potential harm it may cause. However, they provide no information forlarger populations with different characteristics from the trial group—age, gender, state ofhealth, ethnic origin and so on.

Therefore, for many medicines and particularly new, complex products, safety monitoringdoes not stop at the manufacturing stage, it must be followed by careful patient monitoringand by further scientific data collection. This aspect of drug monitoring is called post-marketing

B. Postmarketing methodsIn these methods ADRs are observed epidemiologically under conditions of normal use inthe community. Thus, post-marketing surveillance is important to permit detection of less


common, but sometimes very serious ADRs. Therefore, health professionals worldwideshould report on ADRs as it can save lives of their patients and others. The various methodsused are:

Case Reports: This has the advantage of speed and sensitivity, however, the reportsneed to be validated. Case reports have been the first means by which some of the type Breactions have been identified, e.g. Practolol induced dermatitis and keratoconjunctivitis,benoxaprofen induced photosensitivity which is dose related.

Cohort Studies: Cohort of patients receiving a drug under investigation are prospectivelystudied and compared with control population. The cohort studies are excellent methods ofquantifying ADRs, e.g. Royal College of General Practitioner's oral contraceptive study. Thecontraceptive study quantified the risk of cardiovascular diseases and excess mortality dueto oral contraceptives. However, cohort studies are expensive and slow and do notnecessarily, prove causal link.

Prescription event monitoring: Patients who have received specific drugs are identifiedfrom prescription (in UK prescription pricing authority). The general practitioner is thenasked to report any adverse event detected. The method has the advantage of enhancingdetection of new adverse reactions and incidence of event can be calculated. Prescriptionevent monitoring has identified deafness associated with enalapril.

Case control studies (Retrospective): In this prospective method patients who have theidentified disease are matched with a control group who have similar potentially confoundingfactors but who do not have the disease. The drug histories are then compared. The associationbetween aspirin and Reye's syndrome was confirmed using this method and resulted inrecommending removal of the pediatric formulation of aspirin from the market.

Spontaneous Reporting-Yellow card system: Spontaneous reporting of ADRs to a centralbody was started in UK in 1964. However, it is estimated that out of even serious and fatalADRs, only 10% are reported so there is gross underreporting. Reporting may be biased andlimited to serious ADRs. Advantages of this system are that numbers are large, personaldetails are kept confidential and early alerts are available. The yellow card system identifiedthe risk of urticaria and confirmed the occurrence of cough due to captopril and enalapril. Itis recommended that a physician for newer drugs a physician must report all suspectedADRs and for established drugs, he should report all serious suspected ADRs. Advantagesof this system are that it acts as early alerting system.

1. Record linkage: The health records of a defined population are correlated with data onthe use of drugs. This technique is not very sensitive compared to other methods butcan generate hypotheses for further investigation. This method covers large samplesize and there is no recall bias.

Phase-IV clinical studies (Post Marketing surveillance): Post marketing surveillance (PMS)is a regulatory requirement and done for all the drugs after marketing. This surveillanceprovides information of long term safety of drug, safety in extremes of ages, safety in specialpopulation, e.g. pregnant and lactating females. Severe ADRs may lead to withdrawal ofdrugs. In India it is now mandatory to submit results of postmarketing surveillance within 2


years of marketing the drug. Sometimes after this surveillance warnings on ADRs are insertedon labels of drugs.

This monitoring can be done as regional or national level. Other way to monitor is tomonitor disease, rather than drugs, especially in case of Type B bizarre ADRs, that will helpin identifying many serious adverse effects in different subspecialties of medicine and surgery,e.g. carcinoma in young females showed unusual clear cell carcinoma like histopathologicalfeatures, only in these mothers who received stilbesterol during pregnancy, similarly biopsyrevealed pseudomembranous colitis in those treated with tetracycline lead to the path ofdrugs induced adverse effect in the gastroenterology department, while ophthalmicdepartment could observe a different kind of dry eye in those treated with controlled carestudies. Thus, orientation and participation of physicians can help identifying the new drugsreaction, as well as minimizing the adverse effect of dugs through regularly updating theirown knowledge.

WHO promotes drug safety through its International Drug Monitoring Programme, whichbegan to operate in 1968. Initially a pilot project in 10 countries with established nationalreporting systems for ADRs, the network has expanded significantly as more countriesworldwide develop national pharmacovigilance centers for the recording of ADRs. Currently,81 countries are members in the programme.

The Uppsala Monitoring Centre (UMC, WHO), Sweden is maintaining the internationaldatabase of adverse drug reaction (ADR) reports received from several National Centers.By June 2006, the database had 3.67 million adverse drug reaction reports. Vigibase online(web based) system is used for submission of ADR reports. Although, India is participatingin this programme, its contribution to UMC database is very little. This is essentially due tothe absence of a vibrant ADR monitoring system and also the lack of a reporting cultureamong health care workers.

Special need for ADR monitoring in India

Due to huge population, unorganized health sector, use of alternative medicine there is anurgent need for monitoring ADRs in India.

There is variation in ADRs between different countries on account of variation in genetic,environmental, dietary factors and disease patterns and drug used. The reported incidenceof drug induced hepatotoxicity is low in India compared to developed countries. The commondrugs incriminated were antitubercular drugs in India as opposed to halothane reported tobe the commonest in the Danish registry.

In India, in rural areas, over 50% of children are malnourished and 45-70% of populationis iron deficient, which may affect incidence of ADR. There are very few functioning ADRcenters in India. Adequate information is not available even on adverse reactions to olddrugs. There is lack of data on ADR in specialised populations like pregnant, women andchildren.

Due to the increased prevalence of certain diseases in this country certain drugs are usedin a population where they are not recommended, e.g. Ciprofloxacin in children. Many patientstend to use modern drugs along with traditional remedies. Interactions that can result could


lead to adverse reaction and loss of efficacy. Traditional drugs are considered safe but maynot necessarily be safe.

Organization of ADR monitoring system in India

Appreciating the importance and benefits of pharmacovigilance, Central Drugs StandardControl Organization (CDSCO), Ministry of Health and Family Welfare, Govt. of Indialaunched the National Pharmacovigilance Programme (NPP) in November, 2004. It is largelybased on the recommendations made in the WHO document titled "Safety monitoring ofmedicinal products-guidelines for setting up and running a pharmacovigilance centre".

The immediate aim of NPP is to foster the culture of ADR notification by health careworkers in India. Subsequently, it seeks to generate broad based ADR data on the Indianpopulation and share this with WHO database. This would ensure optimum safety of drugsin the Indian market.

Under this programme, the whole country is divided into zones and regions foroperational efficiency. CDSCO, New Delhi is at the top of the hierarchy followed by twozonal pharmacovigilance centers, Seth GS Medical College, Mumbai and AIIMS, New Delhi.There are 5 regional pharmacovigilance centers located at Kolkata (IPGMR-SSKM Hospitals),Mumbai (TN Medical College & BYL Nair Charitable Hospital), Nagpur (Indira GandhiMedical College), New Delhi (Lady Hardinge Medical College) and Pondicherry (JIPMER).Twenty eight peripheral centers, spread country-wide, are attached to their nearest peripheralcenters. ADR reports can be sent only by health care workers (doctors including dentists,nurses, pharmacists) to any one of the nearest pharmacovigilance centre. The full list ofcenters is available at CDSCO website (www.cdsco.nic.in). ADR reports sent by lay publicare not acceptable. Data received at the peripheral centers are forwarded to the respectiveregional centers which will carry out the causality analysis. This information will be forwardedto the zonal centers. From there the data will be forwarded to the CDSCO and UMC database.The ADR form for reporting ADRs in India is given in Appendix-III.

The various factors contribute to poor ADR reporting from India. Doctors feel that theyare trained to treat patients and not monitor ADRs. There is no guarantee of confidentialityof a reported ADR by a doctor and government has no effective machinery to monitorADRs. Patient communities can not report an ADR and population is not educated aboutADRs and interprets it as doctor's negligence.

How to recognize ADRs?

Since ADRs may occur through the same physiological and pathological pathways as differentdiseases, they are difficult and sometimes impossible to distinguish. However, the followingstep-wise approach may be helpful in assessing possible drug-related ADRs:

1. Ensure that the medicine ordered is the medicine received and actually taken by thepatient at the dose advised.

2. Verify that the onset of the suspected ADR was after the drug was taken, not beforeand discuss carefully the observation made by the patient.


3. Determine the time interval between the beginning of drug treatment and the onset ofthe event.

4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose andmonitor the patient's status. If appropriate, restart the drug treatment and monitorrecurrence of any adverse events (dechallenge and rechallenge).

5. Analyse the alternative causes (other than the drug) that could on their own havecaused the reaction.

6. Use relevant up-to-date literature and personal experience as a health professional ondrugs and their ADRs and verify if there are previous conclusive reports on this reaction.The National Pharmacovigilance Centre and Drug Information Centers are veryimportant resources for obtaining information on ADR. The manufacturer of the drugcan also be a resource to consult.

7. Report any suspected ADR to the person nominated for ADR reporting in the hospitalor directly to the National ADR Centre.

What should be reported?

• For "new" drugs - report all suspected reactions, including minor ones. (In many countriesdrugs are still considered "new" up to five years after marketing authorization)

• For established or well-known drugs - report all serious or unexpected (unusual)suspected ADRs

• All life threatening and serious adverse effects• Report all suspected ADRs associated with drug-drug, drug-food or drug-food

supplements (including herbal and complementary products) interactions• Report ADRs in special fields of interest such as drug abuse and drug use in newborns,

pregnancy and during lactation• All reactions to vaccines, report ADRs occurring from overdose or medication error• All drug interactions.

Thus, report all suspected adverse reactions that you consider of clinical importance assoon as possible!

How to report ADRs?

ADR reporting usually occurs retrospectively. Local case report forms (CRF) should beobtained from the National Drug Regulatory Authority. Some countries have included CRFin their National Formularies (British National Formulary, Formularies of South Africa,Zimbabwe, etc.). There are different Case Report Forms in different countries. The ADRreporting form for India is attached as Appendix I. Send filled form to regional centre. Inany case of doubt, you may send this form to the National Pharmacovigilance Centre at:Central Drugs Standard Control Organization, Directorate General of Health Services,Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi-110 011. All forms haveat least four sections which should be completed.


Sample ADR format

1. Patient information• Patient identifier • Age at time of event or date of birth • Gender • Weight

2. Adverse event or product• Problem date of event date of this report

• Description of event or problem

• Relevant tests/laboratory data (if available)• Other relevant patient information/history• Outcomes attributed to adverse event

3. Suspected medication(s):• Name (INN and brand name) dose frequency route used

• Therapy date• Diagnosis for use• Event abated after use stopped or dose reduced• Batch number expiration date

• Event reappeared after• Reintroduction of the treatment• Concomitant medical products and therapy dates

4. Reporter• Name, address and telephone number• Specialty and occupation

OBJECTIVES

At the end of the practical group work the student shall be able to:1. Appreciate the importance of ADR monitoring2. Enumerate methods used for ADR monitoring


3. Identify which adverse effects should be reported4. Find out severity and causality5. Fill ADR monitoring form6. Report an ADR to a monitoring centre.

Exercises in class:

Simulated cases can be given for exercises:The form in Appendix II can be given as exercise to students. The students are divided

into batches and sent to hospital to investigate and report ADR on preselcted cases. Theinformation collected can be discussed in a larger group explaining the importance of allparameters of ADR monitoring.

Example

The patient is a 42-year-old woman who presents to the emergency department with anerythematous rash and audible wheezing. She presented to the medicine OPD days ago fora second evaluation for elevated blood pressure. She was started on benazepril 5 mg po bd.After taking the second dose, she noticed a rash on her torso and upper arms. Shortlythereafter, she began experiencing difficulty in breathing as well as some facial swelling.Her past medical history was notably only for high blood pressure for 4 years that waspreviously controlled by diet and exercise. She has no history of tobacco use or alcohol use.She has no known drug or food allergies. Her current medication is benazepril and she hasnot taken any other prescription or OTC medications for more than 3 weeks. On physicalexam, she is a well developed, well nourished woman in moderate distress. Her vital signsare as follows: blood pressure 100/80 mmHg, heart rate 78 beats per minute, respiratoryrate 32 beats per minute and afebrile. She weighs 62 kg and is 5 feet 5 inches. On examination,she had notable edematous swollen face, inspiratory and expiratory wheezing and a red,maculopapular rash on trunk and upper extremities. She was alert and oriented. Her serumchemistries and complete blood count were within normal limits.

Exercise:1. Has the patient suffered an ADR? If yes, explain severity and causality.2. Did a drug precipitate a reaction in this patient?3. Let's complete an ADR form on this patient.

Therapeutic drug monitoring is a branch of clinical chemistry that specialises in themeasurement of medication levels in blood. It is also part of chemical pharmacology. Itsmain focus is on drugs with a narrow therapeutic index, i.e. drugs that can easily be under oroverdosed.

In pharmacology, many medications are used without monitoring of blood levels, astheir dosage can generally be varied according to the clinical response that a patient gets tothat substance, e.g. dosage adjustment can be done by monitoring the blood pressure forantihypertensives (pharmacodynamic monitoring).

However, in a small group of drugs, this is impossible, as insufficient levels will lead toundertreatment or resistance and excessive levels can lead to toxicity and tissue damage.But for some drugs, there is either no readily available measure of effect or it is not sufficientlysensitive. For example, clinical effects do not serve as a good guidance indicator when drugsare used prophylactically (e.g. anticonvulsants) or when drug effects develop slowly (e.g.antidepressants) or when drug effect cannot be differentiated from the complications ofdisease process (e.g. digoxin). For such drugs, measurement of plasma concentration is veryuseful (pharmacokinetic monitoring).

For these drugs, plasma concentration indicates the dose required to achieve therapeuticlevels for safe and effective outcome. Thus, TDM involves measurement of drug concentrationin body fluids and adjusting the dose in individual patients.

TDM is defined as "individualization of dosage by maintaining plasma or bloodconcentrations within a target range (therapeutic range/therapeutic window). It is pragmaticmanipulation of the dose of a drug using plasma concentration as a guide to optimize itsefficacy, to avoid or identify toxicity and to detect or confirm poor compliance."

The characteristics of drugs which make them suitable for, or make them require,therapeutic drug monitoring are:

• marked pharmacokinetic variability• concentration related therapeutic and adverse effects• narrow therapeutic index• defined therapeutic (target) concentration range• desired therapeutic effect difficult to monitor.

C H A P T E R

Therapeutic Drug Monitoring(TDM)

21


The indications for TDM are listed in Table 21.1.

Table 21.1: Indications for TDM

Indication Drug/s

Narrow therapeutic range drugs Lithium

Drugs with non-linear (zero order) Phenytoinpharmacokinetics

Drugs showing interindividual Tricyclic antidepressantsvariation in metabolism

Prophylactic use Antiepileptics

To check toxicity Aspirin

To check compliance Antiepileptics, antidepressants

To check bioequivalence Two or more brands of the same drug

To check drug interactions Two or more drugs

To check effect of concomitant Phenytoinpathological/physiological conditionon drugs, e.g. pregnancy, organdysfunction

Efficacy failure Antiepileptics

The important steps in TDM are

TIME OF SAMPLING

Drug concentrations are usually measured in serum or whole blood. Saliva can be used if itis difficult to get blood sample. For example, in children for phenytoin. The timing of samplinginfluences the interpretation of a drug concentration measurement. Hence, the correct timeof sampling is very important. Drug concentrations vary over the dosing interval and withthe duration of dosing in relation to achieving a steady state. This is unlike most physiologicalparameters such as serum creatinine or serum sodium which change relatively slowly.Generally, samples are collected after the steady state levels have been reached which takesapproximately five half-lives. This does not apply to drugs such as amiodarone and perhexilinewith very long half-lives and which can cause severe toxicity. Steady state may take monthsto be reached and dose adjustments need to be made along the way. With all drugs, if asample is taken before steady state is reached, allowance needs to be made for this ininterpreting the concentration.

The pre-dose or trough concentration is commonly used for antiepileptics and peakconcentrations may be used for antimicrobials. Antimicrobials are classed as "time dependent"where the aim is to maintain concentration above minimum inhibitory concentration (MIC)throughout the dosage or "concentration dependent" where the aim is to achieve peak

Therapeutic Drug Monitoring (TDM) 189

concentration, but allow the concentration to fall to low levels in between doses. Vancomycinexhibit time dependant activity, hence steady state levels are measuresd. Aminoglycosidesare concentration dependant, hence sampling is recommended 1 hour after dose (peakconcentration). Immediate sampling is recommended in cases of suspected toxicity. In generalfor therapeutic failure, sample should be taken half an hour before next dose and for toxicitysample should be taken half an hour after the last dose.

Drug estimation methods

The sensitivity, specificity and reproducibility of the laboratory method are important. Mosthigh-volume drug assays are now carried out by automated immunoassay methods whichhave these characteristics. The most commonly used methods are:

1. High performance liquid chromatography (HPLC, e.g. antiepileptics)2. Liquid Chromatography Mass Spectroscopy [LC-MS]3. Gas Chromatography Mass Spectroscopy [GC-MS, GC/MS]4. Gas liquid chromatography (GLC, e.g. amiodarone, perhexiline)5. Immunoassay (e.g. antiepileptics)6. Spectrophotometry (e.g. Salicylates).

All methods if used correctly are acceptable. Participation in international quality controlprogrammes will ensure laboratory validity. Recurring cost for HPLC is least of all. However,it requires technical expertise. Usually, plasma or serum is used for drug assays, dependingon the equipment used. However, with cyclosporin there are large shifts of drug betweenred cells and plasma with storage and temperature change so whole blood is assayed. Someblood collecting tubes, especially those containing a gel to separate cells and plasma, maynot be suitable for all drugs due to drug adsorption by the gel or other components in thetube. All analytical methods estimate total drug (free + bound) levels. Although it is the freedrug which has direct access to the site of action. In patients with normal plasma proteinlevels, total drug concentration correlates well with drug effects. However, sometimes it isnecessary to estimate metabolites especially when the metabolite is active and theconcentration is high (e.g. carbamazepine epoxide in children).

Interpretation of plasma concentration data

The concentration measured must always be interpreted in the light of clinical response, thedemographic and clinical status of individual patient, dosage regimen and concomitant drugsused. Ideally interpretation and advice should be there with each report. If the levels exceed90% of therapeutic concentration, the dosage is halved. Dosage is further reduced by 50% ifplasma levels exceed therapeutic concentrations at 4 half-life interval. If the first concentrationis not too high, one can proceed with the same dose. With this procedure undue toxicity canbe avoided.

Therapeutic concentrations are average values and individual patients will showsatisfactory drug response at levels above and below the average values. Plasma concentrationdata must always be considered along with the patient's clinical response.


Dosage adjustment

For drugs with linear kinetics increasing the dose leads to proportionate increase in plasmaconcentration and can be safely carried out.

Revised dose rate = Previous dose rate × target Css

Measured Css

For drugs with nonlinear pharmacokinetics, relatively small increase in dosage can resultin disproportionately large increase in plasma concentrations (e.g. phenytoin) for such adrug it is advisable to use a nomogram.

A list of drugs for which therapeutic drug monitoring is commonly used is shown inTable 21.2 with the target or therapeutic ranges. The ranges used are in most cases derivedfrom observation of therapeutic and adverse effects in small groups of patients. Therefore,when applied to a wider population of patients, there will be individuals who achieve adequateeffects at lower concentrations or experience adverse events within the 'therapeutic range'.

Table 21.2. Drugs and therapeutic range

Drug Time to steady state Therapeutic range mg/LDigoxin 7 days 0.5 - 2.1Amiodarone 2-6 months 1.0 - 2.5Lignocaine 12 hours 2.0 - 5.0Salicylate 2-5 days 150 - 300Theophylline 1-2 days 10 - 20Phenytoin 2-4 weeks 10 - 20Carbamazepine 2 weeks 5.0 - 12Sodium valproate 2-3 days 50 - 100Gentamicin 8 hours trough 1-2; peak 5-10Amikacin 8 hours trough 3-5; peak 20-30Vancomycin 24 hours trough 5-10; steady state 15-25Lithium 3-6 days 0.6 - 1.2

For rational therapeutics TDM can be followed in a stepwise pattern as:


TDM procedure at a glance

With this background information let us now consider the important aspects of therapeuticdrug monitoring keeping in mind Flow chart 21.1.

Antiepileptic Drugs (AED)

Most antiepileptic drugs have a narrow margin of safety and there is considerableinterindividual variation in pharmacokinetics, dosage requirement and response obtained.

Phenytoin

Measurement of plasma levels, commuting with effect, and adjusting the dose as perrequirement is very important and rewarding for phenytoin. Phenytoin has a narrow marginof safety. Levels below l0 μg/ml do not give good seizure control and those above 20 μg/mlare usually associated with toxicity. However, do not consider plasma levels in isolation. Itis seen that about 20% patients achieve good seizure control despite phenytoin levels below10 μg/ml on the other hand 3-5% patients are well controlled only with levels above 20 μg/ml and show no sign of toxicity. Patient compliance is a very important variable in AEDtreatment. When a patient shows subtherapeutic levels despite standard doses, compliancemust be checked before increasing the dose. In majority of the patients receiving 300 mgphenytoin per day levels below 5 μg/ml were found to be simply due to non compliance.Patient counseling, simpler drug and dosage regimens, and recording intake helps to controlseizures effectively in many patients.

Flow chart 21.1: TDM process at a glance


Phenytoin has nonlinear kinetics and dose increments result in proportionately largeincreases in plasma concentrations leading to toxicity. Hence, it is necessary to use a nomogramfor calculating dose requirement.

One of the limitations of phenytoin tablets and capsules available in India is their dosagestrength, all are of 100 mg strength (and syrup is 125 mg/5ml). On account of the nonlinearkinetics, dose increments of 100 mg may lead to toxic levels in some patients. It is observedthat nearly 20% of the patients need dose increments of only 25 or 50 mg to achieve desiredtherapeutic concentrations. Appropriate dosage adjustment and achieving therapeuticconcentration results in over 70% of patients getting good seizure control.

Carbamazepine

Therapeutic range of carbamazepine is 4-12 μg/ml. Samples should be collected after steadystate levels are reached. Some reduction in plasma concentration thereafter is to be expectedon account of autoinduction. In adults, fluctuations in carbamazepine plasma levels betweendosing intervals are not large and blood sample can be collected at trough or peak time. Inchildren due to short half-life and specially with liquid formulations which can be rapidlyabsorbed, the difference between peak and trough levels can be substantial, requiringmeasurement of both levels depending on indication. Drug monitoring is most useful indeciding the extent to which dose can be increased in patients who are not responding tostandard dose inspite of good compliance.

Phenobarbitone

Therapeutic range for phenobarbitone is 10-40 μg/ml and monitoring is mainly useful fordeciding maximum increase in dose (side effect of drowsiness experienced by the patient ismost important limiting factor).

Is TDM cost-effective?

Therapeutic drug monitoring is has become very important in managing the difficulties inusing some drugs. While the digoxin therapeutic range is somewhat 'loose', the advent ofmonitoring resulted in a far greater appreciation of the toxicity of digoxin and of the needfor rational dosing. Similarly, theophylline, while now falling out of favour for other reasons,was rescued from oblivion when the advent of therapeutic drug monitoring in the 1970sallowed its use largely without the serious toxicity previously associated with it. The use ofany of the drugs in Table 21.2 without monitoring would be difficult and often dangerous.Emphasis should be placed not so much on whether monitoring is necessary as on how touse it in the most cost-effective and clinically effective manner possible.

OBJECTIVES

At the end of the session the student shall be able to:1. Understand and define therapeutic drug monitoring2. List indications for TDM with examples


3. Suggest the timing of sampling for TDM depending on the given clinical situation.4. Suggest modification of dosage/treatment by interpreting given plasma levels of drugs.

Exercises:

Exerices can be given in small groups to students. These exercises can be in the form of caseson cards. Then the cases can be discussed in a bigger group.

Exercises:1. When samples should be collected for following clinical conditions:

a) Failure of antiepileptic therapy

b) Suspected aspirin toxicity

c) Cyclosporine in organ transplantation

d) Starting gentamicin therapy

2. A 35-year-old male was given Tab. Theophylline 300 mg bd for bronchial asthma.There was good clinical response as evidenced by pulmonary function tests, but patientcomplained of tremor, anxiety and palpitations.What would you advise the doctor on duty?Investigations – Theophylline blood levels–7 mg/l(Normal 5-15 μg/ml).

3. A 49-year-old male was prescribed phenytoin for seizure prophylaxis. After receivinga 400 mg loading dose of phenytoin, the patient received 200 mg phenytoin qid, butexperienced disturbance in sensorium.

You are approached by neurologist to comment on. What you would advise?Investigations-phenytoin blood levels 26 μg/ml.(Normal levels of phenytoin 10-20 μg/ml, Toxic levels > 20 μg/ml).

Certain pathological and physiological condition can change pharmacokinetics of a drugaffecting its action. Hence, dose adjustment is needed in these conditions. Let us discussthem one by one.

A. CHILDREN

Very old are very young patients are more prone to adverse drug reactions (ADRs). Whenthe drug manufacturer does not provide adequate information about pediatric dosage, therecan be substantial risk in deriving a dose for children and infants from an adult dose. Childrenand particularly neonates, differ from adults in their response to drugs. Special care is neededin the neonatal period (first 30 days of life) and doses should always be calculated with care.At this age, the risk of toxicity is increased by inefficient renal function, relative enzymedeficiencies, differing target organ sensitivity and inadequate metabolism systems causingdelayed elimination.

Factors affecting drug disposition in children

• Absorptiono Variable gastric and intestinal transit time: in young infants, gastric emptying time is

prolonged and only approaches adult values at around 6 months of age. In olderinfants, intestinal hurry may occur.

o Increased gastric pH: gastric acid output does not reach adult values until the secondyear of life.

o Other factors: gastrointestinal contents, posture, disease states and therapeuticinterventions, such as drug therapy, can also affect the absorption process.

o Bioavailability of rifampicin, gentamicin, phenytoin, phenobarbitone andacetaminophen is increased in children.

o Topical drugs are absorbed promptly in children.• Distribution:

o Increased total body water: as a percentage of total body weight, the total bodywater and extracellular fluid volume decrease with increasing age. Neonates requirehigher doses of water soluble drugs on an mg/kg basis than adults.

C H A P T E R

22Drug Use in Special Population/Diseases/PhysiologicalConditions

Drug Use in Special Population/Diseases/Physiological Conditions 195

o Decreased plasma protein binding: plasma protein binding in neonates is reduced asa result of low levels of albumin and globulins and an altered binding capacity, e.g.increased free levels of aspirin. High circulating bilirubin levels in neonates may displacedrugs from albumin.

• Metabolismo Enzyme systems mature at different times and may be absent at birth, or present in

considerably reduced amounts. Phase 2 reactions are not well developed, e.g. Graybaby syndrome with Chloramphenicol in neonates.

o Altered metabolic pathways may exist for some drugs.o Metabolic rate in children is often greater than in adults. Compared with adults,

children may require more frequent dosing or higher doses on an mg/kg basis.• Excretion

o Complete maturation of renal function is not reached until 6-8 months of age.Similarly pharmacodynamic vary in children. There is immaturity in receptor and

neurotransmitter development. Similarly ciprofloxacin can lead to tendon damageand rupture and it is not recommended for children, but in our country there is norestriction for its use in children.

Children are not mini-adults. Always calculate the appropriate dose for the child. Dosecan be calculated based on body weight, age or surface area. The commonly used method isbased on weight but the most accurate method is based on surface area. The followingmethods can be used to calculate dose in children:

1. Young's formula

Dose in child = Age × Adult dose

Age + 12

2. Clark's rule

Dose in child = Adult dose × Weight (Pounds)150

3. Fried's rule

Dose in child = Adult dose × Age in months

150

4. Based on surface area

Dose in child = 2

2

Adult dose × Body surface area (m )Adult body surface area (1.7 m )

Dosage form, compliance, vomiting, shaking of suspensions, measurements withhousehold measures, taste of drugs are some of the practical issues in children.


Golden rules in children are:

• Always calculate appropriate dose• Do not use newer drugs, use only well established drugs• Avoid polytherapy

Some drugs should be avoided as far as possible. These are given in Table 22.1:

Table 22.1. Drug to be avoided in children

S. No. Drug Adverse effect1 Aspirin Reye's syndrome2 Chloramphenicol Gray baby syndrome3 Fluoroquinolones Arthropathy4 Tetracyclines Teeth and bone abnormalities5 Stunned growth Corticosteroids6 Aminoglycosides Ototoxicity

B. ELDERLY

It is estimated that by the year 2020 elderly people will constitute 11-12% of total population.In treatment of the elderly (geriatric) many variations are required from standard recognizedtreatment due to both aging itself and common age related diseases. Variations occur inpharmacokinetics and pharmacodynamic with age. Moreover elderly people often sufferfrom multiple diseases and are treated with multiple drugs. Multiple drug use and alteredresponsiveness expose elderly more to adverse drug reactions making it difficult to prescriberationally. Providing safe, effective drug therapy is one of the greatest challenges in geriatrics.The following changes happen in the elderly:

Pharmacokinetic changes

Decreased first pass metabolism can lead to increased levels of propranolol. Decreased leanbody mass can lead to increased level of water soluble drugs, e.g. digoxin. Decreased plasmaprotein binding can cause increased activity of highly plasma protein bound drugs, e.g.warfarin. Impaired renal elimination can cause accumulation of digoxin. Impaired hepaticelimination can lead to increased levels of theophylline.

Pharmacodynamic changes

Physiologic changes and loss of homeostatic resilience can result in increased sensitivity tounwanted effects of drugs, such as hypotension from psychotropic medications andhemorrhage from anticoagulants, even if dosage is appropriately adjusted to account for theage. Drugs that depress the central nervous system produce increased effects at any givenplasma concentration.


In addition, drug therapy should be employed only after nonpharmacologic means havebeen considered or tried and only when the benefit clearly outweighs the risk. Oncepharmacotherapy has been decided upon, it should begin at less than the usual adult dosageand the dose should be increased slowly. However, given the marked variability inpharmacokinetics and pharmacodynamics in the elderly, dose escalation should continueuntil either a successful endpoint is reached or an intolerable side effect is encountered. Thefinal dosage schedule should be kept as simple as possible, and the number of pills should bekept as low as possible.

Other factors which affect therapy:

• Impaired memory• Impaired eyesight• Tremors in hands• Constipation.

Compliance is often poor (60%) in the old patients particularly in persons taking toomany drugs. This may be due to forgetfulness, confusion (the patient takes too many doses),deliberate and immobility lethargy. Be careful about following drug groups in elderly:

Sedative-Hypnotics

If nonpharmacologic treatment of insomnia is unsuccessful, use intermediate-acting agentwhose metabolism is not affected by age (e.g. oxazepam, 10 to 30 mg/d).

Antibiotics

Serum creatinine is not a good index of renal function in old people, concentrations of relevantantibiotics should be measured directly.

Cardiac Drugs

In older patients, digitalis, procainamide and quinidine have prolonged half-lives and narrowtherapeutic windows. Toxicity is common at the usual dosages.

Antipsychotics and Tricyclic Antidepressants

These drugs can produce anticholinergic side effects in old people (e.g. confusion, urinaryretention, constipation, dry mouth. The newer potent antipsychotics (e.g. risperidone,olanzapine, quetiapine, and clozapine) are relative exceptions to this rule.

Analgesics

Of the NSAIDs, indomethacin is most likely to induce confusion, fluid retention andgastrointestinal bleeding. Each of these agents should be avoided in the elderly.Cyclooxygenase 2 (COX-2) inhibitors are safer than nonselective NSAIDs for older adults.However, they are more expensive and can cause fluid retention with consequent worseningof hypertension and nocturnal incontinence.


Avoidance of Overtreatment

Drugs are frequently not indicated in some common clinical situations in elderly. For instance,antibiotics need not be given for asymptomatic bacteriuria unless obstructive uropathy, otheranatomic abnormalities or stones are also present. Ankle edema is often due to venousinsufficiency, drugs such as NSAIDs or some calcium antagonists or even inactivity ormalnutrition in chairbound patients. Diuretics are usually not indicated unless edema isassociated with heart failure. Fitted, pressure gradient stockings are often helpful. Forclaudication, regular exercise should be prescribed before cilostazol.

Golden rules in treatment of elderly are:

• Start slow, go slow• One drug, one dose• Start at right time, stop at right time• Avoid certain drugs• Think about necessity of drug• Think about drug dose and dosage form• Check compliance.

C. PREGNANCY

Drugs given during pregnancy may affect fetus. Thalidomide is a classical example ofteratogenic effects. It was synthesized in 1954 in Germany and four years later was marketedas sedative. It was widely used by pregnant females for nausea and vomiting. It wasconsidered safe because in toxicity studies in rodents, it did not produce any toxic effect.Thalidomide led to birth of babies with seal like limbs (phocomelia). It is estimated thatapproximately 20,000 babies suffered toxicity of thalidomide. It was withdrawn in 1961.

There are so many physiological changes during pregnancy which can affect drug action.In pregnant state pharmacokinetics and pharmacodynamic of a drug change considerably.Total body water increases by 8%, diluting the drugs in the body. Plasma protein bindingundergoes a considerable change. Some metabolic pathways may be induced. Renal plasmaflow is doubled during 3rd trimester, so clearance of some drurg may increase. Thispredisposes a pregnant female to adverse drug reactions.

An important aspect of human teratology is that teratogenic medications administeredafter the vulnerable period will not usually cause structural malformations but may inducefunctional adversity. Thus, the timing of drug intake is crucial:(a) Conception to about 17 days of gestation:

It is likely that the deleterious effects on the zygote will lead to abortion.(b) From is 18 to 55 days of intra-uterine life:

It is the most susceptible period for adverse effects. The rapidly multiplying anddifferentiating cells are vulnerable to any agent (Table 22.2) affecting division, enzymes,protein synthesis or replication. As many organs are for concurrently, it is not surprising


that a dysmorphogenic agent interferes with simultaneous organization of many systemsmay produce a multiplicity of malformation various sites. It is recommended that nodrug should be given in first trimester of pregnancy.

(c) By the day-56 of gestation, most organs are well formed and drugs can no longer producemalformations, but they may still impair the growth, development and functioningparticularly in organs which are not yet fully differentiated.

Drug given prior to labour: drugs can lead to adverse postnatal effects in infants,e.g. CNS depressants can lead to neurological, respiratory or muscular dysfunction inthe neonate.

Drugs given during labour: Anaesthetics, analgesics, etc. used during labour cansuppress foetal respiration and prolong labour.

Drugs which are considered safe in pregnancy are: penicillin, pyrimethamine,thiazides, atenolol, ACE inhibitors and prazocin.According to their effect on fetus drug are classified into categories.

CATEGORY

A: Adequate, well-controlled studies in pregnant women have not shown an increased riskof fetal abnormalities to the fetus in any trimester of pregnancy, e.g. Folic acid Thyroxine

B: Animal studies have revealed no evidence of harm to the fetus, however, there are noadequate and well-controlled studies in pregnant women.

Or, Animal studies have shown an adverse effect, but adequate and well-controlledstudies in pregnant women have failed to demonstrate a risk to the fetus in any trimester,e.g. Amoxycillin, Paracetamol.

C: Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.

Or, No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women, e.g. Morphine, Atropine.

D: Adequate well-controlled or observational studies in pregnant women have demonstrateda risk to the fetus. However, the benefits of therapy may outweigh the potential risk.For example, the drug may be acceptable if needed in a life-threatening situation orserious disease for which safer drugs cannot be used or are ineffective, e.g. Aspirin,Phenytoin.

E: Adequate well-controlled or observational studies in animals or pregnant women havedemonstrated positive evidence of fetal abnormalities or risks. The use of the product iscontraindicated in women who are or may become pregnant, e.g. Isotretinoin,Ergometrine.You must assess the benefit/risk ratio for the condition being treated.


Table 22.2. Common drugs that are teratogenic

ACE inhibitors LithiumAlcohol MethotrexateAmantadine MisoprostolAntithyroid NSAIDs (third trimester)Androgens Opioids (prolonged use)Anticonvulsants Oral hypoglycemicsAspirin and other salicylates (third trimester) ProgestinsBenzodiazepines RadioiodineChloramphenicol (third trimester) ReserpineCyclophosphamide RibavirinDiazoxide Sulfonamides (third trimester)Diethylstilbestrol Tetracycline (third trimester)Disulfiram ThalidomideErgotamine Tobacco smokingEstrogens Trimethoprim (third trimester)Griseofulvin Warfarin and other coumarinIsotretinoin anticoagulants

Dosage adjustment and plasma level monitoring

Points to remember while prescribing in pregnancy:• Dosage adjustment becomes difficult due to changes in pharmacokinetics and complex

nature of maternal-placental-fetal complex (Fig. 22.1). Be careful when narrowtherapeutic index drugs are given, e.g. phenytoin levels tend to fall during pregnancy,hence dosage has to be increased.

• If possible counselling of women before a plannedpregnancy should be carried out including discussion ofrisks associated with specific drugs.

• Drugs should be prescribed in pregnancy only if theexpected benefits to the mother are thought to be greaterthan the risk to the fetus.

• All drugs should be avoided if possible during the firsttrimester.

• Drugs which have been used extensively in pregnancy andappear to be usually safe should be prescribed in preferenceto new drugs and the smallest effective dose should beused.

• Well known single component drugs should usually bepreferred to multidrug therapy.

Fig. 22.1: Fetus in uteruswith placenta


D. LACTATION

Most drugs are secreted in breast milk in very small quantities. These do not affect sucklinginfant. However, there are few drugs, which readily enters breast milk and adversely affectnursing infant. Care should be taken while prescribing drugs to lactating mothers. Drugsmay be classified as per the following criteria:

a. Drugs undetected in breast milk: aminoglycosidesb. Drugs reach the baby but insignificant dose: non-narcotic analgesics, penicillinc. Drugs reach the baby with significant dose: aspirin, benzodiazepines, barbiturates,

tetracyclines, carbimazole.The following principles should be followed when prescribing for breastfeeding mothers:

• Avoid unnecessary drug use and limit use of over-the-counter (OTC) products, e.g.opiates, benzodiazepines, Isoniazid, anticancer drugs

• Breastfeeding mothers should seek advice on the suitability of OTC products• Avoid use of drugs known to cause serious toxicity in adults or children• Neonates (and particularly premature infants) are at greater risk from exposure to

drugs via breast milk, because of immature excretory functions and the consequentrisk of drug accumulation

• Choose a regimen and route of administration which presents the minimum amountof drug to the infant

• It is best to avoid long-acting preparations, especially those of drugs likely to causeserious side effects (e.g. antipsychotic agents).

• Multiple drug regimens may pose an increased risk especially when adverse effectssuch as drowsiness are additive

• Infants exposed to drugs via breast milk should be monitored for unusual signs orsymptoms

• Avoid new drugs if a therapeutically equivalent alternative that has been more widelyused is available. A robust assessment of the balance of benefit to risk requires databoth on the drug's passage into breast milk and its effects in infants: there is rarelyenough information available for new drugs to allow such an assessment to be made

• Assess the benefit/risk ratio for both mother and infant.

E. HEPATIC DISEASE

Drugs which are mainly eliminated by liver are affected. There can be accumulation of drugor failure to get converted to active moiety (prodrug). Hence, Dose adjustment is needed.Unfortunately, unlike renal disease where creatinine clearance can provide an indication ofthe extent of renal dysfunction, there is no simple test to assess hepatic functions. Most ofthe conventional liver function tests do not reflect the capacity of the liver to metabolise.

Hepatic blood supply: this decreases in old age and with use of beta blockers. Dosageof drugs with high extraction ratio need to be decreased in this case, e.g. lignocaine,imipramine.

First pass metabolism: dosage of drugs undergoing extensive first pass metabolism needto be decreased, e.g. propranolol.


Prodrugs: these drugs get activated by metabolism in liver, hence in hepatic dysfunctionthey might become ineffective, e.g. captopril.

Hepatotoxic drugs: avoid all drugs which are hepatotixic, e.g. tetracyclines, methotrexate.Hypoalbiminaemia: this leads to increased concentration of highly plasma protein bound

drugs, e.g. warfarin.Remember that in while prescribing for patients with hepatic disease:

• Avoid drugs which undergo extensive first pass metabolism• Measure plasma levels• Be careful about drug interactions• Drugs mainly metabolized by kidneys can be used.

F. RENAL DISEASES

Drugs which are eliminated from body through kidneys are mainly affected. There can beaccumulation of drug at therapeutic doses, leading to toxicity. Elimination of a drug is linearlyand hence, predicably related to GFR (Table 22.3) which is best expressed clinically as thecreatinine clearance. Dose adjustment is done according to creatinine clearance (CLcr).

Creatinine clearance is calculated as (Cockroft Gault formula):

Male = 140 – Age

Ccr

× Wt72

ml/min

Female = 0.85 ×

140 – AgeCcr

× Wt72

ml/min

Ccr is serum creatinine concentration in mg/dlThis formula is invalid with Ccr > 5 mg/dlThe loading dose is not changed. The maintenance dose is altered based on the clinical

condition. The maintenance dose of a drug can be reduced either by reducing the individualdose amount leaving the normal interval between doses unchanged or by increasing theinterval between doses without changing the dose. The interval extension method may providethe benefits of convenience and decreased cost, while the dose reduction method providesmore constant plasma concentration.

Based on CLcr, 2 methods to calculate the dosage can be used

a. Clearance methodb. Dose fraction methoda. Clearance method

It is the most accurate method, but clearance data of drug is needed. This method can beused to determine:i. Dose amount

DRF = D ×

CLcr100


DRF – dose in renal failureD – standard dose

ii. Dosage interval

DI (revised) = DI (standard) ×

CLClrf

iii. Infusion rateDRF = CLRF × Cp

iv. Oral doseDRF/F (fraction of absorption).

b. Dose Fraction methodIt is less accurate as it uses renal clearance only, but it is more user friendly.

DRF = D ×

KRFK

The known dose fraction (KRF/K) of a drug (at CLcr zero) is plotted on the Nomograsm,against estimated CLcr and the required dose fraction in renal failure is obtained.

In adjusting the dosage for patients with renal failure the initial loading dose usuallyneeds little or no reduction. A few notable exceptions to this principle are digoxin andmorphine (because of changes in distribution volume and sensitivity). After the initial doseachieves the peak plasma concentration, the plasma level will decrease more slowly, i.e. thehalf life will be prolonged in proportion to the severity of renal failure as reflected by theplasma creatinine concentration. The prolonged half life means that the plasma concentrationwill be higher than usual when the next dose is due.

A marked reduction in dosage will be required when the kidney is the only route ofexcretion of a drug and renal failure is severe. Obviously the half lives of those drugseliminated predominantly by extrarenal routes will be affected little by renal failure andintermediate effects will result when elimination is partially renal. The fractional eliminationby the kidney (the renal clearance as a fraction of total plasma clearance) determines theextent of dosage adjustment required in renal failure.

Avoid all nephrotoxic drugs, e.g. aminoglycosides, NSAIDsRemember that in while prescribing for patients with renal disease:

• Avoid/adjust dosage of drugs which undergo extensive renal elimination• Measure plasma levels• Be careful about drug interactions• Drugs mainly metabolized in liver can be used.For patients in whom renal function is compromised, dosing nomograms have been

developed to help achieve the usual therapeutic plasma concentrations of a drug.Renal impairment is usually divided into three grades:Mild—GFR 20 – 50 ml/minuteModerate—GFR 10 – 20 ml/minuteSevere—GFR < 10 ml/minute


Table 22.3. Drugs requiring dose/interval adjustment in renal dysfunction

Drug Adjustment GFR (ml/min)> 50 10-50 < 10

Aminoglycosides Dose reduction 60-90% 30-70% 20-30%Cefazolin Interval extension 8 h 12 h 24-48 hAmoxicillin Interval extension 1 h 6 h 6-12 hLithium Dose reduction 100% 50-75% 25-50%Atenolol Dose reduction 100% 50% 25%Spironolactone Interval extension 6-12 h 12-24 h avoidFamotidine Dose reduction 100% 75% 25-50%

G. GENETIC VARIATIONS

Sometimes dose adjustment is required due to genetic variations (Table 22.4).

Table 22.4. Drugs causing hemolysis in glucose 6 phosphate dehydrogenasedeficient individuals

o Definite association: primaquine, sulfanilamide, sulfacetamide, dapsone, nitrofurantoin,nalidixicacid, niridazole, methylene blue, phenazopyridine, naphthalene, toluidine blue.

o Probable association: chloroquine, quinine,sulfadiazine, sulfisoxazole, aspirin,paracetamol, phenacitin, ciprofloxacin, norfloxacin, L-dopa, chloramphenicol, vitaminK analogs, probenecid,vitamin C

OBJECTIVES

At the end of the session the student will be able to:1. Understand the modification in the pharmacokinetics of some common drugs in

children, elderly, pregnancy, lactation, hepatic and renal disease.2. List and choose drugs based on efficacy, suitability, tolerability and cost in these

conditions.3. Calculate dose of a given drug in children and in renal disease.

Exercises in class:

Exercises can be given in small groups. The problem is then discussed in a larger group.


Examples:a) Which drugs you will choose in following conditions. Explain with reasons.

1. Pregnant woman suffering from grand mal epilepsy.

2. Hyperthyroid pregnant female.

3. 70-year-old suffering from insomnia.

4. 40-year-old hypertensive with impaired renal function.

5. 42-year-old lady with hepatic dysfunction and suffering from tuberculosis.

6. 35-year-old male suffering from gram negative infection with renal dysfunction.

7. The creatinine clearance of a patient with renal failure is 35 ml/min. How wouldyou adjust the normal dosage of gentamicin for this patient using the nomogramprovided. (dose of gentamicin 80 mg three times a day).

8. Seven year child suffering from status epilepticus.

9. Can tetracycline be prescribed to children and pregnant females.

10. 70-year-old diabetic patient.


b) The parenteral dose of erythromycin injection is 10 mg/kg/24 hours. Calculate thedaily dose of this drug for a 20 kg child.

c) A 23 kg, 7-year-old girl of average height is to begin Griseofulvin therapy. The doseof this drug is 10 mg/kg/24 -4 doses, orally. The average adult dose is 500 mg dailyin divided doses.

d) Each numbered term in column A below indicates a method of solving the dailychild's dose for the given data. Once you have solved the child's dose according toeach method, find it in column B and enter the corresponding letter in the blank.Column A Column B(Method) (Daily Dose)1. Clark's Rule.2. Young's Rule.3. Calculation using mg/kg dose4. Calculation as fraction of adult5. Calculate based on surface area.

e) The child has a body surface area of 0.67 M2. The adult dose of drug A is 40 mg/day.The physician prescribed 8 mg. Is the dosage correct?

There seems to be a glamour about anything new. A new car or a new movie, you knowthese days how these things are advertised. Similarly, pharmaceutical Industry has multitrackapproach for providing information to physicians. This is the commonest source of druginformation for physicians and available through all channels of communication, i.e. verbal,written and computerised. These channels also include professional meeting, advertising injournals, direct mailing, medical representatives, etc.

Advertising is paid, one-way communication through a medium in which the sponsor isidentified and the message is controlled. 15-20% of budget of a pharmaceutical industry isfor promotion of products. Out of those > 50% is spent on medical representatives. 90% ofthe physicians see medical representatives (MRs). This is the easiest way to gather new druginformation. A substantial percentage of physicians heavily rely on representatives as sourceof information about drugs (and gifts!). But, it has been observed that these representativesemphasize only the positive aspects of products and overlook or give little coverage to thenegative aspects (ADRs). Most of the information is commercially driven. Theseadvertisements highlight the advantages of the drug in question and the disadvantages orthe limitations of the drug being suppressed. The general principles of advertising are alsoapplied to drug advertising. There is a huge difference in criteria when you want to select avehicle or mobile phone as compared to selecting a drug. Ethically speaking the criteria forselection of drug should be entirely driven by patient's disorder or disease. For that a doctordo not need advertisement but a scientifically validated information about drugs.

Whenever you are shown an advertisement about drugs by MRs, look carefully for thesize of the letters used for brand name, generic names, efficacy, and adverse effects. Criticallyanalyse the given advertisements for:

a) Validity of scientific claimsb) Content of scientific informationc) Relevance of references citedd) Appropriateness of illustrations.

The following sources of drug information can be used for this purpose:

C H A P T E R

Critical Appraisal of DrugPromotional Literature

23


Source of drug information

Although pharma houses provide knowledge about the drug and their hazardous eventsthat may occur during their use in therapeutic indications with recommended dosage theinformation given by these houses is often incomplete and hence the data loses its reliability.There should be pooled information given by drug safety committee to be backed by WHOand a regular update must appear especially on the adverse effect of newer drugs in theleading medical journals, so that physicians remain comprehensively updated to face anyeventuality.

The typical example of how the information provided can change the concepts and beliefsof the patients, doctors and community is information on new selective COX-2 inhibitorNSAIDs. Many doctors also gained the false impression that selective drugs were also lesslikely than conventional NSAIDs to have adverse effects on blood pressure and the kidneys.This view was also held by some key opinion leaders, people who always have a majorinfluence on prescribing patterns and, for this reason, are invited by pharmaceutical companiesto talk to groups of prescribers. To complicate the situation, the media persuaded consumersthat the new 'wonder' drugs were more efficacious than older medications. Word of mouthcompleted a marketer's dream situation. Certainly the drugs were heavily promoted byboth industry and the media, but why did prescribers fail to follow ethical principles? Thefacts were all there in many independent sources of information. The present status is thatCox-2 inhibitors are either being banned (nimesulide) or withdrawn voluntary bymanufacturer (rofecoxib). The manufacture is paying heavy claims to the patients who sufferedfrom adverse effects.

There is no merit in being among the first to prescribe a new drug whatever the pressuresfrom patients and drug companies. Of course industry puts the best possible spin on itsmarketing messages, but doctors should be smart enough to see through the hype created.They need to know that when a drug first appears on the market only limited safety data areavailable and long term outcomes, both good and bad, can only emerge with time andappropriately designed, prospective safety studies. It is well established that most prescribersobtain the majority of their information from the pharmaceutical industry and they, thereforeneed more training in how to evaluate the information and what questions to ask drugrepresentatives.

How doctors can get updated about drugs?

Knowledge and ideas about drugs are constantly changing. More and more new drugs arecoming on the market. New experience with existing drugs is expanding (side effects, newindications/ways of using). A Physician is expected to know about new developments indrug therapy. However, in many parts of the world, objective and unbiased informationabout drugs is a luxury which is difficult for most of the physicians to access. It is difficult forbusy physicians to have satisfactory knowledge of all these drugs. Hence, selection and useof right drug in an appropriate manner becomes a challenge.

How you can keep up-to-date about drug information inspite of your busy schedule?

Critical Appraisal of Drug Promotional Literature 209

The sources of information are:

1. Written form-journals, reference books, drug bulletins, books2. Verbally-through discussions in CMEs, meetings, journal clubs in institutions3. Tape/video/online-journals, CDs4. Drug Information Centers5. Pharmaceutical industry6. Internet.

Others written forms which can be used are:1. Drug compendia—these list the drugs available on the market2. National list of essential drugs and standard treatment guidelines3. General Pharmacological reference—Goodman and Gilman's: The Pharmacological basis

of Therapeutics4. Martindale's The extra Pharmacopoeia—excellent reference book, gives all information

on all chemicals used with references5. Avery' drug treatment—more specialised6. Meyler's side effects of drugs7. MIMS—monthly index of medical specialties—these provide information on:

• Generic/brand names• Chemical composition• Indications/contraindications• Side effects, interactions• Price.

[Current Index of Medical Specialties (CIMS), Indian Drug Review (IDR), Drug Index(DI), Drugs Today, etc.]Drug bulletins are preferred because they are:

• Critical source of new drug information• Promote rational drug therapy• Appear at frequent intervals• Sponsors—government agencies, university departments, professional bodies, non-

industry sponsored.Some drug bulletins available In India are:Drug bulletinsAustralian prescriber is available free of chargeOthers are: Drugs and therapeutic bulletin (UK)Medical letter (USA)


Medical Journals

The important ones are: The Lancet, New England Journal of Medicine, and British MedicalJournal. Tons of information is available in these journals. Thousands are published and theyvary enormously in quality.

• Only a small proportion publish scientifically validated articles• Good journal are peer reviewed by independent experts, usually no advertisements

are there• Define range of drugs available to prescriber• Consensus on the treatment of choice for the most common diseases and complaints• Index Medicus has list of major reputable journals.

Symposia/conferences

Symposia are useful for disseminating information. The objective scientific content of suchmeetings should be paramount, and presentations by independent scientists and healthprofessionals are helpful to this end.

DIC (Drug Information Centre)

• Very useful• Prescribers and general public can call• Use reference books online.

Examples

• DIC-Philippines-Dept. of Pharmacology• DIC-Kathmandu, Nepal

2 Clinical pharmacologists1 Pharmacist.

Internet

Adverse effects are the prime health hazards of drugs. In order to manage an adverse drugreaction it is important to be aware of all possible drug reactions and drug interactions.However, given the current scenario of introduction of new drugs into market, it is impossibleto keep track of all reports of reactions. This is where the web comes to the rescue. Internetis another source of drug information, but all the information available is not authentic.Check the authenticity of the website.

Advantages

• A large number of sources• Quick and easy.


Disadvantages

• Illegal advertising and complaints have increased• Use catchy slogans, e.g. Scientific breakthrough, miraculous cure, secret formula, ancient

ingredients, antiageing, all natural• Use case histories of successful consumers, authenticity of whom is questionable

Keeping up-to-date should not be too difficult for physicians in developed countries,but it can be far from easy in some parts of the world where access to independentsources of drug information is very limited. But wherever you live and work it isimportant to develop a strategy to maximize your access to key information you needfor optimal benefit of the drugs you prescribe.

Ethical criteria for drug promotion

WHO has formulated ethical criteria for medicinal drug promotion. The main objective ofethical criteria for medicinal drug promotion is to support and encourage the improvementof health care through the rational use of medicinal drugs. The essential features are:

1. Ethical criteria for drug promotion provides the foundation for proper behaviourconcerning the promotion of medicinal drugs, consistent with the search for truthfulnessand righteousness. These criteria constitute general principles for ethical standardswhich could be adapted by governments to national circumstances as appropriate totheir political, economic, cultural, social, educational, scientific and technical situation,laws and regulations, disease profile, therapeutic traditions and the level of developmentof their health system. They apply to prescription and non-prescription medicinal drugs("over-the-counter drugs"). They also apply generally to traditional medicines asappropriate, and to any other product promoted as a medicine.

2. "Promotion" refers to all informational and persuasive activities by manufacturers anddistributors, the effect of which is to induce the prescription, supply, purchase and/oruse of medicinal drugs. All promotion making claims concerning medicinal drugs shouldbe reliable, accurate, truthful, informative, balanced, up-to-date, capable ofsubstantiation and in good taste. They should not contain misleading or unverifiablestatements or omissions likely to induce medically unjustifiable drug use or to give riseto undue risks. The word "safe" should only be used if properly qualified. Comparisonof products should be factual, fair and capable of substantiation. Scientific data in thepublic domain should be made available to prescribers and any other person entitled toreceive it, on request, as appropriate to their requirements. Scientific and educationalactivities should not be deliberately used for promotional purposes.

3. Information that such advertisements should usually contain, among others includes:• The name(s) of the active ingredient(s) using either international nonproprietary names

(INN) or the approved generic name of the drug.• Brand name.• Content of active ingredient(s) per dosage form or regimen;


• Name of other ingredients known to cause problems;• Approved therapeutic uses;• Dosage form or regimen;• Side-effects and major adverse drug reactions;• Precautions, contraindications and warnings;• Major interactions;• Name and address of manufacturer or distributor;• Reference to scientific literature as appropriate.

4. To fight drug addiction and dependency, scheduled narcotic and psychotropic drugsshould not be advertised to the general public. While health education aimed at childrenis highly desirable, drug advertisements should not be directed at children.

5. Medical representatives should have an appropriate educational background. Theyshould be adequately trained. They should possess sufficient medical and technicalknowledge and integrity to present information on products and carry out otherpromotional activities in an accurate and responsible manner. Exposure of medicalrepresentatives and trainees to feedback from the medical and allied professions andfrom independent members of the public, particularly regarding risks, can be salutary.Medical representatives should make available to prescribers and dispensers completeand unbiased information for each product discussed, such as an approved scientificdata sheet or other source of information with similar content.

6. Free samples of legally available prescription drugs may be provided in modest quantitiesto prescribers, generally on request. Free samples of non-prescription drugs to thegeneral public for promotional purposes.

7. Postmarketing scientific studies and surveillance should not be misused as a disguisedform of promotion.

8. Appropriate information being important to ensure the rational use of drugs, allpackaging and labeling material should provide information consistent with thatapproved by the country's drug regulatory authority. Adequate information on the useof medicinal drugs should be made available to patients.

Should you avoid representatives?

Medical representatives are criticized a lot, but there network is very huge and now theyhave become an integral part of medical infrastructure in the country. Hence, make best useof this huge network for getting drug information in a desirable way! Ask about publicationof drug safety in an authentic medical journal. Optimize the time spent with medicalrepresentatives. Remember following points while dealing with a representative:

• Take control of the discussion• You get the information you need• Ask for officially registered drug information and compare it with what industry has

got printed


• Comparison with standard treatment use• Particularly look for side effects and contraindications• Ask for published references on efficacy and safety• If it is 'me too' drug (analogue of same class, e.g. new proton pump inhibitor) ask about

price• Do not start by using free samples on a few patients or family members• Do not base your conclusions on the treatment of a few patients.

OBJECTIVES

At the end of the practical class the student shall be able to:1. Understands concept of advertisement.2. Critically analyze a given drug advertisement.3. Identify unethical points in advertisement.4. Enumerate authentic sources of drug information.5. Appreciate the merits and limitations of the various sources.

Exercise in class

Drug promotional literature is given to batch of 4-5 students. They are given 15 minutes toanalyse and write their points. The group leader gets 5 minute to speak about advertisementwhich is projected through LCD projector in front of whole class. In this way you can covera large number of advertisements and all aspects of advertisements.

Exercises

Find out the following information from the appropriate books and mention the source ofinformation:

1. What is the plasma half life of atenolol?

2. Does the clearance of gentamicin get altered in the renal insufficiency?

3. What is the Vd of amiodarone?


4. What is dose of paracetamol in children?

5. Select the cheapest preparation of ciprofloxacin (500 mg tablet).

6. Select the cheapest and costliest preparation of diclofenac (50 mg tablet).

7. What is the incidence of anaphylaxis with penicillin injection?

8. Can nimesulide be prescribed to a 3-year-old child?

9. What are precautions while taking doxycyline tablet?

10. Name 3 new antiepileptic drugs.

11. Why rofecoxib was withdrawn from market?

12. Write 5 brand names of enalapril tablet.

Cases are identified in the hospital. Students are divided into batches. Each batch has 4-5students. They are allotted cases. They go to their respective cases and work up on the caseand fill the following required information.

Clinical Pharmacology Exercise Form (Therapeutic follow-up for any case)

Student's Name Roll No. MBBS 2nd Prof.(Year) Semester Clinical Assignment of

INSTRUCTIONS

1. Fill up the Performa with appropriate data.2. Write down the presenting complaint, chief complaints and other symptoms of disease

in this patient.3. Write down the various parameters to follow improvement in this disease and enter

the observation daily/ periodically in the columns provided.4. Write the name of the drug, dose, route, and frequency of administration. Tick (√) in

the appropriate date column when each drug is started and put (X) when the drug isdiscontinued.

5. Any fresh sign/ symptom appearing during the treatment should be recorded. Tick (√)when these appear and put (X) when these disappear.

Salient Features of the case: Clinical DepartmentRegistration No. DOA/DOD

Name of patient. Age and Sex,Body weight Ht. Pregnant Lactating

Smoking Y/NAlcohol Y/N

C H A P T E R

Therapeutic Follow-upCases/Problems

24


Major Sign and Symptoms: (Write down all the symptoms in chronological order)

Symptoms Signs/ Diagnostic test1.2.3.4.5.6.

Drugs used

Name of drug Dose Route Frequency Change/Date Daily cost

Parameters monitored

(General)

Day/time Temp Pulse Res. Rate BP Others Others Others Others

Therapeutic Follow-up Cases/Problems 217

Specific parameters

Investigation Date Day- Day- Day- Day-

1

2

3

4

5

C. Investigations during treatment with date and rational/ reasons1.2.3.4.5.

D. Fresh signs and symptoms/adverse effects (developed during treatment)1.2.3.4.

E. Comment on:Common trade names of the drugs usedCostShelf life/StorageSchedule (H/X, etc.)

Method of administration (With/without food, milk, other drugs, posture, inhalation,Dilution/Infusion, etc.)

Information to patient (About expected side effects which are not serious/whenconsultation should be sought)Specific Antidote (In case of poisoning)Advice to attendant/family members to ensure compliance and assess improvement

F. Therapeutic follow-upG. Advice on discharge


H. Other alternative drugs available for this caseII. Alternatives to be used in old/Children/Pregnant/presence of concurrent hepatic

or renal diseaseIII. Non-Pharmacological Measures to be taken. (Diet, exercise, smoking, alcohol,

etc.)

OBJECTIVES

1. Complete few therapeutic follow-up cases2. Present these cases and highlight drug management.

Students will fix the copies of this performa in their practical notebook. The case willbe discussed during the presence of full class. The student will present the case andother students would be allowed to comment/ask questions. The number of casescovered can vary from 20 to 40 depending upon the schedule. Later on problembased questions can be taken out from these cases. Put them on card along with 3-4questions and make them as one of the OSPE stations.

Example: This is taken from history of a parkinsonism patient.

A 60-year-male was on phenothiazines therapy for psychotic illness. He developedparkinsonism disease. He was given L-dopa 250 mg OD but there was no improvement.The dose of which then increased to 750 mg OD but still there was no improvement.Q1. Why he developed parkinsonism?Q2. Why he was not benefited by increasing the L-dopa dose even?Q3. What alternate should be given?

New drug development involves animal toxicity studies followed by clinical trial in humans.Potentially useful compounds are studied in animals to evaluate desired effects and toxicity.Animal toxicity studies are done to see whether the chemical is safe or not. Compounds thatappear effective and safe are candidates for human studies. For all new drugs, it is mandatoryto do toxicity studies in animals. After that the drug enters various phases of clinical trials.

The various phases of drug development are:

Drug development is an extremely arduous, highly technical, time-consuming and veryexpensive process. The investment to produce one marketed drug is approximately US$800million and 12-15 years. The idea starts from folklore or screening of natural products. Butnowadays drugs are designed on computer keeping in view the target, e.g. agonists andantagonists are synthesized for receptors.

Chemical synthesis is done by chemists by using computer models these days. Variouscombinations are designed using CADD (computer assisted drug designing) and then bestmolecules are chosen for study in animals. They are given code numbers, e.g. M1001-M1210.

C H A P T E R

New Drug Development25


The molecules are synthesized and a formulation is made. It is tested in animals. Variousscreening methods are available depending on the disease condition. Selected moleculesfrom screening are further subjected to animal toxicity studies. If the molecule is found to besafe it enters clinical trials. It is estimated that to have one successful drug we need to startwith 10,000 molecules.

Clinical trial is defined as “a carefully and ethically designed experiment with the aim ofanswering some precisely framed questions. To carry out each phase of clinical trial in India,permission from Drug Controller General of India (DCGI) is required. In US the regulatoryauthority is Food and Drug Administration’s (FDA).

Clinical trial is systematic study of pharmaceutical products on human subjects (whetherpatients or non patient volunteers) in order to discover or verify the clinical, pharmacological(including pharmacodynamics/pharmacokinetics) and/or adverse effects, with the object ofdetermining their safety and/or efficacy. There are five phases of clinical trials.

Phase 0

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordancewith the FDA 2006 guidelines. Phase 0 trials are designed to expedite the development ofpromising therapeutic or imaging agents by establishing very early on whether the agentbehaves in human subjects as was anticipated from preclinical studies. Distinctive features ofPhase 0 trials include the administration of single subtherapeutic doses of investigationalagent to a small number of subjects (10 to 15) to gather preliminary data on the agent’spharmacokinetic and pharmacodynamic properties and mechanism of action.

Phase I

The objective of phase I of trials is to determine the maximum tolerated dose in humans,pharmacodynamic effect, adverse reactions, if any, with their nature and intensity andpharmacokinetic behaviour of the drug as far as possible. These studies are often carried outin healthy adult volunteers (20-25) using clinical, physiological and biochemical observations.The main aim is to find out the safety of the drug in humans.

Phase I trials are usually carried out by investigators trained in clinical pharmacologyand having the necessary facilities to closely observe and monitor the subjects. These may becarried out at one or two centres. The perquisite to start phase I trials is submission ofresults of animal toxicity studies.

Phase II-Exploratory trials

In phase II trials a limited number of patients (20-200) are studied carefully to determinepossible therapeutic uses, effective dose range and further evaluation of safety andpharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studiesare usually limited to 3-4 centres and carried out by clinicians specialized on the concernedtherapeutic areas and having adequate facilities to perform the necessary investigations forefficacy and safety. The perquisite to start phase II trials is submission of results of phase I.

New Drug Development 221

Phase III-Confirmatory trials

The purpose of these trials is to obtain sufficient evidence about the efficacy and safety ofthe drug in a larger number of patients (250-1000), generally in comparison with a standarddrug and/or a placebo as appropriate. These are real life situations. These trials may becarried out by clinicians in the concerned therapeutic areas, having facilities appropriate tothe protocol.

Data on ADRs observed during clinical use of the drug should be reported along with areport on its efficacy in the prescribed format. The perquisite to start phase III trials issubmission of results of phase II. However, if the drug is already approved/marketed inother countries, then you need to carry on directly phase III study (known as bridgingstudy) on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacyand safety of the drug, in Indian patients. The prerequisite is submission of data of marketeddrug in other countries. In this case you need to conduct bioequivalence studies also.

Phase IV

These are studies performed after marketing of the pharmaceutical product. Trials in phaseIV are carried out on the basis of the product characteristics on which the marketingauthorization was granted and are normally in the form of postmarketing surveillance,assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studiesshould use the same scientific and ethical standards as applied in pre-marketing studies.This phase has now become mandatory in India under Schedule Y.

After a product has been placed on the market, clinical trials designed to explore newindications, new methods of administration or new combinations, etc. are normally consideredas trials for new pharmaceutical products.A protocol for clinical trials has following information:

• Title:• Introduction: (brief, justification and problem definition)• Hypothesis:• Aims and Objectives:• Materials and Methods:

(a) Type of Study: prospective, observational(b) Setting:(c) Subjects: patients, healthy volunteers(d) No. of Groups: Randomisation, blinding(e) Sample size calculation: power of study(f) Study design:(g) Treatment:(h) Primary outcome measures:(i) Secondary outcome measures:


(j) Stopping rule:(k) Analysis:(l) Ethics:

OBJECTIVES

At the end of the session a student shall be able to:1. Understand concept of new drug development.2. Understand various phases of clinical trials.

Posology is the science of dosage. It deals with the amount of drug necessary to produce adesired physiological, therapeutic, or prophylactic effect.

Dose

It is the appropriate amount of a drug required to produce a certain degree of response in apatient given at a time and which can be repeated at an appropriate interval to produce adesired therapeutic effect or it is quantity of drug which is sufficient to diagnose, prevent orcure a disease.

Dosage

It is schedule of dose, frequency and duration of administration of drug.

Dose may be:

1. Standard doseThe same average dose is given to all the patients, e.g. diclofenac 50 mg three times aday.

a. The minimum dose is the smallest dose that produces a therapeutic effect.b. The maximum dose is the largest dose that can be safely administered.c. The toxic dose is the dose that produces harmful effects.d. The lethal dose is the dose that will result in death. The minimum lethal dose

(MLD) is the smallest amount that will cause death.e. The single dose is the amount of a drug taken at one time.f. The daily dose is the total amount of a drug taken in 24 hours.g. A continuous dose consists of small doses taken at short intervals.

2. Regulated or Titrated doseDose is adjusted based on measurement of a body function.For example: antihypertensive drugs as per BP measurementAntidiabetic drugs as per blood glucose measurement.

C H A P T E R

Calculation of Drug Dosesand Dilutions

26


3. Target level dosePlasma concentration of a drug is monitored for adjustment of dose, e.g. Phenytoin inepilepsy based on plasma level achieved. Target concentration is 10-20 microgrms/dl.

Fixed-Dose Combinations (FDC)

The concomitant use of two or more drugs adds to the complexity of individualization ofdrug therapy of a disease. The dose of each drug should be adjustable to achieve optimalbenefit. But patient compliance is more difficult to achieve. To obviate the latter problem,many fixed-dose drug combinations have been marketed. The use of such combinations isbeneficial only if the ratio of the fixed doses of drugs corresponds to the needs of the individualpatient. Most of the FDCs are banned in India and other countries.

Drug doses may also be calculated based on body weight or surface area in adults.Anticancer drugs are calculated based on body surface area.

Ratio-proportions

Ratios indicate a relationship between two numbers with a colon between the numbers. Thecolon represents division. For example 3:4 = 3/4.

A ratio is the relation between like numbers or values, or a way to express a fractionalpart of a whole. Ratios may be written:

As a fraction: 23

As a division: 2 ÷ 3The strength or concentration of various drugs can be expressed as a ratio.

First, read the label of the drug and find the strength or concentration. Express thisstrength as a ratio in fractional form, as in the following examples.

Kanamycin injection, 1.0 gm/3 ml =

1.0 gm3 ml

Isoproterenol inhalation, 1:200 =

1200

Epinephrine injection, 1:1000 =

11000

Proportions are equations containing ratios of equal value.A proportion consists of two equal ratios and is essentially a statement of equality between

two ratios. For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8.The value of the ratio on the right must always equal the value of the ratio on the left. A

proportion may be written with the double colon, or proportion sign (::), or with the sign ofequality (=).

Calculation of Drug Doses and Dilutions 225

Means

2 :5 :: 4: 10 or

2 = 45 = 10

ExtremesIn a proportion, there are four numbers. The two middle numbers are known as MEANS

and the two end numbers are known as EXTREMES.Example: You find a 10-ml vial of Aminophylline in supply labeled "25 mg per ml." Thus,

there are 250 mg of drug in this 10-ml vial. (extreme) 25 mg = 250 mg (mean)(mean) 1 ml = 10 ml (extreme)Notice that when you multiply the two extremes and the two means, the products are

equal.For example: 25 × 10 = 250 × 1.Multiply the extremes: 25 × 10 = 250Multiply the means: 1 × 250 = 250In a proportion, the product of the means is always equal to the product of the extremes.

Therefore, when you do not know one value (x), you can determine it, if the other threevalues are known. When setting up a ratio, the known factor (on hand) is stated first, thedesired is stated second.

When doing calculation, use the following steps to solve for X.

(1) Step 1. State problem in "if-then" form.(2) Step 2. Convert the problem to an equation.

(a) Known information (labeled strength, and so forth) should be your IF ratio.(b) The unknown ratio including X will be your THEN ratio.(c) Put like units on the same side of each ratio. (For example, if the left side of the

equation is expressed in mg/ml, then the right side must also be expressed inmg/ml).

(3) Step 3. Cross multiply means and extremes.(4) Step 4. Solve for X.

Example 1:

Prescribed: 600,000 units of penicillin po q6hAvailable: 400,000 units per scored tabletHow many tablets will you administer?400,000 units : 1 tablet = 600,000 units : x600,000 = 400,000x600,000 = x = 1.5 tablets


400,000or the formula method can be used:D/H X Q = XD - dosage desired or orderedH - what is on hand (available)Q - unit of measure that contains the available dose. When using solid products (tablets,capsules) Q is always 1 and can be eliminated. Q varies when using liquid measures.X - the unknown dosage you need to administer.

Example 2:

Prescribed: Potassium Chloride 20 mEq added to the IV.Available: 40 mEq per 10 cc.How much potassium will you add? D = 20 mEq H = 40 mEq Q = 10 cc20 mEq X 10 cc = X 40 mEq0.5 X 10 = X = 5 ccIt doesn't matter if you use ratios, fractions or the formula, the answer will be the sameCalculating dosages in units (insulin, heparin, pitocin, vitamins, some antibiotics).

Example 3:

Prescribed: Ampicillin 400 mg IM q6hAvailable: Vial with powder.Label reads: For IM injection, add 3.5 ml diluent (read accompanying circular). Resultingsolution contains 250 mg Ampicillin per ml. Use solution within one hour.How many ml will you administerRatio-proportion method:250 mg : 1 ml = 400 mg : x400 = 250 x400÷250 = 1.6 ml Formula method:D/H X Q = X400 mg X 1 ml = X250 mg1.6 ml = X.


Example 4:

Prescribed: Heparin 8000 units subcutaneous q12hAvailable: Heparin 10,000 units per mlHow much will you administer? Formula: 8000 units X 1 ml = 0.8 ml 10,000 units Ratio: 10,000 units : 1 ml = 8000 units : x8000 units X 1 ml = 10,000 units x8000/10,000 = x0.8 ml = x.

Conversion within the metric system

To convert a quantity in the metric system to a larger unit, we divide or move the decimalpoint to the left. To convert to a smaller unit, we multiply or move the decimal point to theright. Alternatively, we can use ratio and proportion as illustrated in the following examples:

Example 1: Convert 0.3 mg to grams. (There are 1000 mg in 1 gram.)

IF 1000 mg THEN 0.3 mg1 gm = X gm1000 x X = 0.3 x 11000X = 0.3X = 0.0003 gm (answer).

Example 2: Express 30 liters in terms of milliliters. (There are 1000 ml in 1liter.)

IF 1000 ml THEN X ml.1 liter = 30 liters1 x X = 1000 x 30 litersX = 30,000 ml (answer).The labeled strength of a 30 ml vial of Meperidine injection is 50 mg/ml. How manymilliliters must be injected to provide a 75 mg dose?IF 50 mg THEN 75 mg1 ml = X ml50 x X = 1 x 7550X = 75X = 1.5 ml.


Calculate drop rate:

Example 1:

Prescribed: Infuse 2 L of Lactated Ringers solution in 24 hours.The administration set has 12 gtts/ml.How many gtts/min will you administer the IV?2000 ml X 12 gtts/ml = x 24 hr 60 min/hr24000 = x144016.7 gtts/min or 17 gtts/min = x.

Example 2:

Ordered: Gentamicin 100 mg/100 ml IV q8h. The IV handbook states that it should begiven over 90 min. What rate will you set on your IV pump?100 ml = x 90 min 60 min 90 x = 6000 x = 6000/90 x = 66.7 or 67 ml/hr.

Liquids

Example 1:

A three-month old boy who is 24.5 inches long and weighs 11 pounds, 8 ounces, is to receivePhenobarbital elixir labeled 20 mg/5 ml. The anticonvulsant dose of Phenobarbital is 125mg/m² dose.(1) Calculate the single dose of Phenobarbital in mg.

SURFACE AREA = 0.31 m²CHILD'S DOSE = 0.31 x 125 mg = 40 mg, approximately

(2) How many milliliters will be administered for each single dose?IF 20 mg THEN 40 mg5 ml = X ml20 x X = 5 _ 40X = 200 = 10 ml (answer)20.

Example 2:

How many grams of potassium permanganate should be used in preparing 500 ml of a 1:2500solution? 1:2500 = 0.04%


500x0.0004 = 0.2 gm or1:2500 means 1gm in 2500 ml2500:500 = 1xXX = 0.2 gm.

OBJECTIVES

At the end of the session the student shall be able to:1. Calculate the quantity of drug present in a given solution.2. Appreciate the importance of calculating the total quantity of drug and its conversion

from percentage and molar solutions for individualization of therapy.3. Calculate number of tablets, quantity of solution, drip rate for given condition.

Exercises in class:

These can be given to small groups on cards. Later on these cards can be used as one of thestations in OSPE.

1. How many milliliters of promethazine hydrochloride injection labeled 25 mg/ml mustbe administered to provide a dose of 12.5 mg?

2. A patient is prescribed 30 milligrams of furosemide intravenously. 10 milligrams in 1millilitre of liquid for IV. Injection is available. How many millilitres will you administer?

3. A patient is prescribed 22 milligrams of gentamicin sulphate by intramuscular injection.20 milligrams in 2 millilitres of liquid for IM. Injection is available. How many millilitreswill you administer?

4. A patient is prescribed 75 micrograms of fentanyl citrate intravenously. 0.1 milligramsin 1 millilitre of liquid for IV. Injection is available. How many millilitres will youadminister?

5. A patient is prescribed 50 milligrams of sodium valproate orally. 200 milligrams in 5millilitres of syrup is available. How many millilitres will you administer?


6. A patient is prescribed 200 milligrams of Amoxicillin trihydrate orally. 250 milligramsin 5 millilitres of Syrup is available. How many millilitres will you administer?

7. A patient is prescribed 15 mg of stemetil. You have 2 ml of solution on hand whichcontains 25 mg Stemetil. What volume of solution would you give?

8. A dose of 75 mg of pethidine has been prescribed. It is available in ampoules containing100 mg in 2 ml. What volume must be administered?

9. Calculate the drip rate for 100 mls of IV fluids to be given over a half hour via a givingset which delivers 10 drops/ml.

10. Calculate the drip rate for 500 ml of normal saline to be given over 4.5 hours via agiving set which delivers 15 drops/ml.

11. Calculate the drip rate for 500 ml of dextrose 5% in water to be given over 4 hours viaa giving set which delivers 15 drops/ml.

12. A patient is prescribed 50 milligrams of amitriptyline. 25 milligram tablets are available.How many tablets will you give?

13. A patient is prescribed 300 milligrams of carbamazepine. 200 milligram tablets areavailable. How many tablets will you give?


14. A child weighing 12 kg has been prescribed syrup chloroquine (one bottle of 60 ml,each ml containing 10 mg of chloroquine base). The initial dose of chloroquine is10 mg/kg. Calculate the amount of syrup to be administered to the child.

15. A patient is prescribed 2.5 grams of neomycin sulphate. 500 milligram tablets areavailable. How many tablets will you give?

16. Convert 93074 milligrams to grams.

17. Convert 64343 millilitres to litres.

18. Convert 97.196 micrograms to milligrams.

Rational therapeutics is an important clinical aspect of applied pharmacology. Formulation isan integral part of therapeutics.

Hence, following aspects of formulation for a given disease will be discussed

1. Labeling:2. Cost:3. Rational Therapeutic:4. Essential drug concept:

Pharmaceutical companies manufacture the drugs. They usually provide the informationsheets/package inserts/brochures for their products. Though, they should provide thescientific information for their products, largely such information is prepared from commercialangle and for marketing of their products rather than giving scientific information.

Often the companies provide the information which is incomplete, irrelevant and havingtall claims. Therefore, it is necessary that these information sheets/brochures/literatureprovided by the pharmaceutical companies should be evaluated on the basis of above points.In addition to this one should pay special attention to the following points:

1. Physical presentation: quality of paper, print, colour, etc.2. Figures, diagrams, tables, pictures, cartoon, etc.3. Quality of statements made, i.e. broken, convenient statements and their source4. References: their authenticity, time of publication, etc.5. Cost, if mentioned.

The following aspects of labeling and package inserts should be considered:

1. Consumer information which is simple and not confusing2. Indication of the item as a medicinal product3. Composition of the product including international nonproprietary name (INN)/generic

name of the active substance4. Uses for which the product is intended

C H A P T E R

Evaluation of Drug Formulations27

Evaluations of Drug Formulations 233

5. Mode of use, including route of administration (systemic or local), maximum singledose, maximum daily dose and duration of treatment

6. The product is intended for (children or adults)7. Presentation of the most important precautions, contraindications and adverse effects

clearly stated in easily understandable language. The size of letters.8. Specific warnings and information for use during physiological/pathological variations

such as pregnancy, lactation, the elderly, or in patients with renal or hepatic failure.9. When medical advice should be sought

10. Duration of use11. Information on storage conditions and shelf-life12. Inactive ingredients listed13. Expected benefit when the drug is used properly14. Expiry date15. Overdosage: Brief clinical description of symptoms, non-drug treatment and supportive

therapy and specific antidotesMany developing countries including India, have a limited budget allocated to health

care especially for drug procurement. Therefore, it is imperative to optimize expendituresfor drug purchases by selecting an essential drug list and promoting the rational use ofdrugs.

Rational drug use:

RUD means use of a right medicine, in the right manner (dose, route and frequency ofadministration, duration of therapy), in right type of a patient, at a right cost, i.e. the rule ofright. Rational drug use also means using the drug when necessary (chloroquine in malaria)and more importantly, not using it when unnecessary (expectorant mixture in common cold).When the word 'right' is replaced by the word 'wrong' it becomes irrational drug therapywhich is more frequent than assumed.

Irrational use of medicines is a major problem worldwide. WHO estimates that morethan half of all medicines are prescribed, dispensed or sold inappropriately and that half ofall patients fail to take them correctly. Inappropriate, ineffective and inefficient use of drugscommonly occurs at health facilities in developing and developed countries. Common typesof irrational use of drugs include:

• Non-compliance with health worker prescription• Self-medication with prescription drugs• Overuse and misuse of antibiotics• Overuse and misuse of antidiarrhoeals for non-specific childhood diarrhea• Multiple or overprescription• Overuse of injections and overuse of relatively safe drugs• Use of unnecessary expensive drugs and poor patient compliance• Unnecessary use of tonics and multivitamins• Short consulting time.


Many individuals or factors influence the irrational use of drugs such as patients,prescribers, the workplace environment, the supply system including industry influences,government regulation, drug information and misinformation.

In addition to optimizing the use of limited budget, promoting the rational use of drugsaims to improve quality, increase accessibility and equity of health and medical care for thecommunity.

Essential drug concept:

The concept of essential drugs was first time mooted by the World Health Organisation(WHO) in 1977 and the first list of essential list was published in 1977. The list is revisedevery two years. Currently the 15th list (March, 2007) is in use (http://www.whoindia.org/LinkFiles/Essential_Medicine_List_EML15.pdf). The essential drug list of India wasformulated in 1996 and revised in 2003. It has 354 drugs (Appendix IV). Many drugs includedin the list are preceded by a box in WHO list to indicate that they represent an example of atherapeutic group and that various drugs could serve as alternatives. It is imperative thatthis is understood when drugs are selected at national level, since choice is then influencedby the comparative cost and availability of equivalent products.

Definition: Essential medicines are those that satisfy the priority health care needs ofthe population.

Selection criteria: Essential medicines are selected with due regard to disease prevalence,evidence on efficacy and safety and comparative cost-effectiveness. Essential drugs areselected to fulfill the real needs of the majority of the population in diagnostic, prophylactic,therapeutic and rehabilitative services using criteria of risk-benefit ratio, cost-effectiveness,quality, practical administration as well as patient compliance and acceptance.

Purpose: Essential medicines are intended to be available within the context of functioninghealth systems at all times, in adequate amounts, in the appropriate dosage forms, withassured quality and at a price the individual and the community can afford.

Implementation: The implementation of the concept of essential medicines is intendedto be flexible and adaptable to many different situations; exactly which medicines are regardedas essential remains a national responsibility.

Clinical guidelines and a list of essential medicines lead to better patient care and effectiveprevention.

The principle of the concept is that a limited number of drugs lead to:

• Better supply of drugs• More rational prescribing• Procurement of good quality drugs at lower costs• Easier storage, distribution and dispensing• Focused training and drug information• Prescribers gain more experience with fewer drugs and recognize ADR better.


Essential drugs are selected based on:

• Morbidity pattern• Evidence of efficacy and safety• Relative cost effectiveness• Local manufacturing facilities• Pharmacokinetics considerations• Ensured quality, bio-availability, stability• Single compounds preferred over FDC• FDCs only if proven advantage of combination, decreasing emergence of resistance,

i.e. malaria, tuberculosis, HIV/AIDS.

Essential drug list should be:

• Evidence BasedBest balance of efficacy, safety, quality and cost

• EfficientFocuses therapeutic, decision, professional training, public information, finances

• FlexibleImplemented from primary to tertiary health care

• Forward LookingRegularly updated in accordance with new needs and information.

Rational drug use and essential drug concept are interdependent and interlinked.Availability of essential drugs will undoubtedly lead to more rational drug use and rationaluse of drugs shall promote more production and supply of essential drugs. There are threebroad categories of interventions to improve rational drug use. These have been classifiedas educational approaches, managerial approaches and regulatory approaches. Educationalapproaches attempt to inform or persuade prescribers, dispensers or patients to use drugs inthe proper, rational and efficient way. There are many types of this approach such as in-service training, face-to-face education, small group discussions, seminars, workshops andprinted education materials.

Managerial strategies attempt to improve drug decision-making by a variety of techniquesincluding use of specific processes, forms, packages and monetary incentives. The interventionsusing this approach include developing and implementing Essential Drug Lists or DrugFormularies, Standard Treatment Guidelines, implementing drug supply kit system,monitoring and feedback, establishing representative Pharmacy and Therapeutics Committees,establishing structured drug prescribing form, providing cost information, and set-upfinancing. Essential Drug Lists or Drug Formularies provide prescribers with a list of thedrugs felt to be most effective and economic in treating important health problems.

Regulatory approaches attempt to restrict allowable decisions by placing absolute limitson availability of drugs. These strategies rely on rules or regulations to change behavior.


Interventions using this approach are limiting or banning registration, changing productregistration status as well as prescribing and dispensing controls.

In general a combined intervention is likely to have a synergistic effect

Fixed-dose Drug Combinations (FDCs): They are produced and used to meet the followingobjectives:

1. To produce drug synergism in order to achieve a better therapeutic response than eachdrug used alone. Atleast they must have additive effect, for example, cotrimoxazole.

2. To reduce the incidence/severity of adverse effects of one drug by the other, for example,atenolol + amlodipine, combinations of antitubercular drugs.

3. To provide convenience of administration and to reduce cost of drug, leading to betterpatient compliance, for example, levodopa + carbidopa.

As against these, following are the demerits of majority of the currently available FDCs inIndia.

1. dosage alteration of one drug is not possible without alternation of other drugs.2. differing pharmacokinetics of constituent drugs pose the problem of frequency of

administration of the formulation.3. overprescribing and polypharmacy leading to consumption of unnecessary drugs.4. increased chance of adverse drug effects and drug interactions.5. increased cost.6. when an FDC has large number of ingredients (4 or more), as in the case of tonics,

haematinics and cough mixtures, a doctor may not know what are the ingredients inthe formulation he is prescribing.

WHO essential drug list has only 2.1% FDCs. As against this, according to a roughestimate, approximately 1,00,000 drug formulations are marketed in India. According to aconservative estimate nearly 70% of them are FDCs. A large majority of these FDCs are non-essential or useless at the best and irrational or harmful at the worst.

In India, doctors get information about various drugs largely from the medicalrepresentatives visiting them or from the promotional literature mailed to them by thepharmaceutical industry. More often a doctor consults various indexes like, Monthly Indexof Medical Specialties (MIMS), Current Index of Medical Specialties (CIMS), Indian DrugReview (IDR) or Drug Index (DI) to get information on drugs. The claimed objective of thesepublications is to share information but hidden agenda is to promote the commercial interest.One gets lost in the 'therapeutic jungle'. It becomes virtually impossible to choose the rightmedicine from plethora of drugs.

Therefore, it is essential for a doctor to develop the skill of critically evaluating theavailable drug formulations for their rationality based on efficacy, safety, cost and convenienceof administration before embarking on their use.


OBJECTIVES

1. Work out the cost of drug treatment for the given condition. Compare the drug costfor different brands.

2. Assign the status as rational/semirational/irrational to the given drug formulation asa whole and giving reason(s) for the same.

3. Comment on the following FDCa) Paracetamol + aspirinb) Paracetamol + Nimesulidec) Amoxycillin + clavulanic acid.

ETHICS

• A discipline dealing with what is good and bad and with moral duty and obligation• A set of moral principles or values• A theory or system of moral values• The principles of conduct governing an individual or a group.

Ethics is the study of right conduct and a rational process for determining the bestcourse of action in the face of conflicting choices. Medical ethics is the science of moral valuesthat guides a medical practitioner in their relationship with their patients, the state andprofessional brethren. It also includes ethical issues associated with providing health care orperusing biomedical research.

The four essential principles of ethics are:

1. Autonomy of Patients: Patients body is his/her own. He/she has right to decide aboutoperations and procedures. When patients come to you it is implied consent for routineprocedures. It is better to explain patient about every procedure and them perform.When special procedures are done stated/special consent is taken. Physician must guidepatients to take right decision.

2. Beneficence: One must remember that whatever we do, it should be done for benefit ofpatients.

3. Non-maleficence: Do no harm.4. Justice: Patient should get the best treatment and justice should be done to all as far as

possible.You need not have ethical worries if you behave in a beneficent, nonmaleficant, just

manner, protecting autonomy and following consistent moral code.Since ethics is an integral part of practice of medicine, its study should parallel that of

study of medicine. The purpose of this session is to make students start understanding ofprincipal moral values governing medical ethics. It should subsequently develop awarenessof frequent existence of ethical issues and dilemmas help develop the capacity for resolution

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Ethics and Humans28

Ethics and Humans 239

of these issues through ethical reasoning and acquire understanding of the function ofinstitutional bodies concerned with ethics. As in every sphere of life, medical profession hasalso moral duty and obligations, and so is in the field of pharmacology. Ethics in pharmacologyare most important when it comes to research on humans and the interaction of doctors andmedical representatives.

Earlier human beings were being used in research without their consent. History is fullof examples showing unethical use of human beings. Nurember code (1947) was the firstattempt to integrate ethics into research. The main emphasis of this code was to protect theintegrity of the research subject. This was followed by declaration of Helsinki in 1964 byWorld Medical Association and International Guidelines for biomedical research involvinghuman subjects by WHO (1982). In India, there are guidelines from ICMR, New Delhi (2000)forconduct of research on human beings. As per these guidelines it is mandatory to take writteninformed consent from any human who is going to be involved in research. This consentform is considered to be document of faith and trust. It safeguards autonomy, respect patient'sright to dignity.

Written Informed consent has following components:

1. Patient Information SheetProvides information to patient about the research work where he is going to beinvolved.

2. Consent FormUsed to document consent in writingInformed consent emerged from the ethical principle of Respect for Persons. Theseprinciples state that:

• Individuals be treated as capable of taking decisions for themselves ("autonomy")• Those with diminished autonomy be protected• Language: The informed consent and information sheet must be available in local

languages in validated format.

Informed consent is a PROCESS and involves:

• Providing all relevant information to the volunteer/patient• The patient/volunteer understanding the information provided• Voluntarily agreeing to participate• It should be in writing, there is no value of verbal consent• Basic right• Maintaining confidentiality.

The information on consent form includes:

a) Name and designation of investigatorb) Institute where the study will be carried out


c) Name and address of the patientd) Age, sex and hospital registration numbere) Title of the studyf) Procedure in layman's languageg) Option to opt out of the study without reasonh) Care will not suffer if he opts outi) Adverse effects (known and unknown)j) Signatures.

Written informed consent is needed in following circumstances:

1. All research projects involving human beings.Special care has to be taken about, double blinding, randomization, serious adverseeffects, whether to give placebo or not, cost of treatment, washout period, informedconsent form in writing, treatment after end of trial, insurance of subjects,randomization, etc.

2. Cancer chemotherapy3. Invasive procedures4. HIV testing5. Thalidomide prescription.

It is necessary to stress that taking informed consent should satisfy the letter and spiritof the procedure. Special groups like pregnant women, children, mentally ill patients werepreviously excluded from clinical trials. However, now the trend has changed to includethese groups in clinical trials so as not to deprive them of the benefits of new drugs andtherapies. Therefore, whenever possible the procedure is explained to the subject (during alucid interval or to a child using pictorial representations) and receiving the individualsconsent in addition to the guardian's consent is mandatory.

Example of an informed consent form:

PATIENT CONSENT DOCUMENT

Example 1

I_________________________ exercising my free power of choice, hereby give my consentto be included in this study of "Drug A" and understand that I will be treated with thisdrug for the disorder I am suffering from. I have been informed to my satisfaction by theattending physician, the purpose of this and follow up including the laboratoryinvestigations required to monitor and safeguard my body functions.

I, have also been explained the risk profile of the drug and am giving consent that I beincluded in the study. I am also aware of my right to opt out of the study at any timeduring the course of the study without having to give reasons for doing so.

Patient Signature: Date:Signature of investigator: Date:

Ethics and Humans 241

PATIENT CONSENT DOCUMENT

Example 2

Patient Consent Form

I exercising my free power of choice, herebygive my consent to be included in the study "Comparison of safety of Drug A and Drug B inIndian patients." I have been informed to my satisfaction by the doctor, the purpose of thisstudy. I will not be given any new medication. I am diagnosed to be suffering from

and will be receiving standard treatment for this disease. I understandthat I will be evaluated for adverse effects of drugs in the OPD only. The information will bekept confidential and will be used only for scientific purpose.

I am also aware of my right to opt out of the study at any time without having to giveany reason for doing so.

Patient Signature: Date:Signature of investigator: Date:

Consent form need to be signed by a relative/guardian for mentally ill patients.

Other ethical issues are:

• Meeting drug medical representatives (MRs)• Acceptance of gifts of equipment, travel, or accommodation from MRs• Attending at sponsored dinners and social or recreational events• Attending at sponsored educational events, continuing medical education, workshops,

conferences or seminars• Conducting drug company sponsored research• Company funding for medical schools, academic chairs, or lecture halls• Undertaking paid consultancy work for drug companies• Giving medication during pregnancy/lactation.

OBJECTIVES

At the end of the session a student shall be able to:1. Understand importance of ethical issues in clinical research.2. Understand the components of a written informed consent form and realize its medico-

legal implications.3. To recognize the specific groups (children, mentally ill patients, etc.) where informed

consent has to be sought from the legal guardian.Example 1:A new selective Cox-II NSAID has been launched to the market. You are invited on itslaunch in a five star hotel in Mumbai. You deliver a lecture in its favour. Its adverse effect


profile has not been investigated adequately. The drug company marketing the NSAIDgives you 500 tablets as sample and asks you to try out the drug on 30 patients. You are alsoinformed that you can present your findings at an international conference to be held after3 months in USA. There is no DCGI permission. The travel arrangement (along with family)will be sponsored by drug company. You agree and start using the drug on patients whoattend the dispensary where you work but not on patients who come to your private clinic.

Comment on ethical issues.

Example 2:

You are conducting a clinical trial in Punjab on hypertension. The informed consent are inEnglish language and there is no information sheet attached to it. The patient is just told tosign on it without giving any explanation. The patient is paying for all investigations doneduring the trial.

Comment on ethical issues.

How apt is the statement that,"A medicine in large dose can act like a poison,a poison in small dose can act like a medicine"A poison or toxin is a substance that can cause temporary or permanent damage if taken

into the body in sufficient quantity. A poison may be swallowed, inhaled, injected, instilledin the eye or absorbed through the skin. Once introduced into the body, a poison can quicklybe carried to all the tissues via the bloodstream. Signs and symptoms vary, depending onthe poison and its method of entry. Vomiting is common to many cases, with the attendantrisk of inhalation of the stomach contents.

Acute poisoning requires accurate assessment and prompt therapy may be needed. Hazardis associated not only with the potency of the poison but also with the quantity ingested, theduration of exposure and the presence of other ingredients in preparations, including solvents.

General principles:

It should be determined if the poisoning:1. Is life-threatening and already compromising vital functions;2. Poses a potential hazard or3. Is essentially harmless.

Early identification of the toxic substance (or ingredients and their potential toxicities)can save time and decrease the risk of toxicity and complications, particularly in instanceswhere a specific antidote could be lifesaving or prevent serious organ damage, e.g. methanol,paracetamol, arsenic, iron poisoning, etc.

Early collection of blood, urine and other body fluid samples to establish baseline valuesfor monitoring the toxin, glucose, electrolytes, acid/base status and organ damage may bevaluable in the management of the poisoned patient.

Obtaining the original toxic substance or container is more valuable and reliable forrapid and positive identification of the poison than depending on laboratory analysis ofblood, urine or other body fluids alone.

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Management of SomeCommon Poisonings

29


Supportive care:

• Contaminated clothing should be removed and the skin washed with soap and water.If contaminated, the hair should be shampooed.

• Reliable venous access should be established in comatose patients.Hypoventilation can be avoided by ensuring an adequate airway with suction, oxygen,

insertion of an airway and mechanical ventilation as required. Most poisons that depressconsciousness also impair respiration. An obstructed airway needs immediate attention.Dentures and oral secretions should be removed and the jaw held forward with the patientturned in a left semiprone position.

Volume depletion secondary to vomiting, diarrhoea and sweating is common and shouldbe corrected.

Hypoglycemia must be excluded in any comatose patient. If present, 50 ml of a 50%dextrose solution should be administered intravenously. Hypoglycemia should be suspectedparticularly in intoxication with oral hypoglycemics, salicylates and ethyl alcohol.

Hypotension is most common in severe barbiturate poisoning and whether due to volumedepletion or venous pooling, frequently necessitates monitoring of central venous pressureto determine fluid requirements.

Hypothermia (< 35° C) may develop in comatose patients.Cardiac conduction defects and arrhythmias may occur in acute poisoning with various

substances. ECG monitoring is advisable and attention should be given to aggravating factorssuch as acidosis, hypoxia and electrolyte/fluid disturbances. Specific treatment will dependon the toxin ingested and the type of arrhythmia.

Convulsions that are single and short-lived do not require immediate anticonvulsivetherapy. Diazepam, given slowly intravenously, should be administered if convulsions areprotracted or recur frequently, keeping in mind that it may produce CNS and particularlyrespiratory depression.

Terminating exposure to ingested toxins:

The stomach should be emptied after the ingestion of most poisons, (there are some notableexceptions, e.g. corrosives, volatile hydrocarbons and convulsants). Gastric emptying is clearlyunnecessary if the risk of toxicity is small or if the patient presents too late. Emptying thestomach more than 4 hours after ingestion is of questionable value, although worthwhilerecovery of tricyclic antidepressants (and other drugs which delay gastric emptying, e.g.anticholinergics, opiates, antihistamines and sympathomimetic amines) can be achieved 4-12hours after ingestion.

Induced emesis may be preferred to lavage in alert patients with an active gag reflex andis usually more efficient than lavage especially when large tablets or capsules have beenswallowed. Emesis is best induced with ipecacuanha.

Gastric lavage via a large-bore orogastric tube (32-40 F in adults and 16-28 F in children)is preferred in patients with a depressed level of consciousness, but only after a cuffed

Management of Some Common Poisonings 245

endotracheal tube has been inserted to prevent aspiration. Warm water is instilled and aftera minute the water is removed. The procedure may have to be repeated 5-6 times until nofurther drug is obtained.

Stomach emptying should be followed by the administration of activated charcoal, whichreduces absorption of many substances.

Activated charcoal

(WHO essential therapeutic group)Activated charcoal is a powerful adsorbent of a wide spectrum of drugs and poisonous

substances thereby reducing absorption from the gut. It is used in cases of overdosage oraccidental poisoning by drugs and other non-corrosive substances, usually after the stomachhas been emptied by lavage or emesis and plays an important role in the management ofpoisoning.

Since charcoal adsorbs ipecacuanha it should not be given before the emetic. Currentopinion favours the use of larger and more frequent doses of charcoal in all instances wherea potential for adsorbing intoxicants exists.

Binding of drugs in the lumen also creates a concentration gradient so that the drug orpoison passes continuously from the circulation into the gut lumen. There are indicationsthat this 'gastrointestinal dialysis' is valuable in hastening the elimination of numerous drugsor toxins that have already been absorbed into the bloodstream.

It is recommended that 2-4 additional doses of 20-50 g be administered in severelypoisoned patients, in cases where slow release tablets have been ingested (e.g. theophylline),in poisoning with drugs that are excreted into the bile, undergoing entero-hepatic recycling(e.g. tricyclic antidepressants, estrogens and progestogens, digitoxin) as well as those secretedinto the intestine (e.g. digoxin, pethidine).

It is of no value in poisoning with strong acids or alkalis, iron salts, lithium, petroleumproducts (including kerosene) and of questionable value in cyanide ingestion.

Activated charcoal may be mildly constipating, but is essentially safe and innocuous.Mixing the suspended dose with 20 ml lactulose and 50% syrup (or sorbitol 70%) makes itmore palatable and prevents the constipating effect.

Adult dose: Usually oral or via gastric tube, 50-100 g, prepared as a thick slurry in 200-500 ml water.

Paediatric dose: Under 6 years, 10 g in 50-100 ml water; older children, 20-50 g in100-300 ml water.

Osmotic laxatives, e.g. saline purgatives (such as sodium sulphate), sorbitol 70% or lactu-lose may usefully assist in clearing the bowel of potentially absorbable poisonous material.

Rough estimates of the dose, the time elapsed since exposure and the physical state ofthe patient determine whether emesis, gastric lavage, supportive care, or specific therapy isrequired, as well as the sequence of such interventions.


Poisoning with drugs

1. Paracetamol poisoningIt is the commonest ingested toxin in UK causing > 300 deaths in the UK each year. It israrely taken alone. The liver is the main target organ in paracetamol poisoning. Doses of 7.5-15 g in an adult may cause severe centrilobular hepatic necrosis. Renal tubular necrosis mayalso develop. Hepatic and renal failure typically manifest only after 3-5 days.

Clinical features: Within a few hours after the overdose (0.5-24 hours) patients experiencesymptoms of gastrointestinal irritability with anorexia, nausea, vomiting, abdominal pain,as well as pallor, malaise and increased sweating. During this phase the patient may, however,appear normal or asymptomatic. During the next 24-48 hours symptoms and signs may becomeless pronounced, but the blood chemistry starts to become abnormal. Very rarely coma andsevere metabolic acidosis develop in patients who have extremely high plasma paracetamolconcentrations (usually > 800 mg/L). Loin pain, haematuria and proteinuria after the first24 hours strongly suggest incipient renal failure. Features of hepatic necrosis with rightsubcostal pain and tenderness, recurrence of nausea, vomiting and jaundice can occur after2-3 days.

Management

Start treatment depending on time elapsed since ingestion of paracetamol:• If within 1 hour give activated charcoal.• If < 4 hours wait for blood levels.• If > 4 hours and >150 mg/kg don't wait for levels.

Emesis or gastric lavage is indicated if less than 6 hours have elapsed since ingestion.Activated charcoal should be administered if the specific antidote is given by the i.v. route,but is contraindicated if the antidote is given orally.

Acetylcysteine is the antidote of choice and is usually given intravenously. Althoughmore effective when administered within 8-12 hours of ingestion of paracetamol, recentstudies have indicated benefit if antidote therapy is initiated up to 96 hours after the overdose.Acetylcysteine has not been shown to contribute to hepatic injury that is already present.

Acetylcysteine: Use with caution in patients with asthma or a history of asthma. Patientsshould be observed carefully for the emergence of hypersensitivity reactions. Thehypersensitivity-type adverse reactions often tend to be due to histamine release and arenot necessarily true allergic reactions. Therefore, acetylcysteine may not need to bediscontinued in mild reactions. These reactions may be overcome by temporary cessation ofthe infusion, IV administration of an antihistamine, followed by a slower infusion rate ofacetylcysteine. Acetylcysteine is incompatible with rubber and metals, silicone rubber andplastic should be used.

Plasma potassium should be monitored. Hypokalaemia and ECG changes have beenassociated with paracetamol overdosage irrespective of the treatment. Considered to berelatively safe during pregnancy and breast feeding.


Adult dose: i.v. infusion, initially 150 mg/kg in 200 mL 5% dextrose over 15 minutes;then 50 mg/kg in 500 mL 5% dextrose over the next 4 hours by continuous infusion; followedby 100 mg/kg in 1 litre 5% dextrose over 16 hours.

The manufacturer's dosage regimen covers only the first 20-24 hours. The recommendeddose for the second 24 hours is 150 mg/kg in 1 litre 5% dextrose water over 24 hours. Theabove represents a minimum dosage requirement and is exceeded in some investigationalregimens.

Oral acetylcysteine is proven to be effective in the treatment of paracetamol overdose.Loading dose of 140 mg/kg followed by 70 mg/kg 4 hourly for 17 doses (over a period of 72hours). Solutions should be diluted to 5% in water or fruit juice/soft drink. Capsules orpowder should be taken with adequate amounts of fluid (250 mL).

If the initial paracetamol level is in the toxic range, full antidote therapy is necessary.Liver damage is likely to occur in 90% of patients with paracetamol levels > 300 mcg/mL at4 hours or > 45 mcg/mL at 15 hours post ingestion. Levels below 120 mcg/mL at 4 hours areunlikely to cause hepatotoxicity. For reliable hepatotoxicity risk assessment, blood for plasmalevels must be drawn after the drug has peaked (at least 4 hours post ingestion).

Patients presenting 24 hours or later after an overdose of paracetamol and havingdetectable plasma levels or biochemical evidence of hepatotoxicity must be givenacetylcysteine. Patients taking drugs that induce hepatic enzymes, e.g. barbiturates, phenytoin,carbamazepine, rifampicin and meprobamate, or alcohol abusers may develop paracetamoltoxicity at lower plasma concentrations; a lower threshold for instituting specific antidotetherapy should be used (50-70% of the potential toxic levels).

If paracetamol levels are in the potentially toxic range, liver and kidney function testsshould be performed daily.

Fatality at below mentioned levels

< 150 mg/kg Unlikely> 250 mg/kg Likely> 12 g total Potentially fatal

Carbocysteine and methionine can be used as alternative to acetylcysteine.2. Opioid poisoning

Respiratory depression is the most important toxic effect of the opioid analgesics. Deathfrom morphine poisoning is nearly always due to respiratory arrest.

Clinical features: Poisoning with morphine and other opioids produces central nervoussystem depression ranging from drowsiness to deep coma, respiratory depression withshallow respiration or apnoea, cyanosis, miosis (pin-point pupils), hypotension andhypothermia. If hypoxia is severe, the pupils may be dilated. In some cases there is spasticity,muscle twitching, convulsions and non-cardiogenic pulmonary oedema. The onset ofpulmonary oedema may be rapid, but in the comatose patient it may be delayed for up to 24hours after recovery from coma (following administration of an opioid antagonist).


Management

Stomach emptying using gastric lavage should be performed in the comatose patient via anorogastric tube after a cuffed endotracheal tube has been inserted to prevent aspiration.(Gastric emptying may be delayed because of opioid-induced pylorospasm.)

Activated charcoal should be administered to adsorb opioid in the intestine and may befollowed by a saline cathartic such as sodium sulphate, magnesium citrate or magnesiumsulphate. Sorbitol 70% or lactulose are also useful cathartics. Immediate attention to an adequateairway, and artificial ventilation, may be indicated.

Naloxone, an opioid antagonist, is administered intravenously or intramuscularly(preferably IV). The initial adult dose is 0.4-2 mg. If improvement does not occur immediatelywith IV administration, it may be repeated at 2-3 minute intervals to a maximum of 10 mg.The diagnosis should be reconsidered if 2-3 doses fail to produce a response. In children, theinitial dose is 0.01 mg/kg, followed if necessary by a dose of 0.1 mg/kg. Intramuscularnaloxone is an alternative in the event that IV access is not possible, or if the patient isthreatening to self-discharge.

Naloxone may precipitate a severe withdrawal syndrome in an addict that cannot bereadily suppressed during the period of action of the antagonist. The duration of action ofnaloxone is shorter than that of most opioids. Patients should be observed carefully; repeateddoses may be required after initial improvement.

Opioid induced pulmonary oedema should be treated with positive- pressure ventilationusing positive end expiratory pressure (PEEP).

Intravenous infusions of naloxone may be useful where repeated doses are required. Aninfusion of 60% of the initial dose per hour is a useful starting point (dose adjusted to clinicalresponse). Infusions are not a substitute for frequent review of the patient's clinical state.

3. Aspirin and other salicylatesToxic doses disturb the acid/base balance and uncouple oxidative phosphorylation whichmay result in metabolic acidosis or compensated respiratory alkalosis. In overdose, salicylatesmay be retained in the stomach for 4-8 hours or longer. Ingestion of large amounts may formconcretions in the stomach which may delay absorption.

Clinical features

These may include restlessness, hyperventilation, tinnitus, deafness, tachycardia, nausea,vomiting, sweating, hyperthermia, dehydration, pulmonary oedema, acute renal failure,hypokalaemia, hypoglycemia and hypoprothrombinaemia. Stupor and coma indicate severepoisoning.

Management

Therapeutic plasma salicylate level lies between 0.7 to 2.2 mmol/L or 100-300 mcg/mL.Severity can be determined by measuring blood salicylate levels 6 or more hours after acuteingestion, but may be misleading in severe acidosis. Emesis or lavage should be followed byactivated charcoal. Studies have indicated that repeated doses, 50-100 g every 4 hours, increaseclearance significantly by a process termed `gastrointestinal dialysis'.


Dehydration, acidosis, hypoglycemia and electrolyte disturbances should be corrected.Hyperthermia is managed by external cooling.

Alkalinisation of the urine (pH 7.5-8.5) by administering sodium bicarbonate orally orby infusion is recommended to increase excretion of salicylates. Care must be taken to avoidfluid overload and renal function closely monitored.

In severe poisoning with decreased urinary flow, pulmonary oedema or progressivedeterioration, charcoal haemoperfusion or haemodialysis should be considered. Antacidsmay be administered to counteract gastric irritation and vitamin K to correct derangedcoagulation mechanisms.

4. MethanolThe potentially fatal human dose of methanol is 30 ml of a 40% solution, although fatalitieshave been reported with 15 ml.

Clinical features

Initially symptoms include those of minor inebriation followed by a latent period of 12-30hours when methanol is metabolised to the toxic products formaldehyde and formic acid.Co-ingestion of alcohol delays the toxic effects. Severe acidosis is due to formic acid andlactic acidosis and the severe retinal toxicity is caused by formaldehyde. Further symptomsand signs include headache, confusion, vertigo, nausea, vomiting, abdominal pain, blurredvision, blindness, Kussmaul's respiration, restlessness, delirium, convulsions and coma.

Management

Gastric lavage or emesis as early as possible. (Charcoal does not absorb methanol welland is of little value.) Ethanol in all cases, while awaiting methanol determination. To maintaina blood level of 100 mg/dl of ethanol begin with a loading dose of 0.6 g/kg, followed by anethanol infusion of 66 mg/kg/hour (for non-drinkers) to 154 mg/kg/hour (for chronic ethanoldrinkers).

Particular attention should be directed towards the correction of metabolic acidosis withsodium bicarbonate. Haemodialysis, if the blood-methanol level is greater than 50 mg/dl,continue until the level is in the range of 20 mg/dl.

The administration of folate, in the form of leucovorin, may have a therapeutic advantage(1 mg/kg, up to 50 mg/dose, followed by the same dose 4 hourly for 6 doses).

Methanol, formic acid and formaldehyde are effectively removed by haemodialysis whichis about 8 times more effective than peritoneal dialysis.

Other indications for haemodialysis include any visual impairment, metabolic acidosisnot correctable with bicarbonate, and renal failure. Ethanol blood levels should be maintainedbetween 100 and 150 mg/dl. Note that ethanol prolongs the elimination half-life of methanolto 24-30 hours so that several days may be required to reduce methanol levels to < 20 mg/dlif haemodialysis is not used.


5. Tricyclic antidepressants (TCAs)Cardiovascular toxicity is the principal cause of fatalities from TCA overdose. It is caused bythe blockade of noradrenalin uptake as well as the anticholinergic, membrane stabilising andalpha-blocking effects of TCAs.

Clinical Features

Overdosage can produce central nervous system, anticholinergic and cardiovascular effects.Nervous system toxic effects include drowsiness, agitation, hallucinations, hyperactive

reflexes, myoclonus, choreoathetosis, muscle twitching and rigidity, convulsions, respiratorydepression and coma. Anticholinergic effects include flushing, dry mouth, dilated pupils,hyperpyrexia, and bladder and bowel paralysis.

Cardiovascular toxic effects include sinus tachycardia, hypotension, conductionabnormalities and arrhythmias, e.g. PR and QRS prolongation, ST and T wave changes,heart block, atypical and regular ventricular tachycardia, and ventricular fibrillation. Patientsmay develop respiratory complications similar to those seen in barbiturate overdose, whichmay include respiratory depression, aspiration pneumonia, adult respiratory distresssyndrome and pulmonary edema.

Management

Ensure a clear airway and adequate ventilation. Check arterial blood gases and correct anyhypoxia. If hypercapnia is present assisted ventilation is indicated. Gastric lavage is useful aslate as 8 hours after ingestion (gastric emptying is delayed by the TCAs).

Lavage should be followed by activated charcoal and further doses, given, e.g. every4-6 hours, may effectively remove enterorecycling drug. Blood pH must be checked andacidosis adequately corrected with bicarbonate to enhance protein binding and decrease theconcentration of free drug in the plasma.

Observe for 6 hours if asymptomatic. Patients who remain asymptomatic and have normalECG by 6 hours are unlikely to develop late complications. Perform 12 lead ECG and monitorcardiac rhythm. Repeat ECG if symptomatic. Check urea and electrolytes and monitor urineoutput.

Resist the temptation to treat arrhythmias with drugs. Arrhythmia is best treated bycorrection of hypoxia and acidosis. Otherwise, phenytoin and lignocaine are the antiarrhythmicdrugs of choice. Seizures may be treated with diazepam (0.1-0.3 mg/kg body weight) orlorazepam (4 mg).

Alkalinisation (with sodium bicarbonate) will usually benefit both convulsive activityand cardiotoxicity 0.5-2 mEq/kg IV bolus followed by i.v. infusion to maintain blood pH of7.5 has been suggested. Both sodium and potassium levels should be monitored closely.

Disopyramide, procainamide and quinidine are contraindicated because of their additivecardiac depressant effect. Physostigmine has been used for delirium, coma, choreo-athetosis,myoclonus and some resistant cardiotoxic effects, but must be used with caution because ofpotentially serious cholinergic effects. It should always be administered under close ECGmonitoring.


Prolonged monitoring is needed in severe poisoning as the half-lives of the TCAs varyfrom 24 to 72 hours, and may be increased in overdose.

6. OPC poisoningThe organophosphates and carbamates are cholinesterase inhibitors, indirectly causing astimulation of muscarinic and nicotinic receptors. They can be absorbed by ingestion,inhalation or via the skin. While the organophosphates form an irreversible complex withcholinesterase, the carbamyl-enzyme complex is reversible, leading to a less severe intoxicationwith a much shorter duration. The carbamates also penetrate the blood-brain barrier poorly,producing fewer CNS effects.

Clinical Features

The onset of features may be delayed for 12-24 hours after skin exposure. Early featuresinclude anxiety, restlessness, insomnia, tiredness, dizziness, headache, nausea, vomiting,abdominal colic, diarrhoea, sweating, hypersalivation, chest tightness and miosis. Muscleweakness and fasciculation may develop.

Severe poisoning causes widespread flaccid paralysis (including ocular and respiratorymuscles), convulsions, coma, pulmonary oedema with copious bronchial secretions,bronchospasm and cardiac dysrhythmias. Hyperglycaemia and glycosuria occur withoutketonuria.

Plasma cholinesterase activity is usually reduced to < 50% with clinical poisoning and to< 10% in severe cases.

Management

Supportive measures are vitally important to prevent further absorption according to routeof exposure. Remove soiled clothing and wash contaminated skin with soap and water (seeskin decontamination). Be sure that any cuts on your hands or face are protected. Pesticidespenetrate broken skin more readily than intact skin. Avoid contaminating yourself. Wearprotective clothing. In one report three emergency department staff suffered toxicity requiringtreatment after exposure to a contaminated patient!!

Consider gastric lavage if a substantial amount has been ingested within 1-2 hours. Careshould be taken to protect the airway, particularly if a hydrocarbon solvent is involved or ifconsciousness is depressed.

If there is bronchorrhoea and/or bronchospasm give atropine. Very large doses areoccasionally required. An initial intravenous 'test dose' of 1 mg in adults and 0.01 mg/kg inchildren provides a measure of severity. The dose of atropine in organophosphate poisoningis 0.05 mg/kg (2-4 mg in adults) every 15 minutes until full atropinisation is reached. Formaintenance therapy, an intermittent or continuous intravenous infusion of 0.05 mg/kg/hrmay be given. High doses of atropine are sometimes required initially (4-5 mg every 15minutes).

The criterion of adequate therapy is control of excessive bronchial and oral secretions. Insevere poisoning ensures a clear airway, adequate ventilation and removal of bronchialsecretions. Give high inspired oxygen concentration.


In moderate or severe poisoning give pralidoxime mesylate (P2S) to reactivatecholinesterase. Dosage instructions follow. Intravenous diazepam (5-10 mg for an adult, 0.02mg/kg body weight for a child) will control twitching and may reduce morbidity andmortality.

In moderate or severe poisoning give pralidoxime 30 mg/kg by intravenous injection(over 5-10 minutes) to reactivate cholinesterase—improvement should be apparent within30 minutes. Repeat doses at 4-6 hourly intervals may be necessary or an intravenous infusionof 8 mg/kg/hour can be given. Atropine administration should be initiated as soon as possible.

Close observation during this stage is essential, as rebound effects of organophosphatetoxicity (due to their lipid solubility) may occur.

Parameters to monitor

Presence of hypersecretion, ECG, pupil size, blood pressure and pulse, serial measurementof vital capacity (preferred to peak flow measurements) to detect respiratory insufficiency,and plasma cholinesterase. Normal levels of plasma cholinesterase are 3000-8500 U/L inadults.

Although cholinesterase reactivators such as obidoxime are widely regarded as valuableadjuvants in the early management of moderate to severe organophosphate poisoning (ifgiven within 24 hours of exposure), it is not clear if their use alters the outcome. Therapyshould be in conjunction with atropine and other supportive measures.

Cholinesterase reactivators, e.g. obidoxime, are contraindicated in carbamate poisoning.

Several complications may follow organophosphate poisoning:

• Since most of these substances have a petroleum base, aspiration may cause a chemicalaspiration pneumonitis.

• Potential toxicity of the vehicle should be taken into account.• Ventricular arrhythmias (with a prolonged QT interval) may occur.• Confusion and convulsions, due to the effects of the organophosphate or to excess

atropine, are best controlled with diazepam.• Aminoglycosides and succinylcholine should be avoided in organophosphate poisoning

because of their blocking effect on the neuromuscular junction.• Phenothiazines, reserpine and theophylline are also contraindicated.

OBJECTIVES

At the end of the session the student will be able to:1. List the general supportive measures to be extended to a patient with poisoning.2. Understand the principles of treatment of a patient with poisoning.3. List the steps in the management of a patient with:

(a) Organophorous poisoning.(b) Opioid poisoning.

One of the most important aspects of training of a doctor is acquisition of practical skills.Objective assessment of practical (psychomotor skills) is thus a challenge for examiners.OSPE is a method of examination which evaluates student's wide range of skills uniformlyand objectively. An OSPE consists of a number of predetermined stations (spots) throughwhich each student rotates. An examiner (observer) may be present on each spot to score thestudent's performance using a predetermined checklist or scoring is done after conduct ofOSPE.

OSPE fulfills all the requirements of a good evaluation method

1. Validity—it measures what it is supposed to measure.2. Reliability—

Is the examination objective assessment?Are results accurate and consistent?There is same station and predetermined checklist, so interobserver variation is

decreased to minimum. The difference in marks obtained in OSPE is because of abilityof the student, rather than due to extraneous factors.

3. FeasibilityIs it feasible to put into practice? The requirements for the staff and accommodation canbe met. It can cope with sufficient no. of students. If 1 minute is given for each station,in total 50 minutes you can objectively examine 50 students.

So, in nutshell OSPE is a form of practical examination which is objective and which owesits objectivity to a structured marking scheme. The OSPE converts subjectivity into objectivity,leading to fair and equal evaluation of students.

Approximately 20-50 spots can be chosen for OSPE. They can be from all branches ofpharmacology, for example:

Problem based therapeuticsProblem based drug interactionPrescription correctionCorrect use of inhaler

C H A P T E R

Objective StructuredPractical Examination (OSPE)

30


Filling injection from vialCalculate pharmacokinetic parameter, e.g. VdCalculation of doseIdentify instrument/apparatusIndication of a drug combinationNew drug delivery systemPharmacy preparationDosage forms, etc.Hence, there is wide inexpensive variety of spots you can choose in your department.

The various spots can be put serial wise in a room. There can be a list of questions for thatspot on each serial number. You need to appoint observers and give them a check list forobservatory spots, e.g. correct use of inhaler.

The various spots can be:

1. Starling heart lever:a. Identify.b. Where it is used?c. Write 1 advantage over simple lever.

2. Frontal writing levera. Identify.b. Where it is used?c. Write 1 advantage over simple lever.

3. Inhalera. Identify.b. Write 2 indications.c. Demonstrate how it is used.

4. Lignocaine 2%a. Identify.b. Write 2 indications.c. Write 1 adverse effect.

5. Calculate Vda. Plasma conc. 20 mg/L.b. Drug administered 1000 mg.c. Write 1 clinical significance of Vd.

6. Advertisement of a druga. Write 2 good points of this advertisement.b. Write 2 bad points of this advertisement.

Objective Structured Practical Examination (OSPE) 255

7. Combination of amoxycillin and clavulanic acida. Write 1 advantage of this combination.b. Write 2 adverse effects of this combination.

8. Fill in the blanks from the sample givena. Manufacturing date-----------b. IP means-----------------------

9. Vial of heparina. Write 1 indication.b. Write 2 adverse effects of this.

10. Skin patch of diclofenaca. Write 1 advantage of this.b. Write 1 adverse effect of this combination.

11. Combination of amoxycillin and clavulanic acida. Write 1 advantage of this combination.b. Write 2 adverse effects of this combination.

12. Informed consent forma. Write 1 reason why it is used in clinical studies in humans.b. Informed consent in clinical trials is mandatory True/False.

13. IV seta. Identify.b. Write 2 drug given by this.

14. Rotahalera. Write 1 advantage of this.b. Write 2 adverse effects of this.c. How it is used?

15. Analgesiometera. Which drugs are screened by this instrument?b. Which animals are used in this experiment?

16. Set up iv infusion on given modela. Write name of 2 drugs given by this route.

17. Inject im in given modela. Write name of 2 drugs given by this route.

18. Inject iv in given modela. Write name of 2 drugs given by this route.

19. Aspirate drug from ampoule.20. Reconstitute solution for injection.


21. Ciprofloxacin stripa. Write 2 brand names of this drug.b. Which is the cheapest brand?

22. OPC poisoninga. Write antidote.b. What is the dose?

23. A 40-year-old woman had a renal failure. She was not able to stick to a salt andprotein restricted diet. She developed an upper respiratory tract infection and comesto the hospital breathless, coughing up with purulent sputum. She got edema and herblood urea is raised. The intern on duty treated the infection with minocycline andedema with furosemide. After a week patient complaint improved but now shecomplained of deafness.a. What is the reason of deafness?b. Why was her blood urea raised?c. What alternate would you choose?

PROPOSED REVISED CURRICULUM

Skills to be acquired in pharmacology practicals as per proposed revised curriculum:

Psychomotor skills1. Dosage forms: Oral, Parenteral, Topical and Others2. Routes of drug administration, setting up an intravenous drip—Administer the required

dose of different drug formulations using appropriate devices and techniques (e.g.hypodermic syringes, inhalers, transdermal patches, etc.)

3. Calculation of drug dosage using appropriate formulae for an individual patient.4. Sources of drug information—how to retrieve information5. ADR monitoring—recognize and report adverse drug reactions to suitable authorities.6. Therapeutic Drug Monitoring—advice and interpret the therapeutic monitoring reports

of important drugs7. Critical appraisal of drug promotional literature—

a. Analyse critically, drug promotional literature for proprietary preparations, interms of the (a) pharmacological actions of their ingredients (b) claims ofpharmaceutical companies (c) economics of use (d) rational or irrational nature offixed dose drug combinations

b. Retrieve drug information from appropriate sources, especially electronic resources8. Essentials of Clinical trials9. Communicating to patients on the proper use of medication

10. Selection of P drug11. Prescription writing, prescription auditing and standard treatment protocols—Write a

correct, complete and legible prescription for common ailments including the conditionsin the National Health Programmes

12. Essential drugs list13. Use of drugs in pregnancy, lactation children and elderly14. Use of drugs in liver disease and renal disease

Appendix I


15. Ethics in clinical trials, therapy16. Preparation of test dose for penicillin solution17. Preparation and use of oral rehydration solution18. Informed Consent Form19. Computer assisted learning (CAL).

Attitudes and Communication skills

1. Communicate to patients regarding the optimal use of drug formulations, devices andstorage of medicines.

2. Follow the drug treatment guidelines laid down for diseases covered under the NationalHealth Programmes and be capable of initiating, monitoring treatment, recordingprogress, and assessing outcomes.

3. Motivate patients with chronic diseases to adhere to the line of management outlinedby the health care provider.

4. Appreciate the relationship between cost of drugs and patient compliance.5. Exercise caution in prescribing drugs likely to produce dependence and recommend

the line of management.6. Understand the legal aspects of prescribing drugs.7. Evaluate the ethics, scientific procedures and social implications involved in the

development and introduction of new drugs.

Appendix II

Schedule of practicals for MBBS 2nd Prof (18 months)(Effective period 15 months)

Theory Lectures Practicals

General pharmacology teaching Clinical pharmacy simultaneously

Pharmacokinetics part of Pharmacokinetic parametersgeneral pharmacology in between clinical pharmacy

ANS Continue clinical pharmacyWhen about to finish ANS Introduction to experimental pharmacology

Experimental pharmacology

CVS Effect of drugs on dog BPAntihypertensives Short experiments

Ethics

CNS Introduction to prescriptionwriting, P drug concept

Prescription examples of ANS, CVS, CNS

Chemotherapy ADR, TDM, Therapeutic follow-up,dose calculation

GIT Drug use in special population,new drug development

Endocrinology Promotional literature, drug interactions,rest of prescriptions and analysis

of prescriptions

Respiratory Formulation evaluation, ethics

Miscellaneous Revision

Appendix III

ESSENTIAL DRUG LIST (INDIA) 2003

The names of drugs are followed by the following letters to indicate their need at variouslevels of medical care:

P-Primary health careS-Secondary health careT-Tertiary health careU-Universal.

The information is given as:• Name of the Drug Category• Medicine Category• Route of Administration/ Strengths• Dosage Form.

1. ANAESTHETICS

1.1 General anaesthetics and OxygenEther S, T InhalationHalothane S, T InhalationIsoflurane* S, T InhalationKetamine HCl U Injection 10 mg/ml 50 mg/mlNitrous Oxide U InhalationOxygen U InhalationThiopentone Na S, T Injection 0.5 g, 1 g powder0.5%, 0.5% + 7.5% Glucose S, T Injection 0.25%

1.2 Local AnaestheticsBupivacaine HCLEthyl Chloride U Spray 1%Lignocaine HCl U Topical Forms 2-5%

* Complementary

Appendix IV

Appendix IV 263

Injection 1-2%Spinal 5% + 7.5% Glucose

Lignocaine HCl + Adrenaline U Injection 1%, 2% +adrenaline 1:200,000 in vial

1.3 Preoperative medication and sedation for short term proceduresAtropine Sulphate U Injection 0.6 mg/mlDiazepam U Tablets 5 mg Injection 5 mg/mlMidazolam U Injection 1 mg/ml 5 mg/mlMorphine Sulphate S, T Injection 10 mg/mlPromethazine U Syrup 5 mg/5 ml

1.4 Postoperative respiratory stimulantDoxapram* T Injection 4 mg/ml

2. ANALGESICS, ANTIPYRETICS, NSAIDS, MEDICINES IN GOUT AND RHEUMATOID DISORDERS

2.1 Non-opioid analgesics, antipyretics and nonsteroidal antiinflammatory medicinesAcetyl Salicylic Acid U Tablets 300-350 mgDiclofenac T Tablets 50 mg, 100 mg

Injection 25 mg/mlIbuprofen U Tablets 200 mg, 400 mgParacetamol U Injection 150 mg/ml

Syrup 125 mg/5mlTablets 500 mg

2.2 Opioid AnalgesicsMorphine Sulphate S, T Injection 10 mg/ml

Tablets 10 mgPentazocine S, T Tablets 25 mg,

Injection 30 mg/mlPethidine HCl S, T Injection 50 mg/ml

2.3 Medicines used to treat GoutAllopurinol S, T Tablets 100 mgColchicine S, T Tablets 0.5 mg

2.4 Disease modifying agents used in rheumatoid disordersAzathioprine S, T Tablets 50 mgChloroquine Phosphate S, T Tablets 150 mgMethotrexate S, T Tablets 2.5 mgSulfasalazine S, T Tablets 500 mg

* Complementary


3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS

Adrenaline Bitartrate U Injection 1 mg/mlChlorpheniramine Maleate U Tablets 4 mgDexchlorpheniramine Maleate Syrup 0.5 mg/5 mlDexamethasone U Tablets 0.5 mg

Injection 4 mg/mlHydrocortisone Sodium Succinate

U Injection 100 mgPheniramine Maleate U Injection 22.75 mg/mlPrednisolone S Tablets 5 mgPromethazine U Tablets 10 mg, 25 mg

Syrup 5 mg/5 ml

4. ANTIDOTES AND OTHER SUBSTANCES USED IN POISONINGS

4.1 NonspecificActivated Charcoal U PowderAtropine Sulphate U Injection 0.6 mg/ml

4.2 SpecificAntisnake Venom U Injection Polyvalent solution/ Lyophilyzed Polyvalent serumCalcium Gluconate S,T Injection 100 mg/mlDesferrioxamine Mesylate S, T Injection 500 mgDimercaprol S, T Injection in oil 50 mg/mlFlumazenil* T Injection 0.1 mg/mlMethylthioninium Chloride (Methylene blue)

S, T Injection 10 mg/mlNaloxone S, T Injection 0.4 mg/mlPenicillamine S, T Tablets or Capsules 250 mgPralidoxime Chloride (2-PAM)

S, T Injection 25 mg/mlSodium Nitrite S, T Injection 30 mg/mlSodium Thio S, T Injection 250 mg/ml

5. ANTIEPILEPTICS

Carbamazepine U Tablets 100 mg, 200 mgSyrup 20 mg/ml

Diazepam U Injection 5 mg/ml

* Complementary

Appendix IV 265

Magnesium Sulphate T Injection 500 mg /mlPhenobarbitone U Tablets 30 mg, 60 mg

ST Injection 200 mg/mlPhenytoin Sodium U Capsules or Tablets 50 mg, 100 mg,

Syrup 25 mg/ml,Injection 50 mg/ml

Sodium Valproate U Tablets 200 mg, 500 mgSyrup 200 mg/5 ml

6. ANTIINFECTIVES

6.1 Anthelminthics6.1.1 Intestinal AnthelminthicsAlbendazole U Tablets 400 mg

Suspension 200 mg/5 mlMebendazole U Tablets 100 mg

Suspension 100 mg/5 mlNiclosamide U Chewable Tablets 500 mgPyrantel Pamoate U Tablets 250 mg

Suspension 250 mg/5 ml6.1.2 AntifilarialsDiethylcarbamazine Citrate U Tablets 50 mg6.1.3 Antischistosomals and AntitrematodePraziquantel S, T Tablets 600 mg

6.2 Antibacterials6.2.1 Beta lactam medicinesAmoxicillin U Powder for suspension 125 mg/5 ml,

Capsules 250 mg, 500 mgAmpicillin U Capsules 250 mg, 500 mg

Powder for suspension 125 mg/5 mlInjection 500 mg

Benzathine Benzylpenicillin U Injection 6 lacs, 12 lacs, 24 lacs unitsBenzylpenicillin U Injection 5 lacs,10 lacs unitsCefotaxime* S, T Injection 125, 250, 500 mgCeftazidime* S, T Injection 250 mg, 1gCeftriaxone* S, T Injection 250 mg, 1 gCefuroxime* S, T Injection 250 mg, 750 mgCloxacillin U Capsules 250 mg, 500 mg

* Complementary


Injection 250 mg, Liquid 125 mg/5 mlProcaine Benzylpenicillin U Injection Crystalline penicillin(1 lac units) +Procaine penicillin (3 lacs units)6.2.2 Other antibacterialsAmikacin* S, T Injection 250 mg/2 mlAzithromycin* S, T Capsules or Tablets 100 mg,

250 mg, 500 mgSuspension 100 mg/5 mlInjection 500 mg

Cephalexin* U Syrup 125 mg/5 mlCapsules 250 mg, 500 mg

Clarithromycin* S, T Capsules 500 mgChloramphenicol S, T Injection 1 g

S, T Suspension 125 mg/5 mlS, T Capsules, Tablets 250 mg, 500 mg

Ciprofloxacin HCl U Injection 200 mg /100 mlTablets 250 mg, 500 mg

Co-Trimoxazole U Tablets 40 + 200 mg(Trimethoprim 80 + 400 mgSulphamethoxazole) Suspension 40 +200 mg/5 mlDoxycycline U Capsules 100 mgErythromycin Estolate U Syrup 125 mg/5 ml

Tablets 250 mg, 500 mg.Gentamicin U Injection 10 mg/ml 40 mg/mlMetronidazole U Tablets 200 mg, 400 mg

Injection 500 mg /100 mlNalidixic Acid U Tablets 250 mg, 500 mgNitrofurantoin U Tablets 100 mgNorfloxacin U Tablets 400 mgRoxithromycin* S, T Tablets 50 mg, 150 mgSulphadiazine* S, T Tablets 500 mgTetracycline U Tablets or Capsules 250 mgVancomycin HCL* T Injection 500 mg, 1 g6.2.3 AntileprosyClofazimine S, T Capsules 50 mg, 100 mgDapsone U Tablets 50 mg, 100 mgRifampicin U Capsules or Tablets 150, 300 mg

* Complementary

Appendix IV 267

6.2.4 Antituberculosis medicinesEthambutol U Tablets 200 mg, 400 mg, 600 mg, 800 mgIsoniazid U Tablets 50 mg, 100 mg, 300 mgOfloxacin* S, T Tablets 100 mg, 200 mg

Syrup 50 mg/5 mlPyrazinamide U Tablets 500 mg, 750 mg, 1000 mg,

1500 mgRifampicin U Capsules/Tablets 50 mg, 150 mg,

300 mg, 450 mgSyrup 100 mg/5 ml

Streptomycin Sulphate U Injection 0.75 g, 1 gThiacetazone + Isoniazid S, T Tablets 150 mg + 300 mg

6.3 Antifungal medicinesAmphotericin B S, T Injection 50 mgClotrimazole U Pessaries 100 mg,200 mg Gel 2%Fluconazole S, T Capsules or Tablets 50 mg,

100 mg, 150 mg, 200 mgFlucytosine S, T Capsules 250 mgGriseofulvin U Capsules or Tablets 125,250 mgKetoconazole S, T Tablets 200 mgNystatin U Tablets 500,000 IU

Pessaries 100,000 IU6.4 Antiviral medicines

6.4.1 Antiherpes medicinesAcyclovir* S, T Tablets 200 mg, 400 mg

Injection 250 mg, 500 mgSuspension 400 mg/5 ml

6.4.2 Antiretroviral medicines*6.4.2.1 Nucleoside reverse transcriptase inhibitors

Didanosine* S, T Tablets 250 mg, 400 mgLamivudine* S, T Tablets 150 mgLamivudine +Nevirapine + Stavudine*

S, T Tablets 150 mg + 200 mg + 30 mgLamivudine + Zidovudine* S, T Tablets 150 mg + 300 mgStavudine* S, T Capsules 15 mg, 30 mg, 40 mgZidovudine* S, T Tablets 100 mg, 300 mg

* Complementary


6.4.2.2 Non-nucleoside reverse transcriptase inhibitorsEfavirenz* S, T Capsules 200 mg, 600 mgNevirapine* S, T Capsules 200 mg

Suspension 50 mg/5 ml6.4.2.3 Protease inhibitors

Indinavir* S, T Capsules 200 mg, 400 mgNelfinavir* S, T Capsules 250 mgRitonavir* S, T Capsules 100 mg

Syrup 400 mg/mlSaquinavir* S, T Capsules 200 mg

6.5 Antiprotozoal6.5.1 Antiamoebic and antigiardiasisDiloxanide Furoate U Tablets 500 mgMetronidazole U Tablets 200 mg, 400 mg

Injection 500 mg/100 mlTinidazole U Tablets 500 mg6.5.2 AntileishmaniasisAmphotericin B S, T Injection 50 mgPentamidine Isothionate S, T Injection 200 mgSodium Stibogluconate S,T Injection 100 mg/ml6.5.3 Antimalarial medicines

6.5.3.1 For curative treatmentArtesunate T Injection 60 mgChloroquine Phosphate base U Tablets 150 mg

Injection 40 mg/ml, Syrup 50 mg/5 mlPrimaquine U Tablets 2.5 mg, 7.5 mgPyrimethamine U Tablets 25 mgQuinine Sulphate U Tablets 300 mg

S, T Injection 300 mg/mlSulfadoxine + Pyrimethamine U Tablets 500 mg + 25 mg

6.5.3.2 For ProphylaxisChloroquine Phosphate base U Tablets 150 mg

Syrup 50 mg/5 ml6.5.4 Antipneumocystosis and AntitoxoplasmosisCo-Trimoxazole (Trimethoprim+ Sulphamethoxazole)

U Tablets 40 + 200 mg, 80 mg + 400 mgSuspension 40 + 200 mg/5 ml

* Complementary

Appendix IV 269

Pentamidine Isothionate S, T Injection 200 mgTrimethoprim U Tablets 100 mg

7. ANTIMIGRAINE MEDICINES

7.1 For Treatment of acute attackAcetyl Salicylic Acid U Tablets 300 - 350 mgDihydroergotamine S, T Tablets 1 mgParacetamol U Tablets 500 mg

7.2 For prophylaxisPropranolol HCl U Tablets 10 mg, 40 mg

8. ANTINEOPLASTIC, IMMUNOSUPPRESSIVES AND MEDICINESIN PALLIATIVE CARE

8.1 Immunosuppressive medicinesAzathioprine* T Tablets 50 mgCyclosporine T Capsules 10 mg, 25 mg, 50 mg, 100 mg

Concentrate for Injection 100 mg/ml8.2 Cytotoxic medicinesActinomycin D* T Injection 0.5 mgAlpha Interferon* T Injection 3 million IUBleomycin* T Injection 15 mgBusulphan* T Tablets 2 mgCisplatin* T Injection 10 mg/vial 50 mg/vialCyclophosphamide* T Tablets 50 mg

Injection 200 mg, 500 mgCytosine Arabinoside* T Injection 100 mg/vial

500 mg/vial, 1000 mg/vialDanazol* T Capsules 50 mg,100 mgDoxorubicin* T Injection 10 mg, 50 mgEtoposide* T Capsules 100 mg

Injection 100 mg/5 mlFlutamide* T Tablet 250 mg5-Fluorouracil* T Injection 250 mg/5 mlFolinic Acid* T Injection 3 mg/mlGemcitabine HCl* T Injection 200 mg, 1 gL- Asparaginase* T Injection 10000 KUMelphalan* T Tablets 2 mg, 5 mg

* Complementary


Mercaptopurine* T Tablets 50 mg,Injection 100 mg/ml

Methotrexate* T Tablets 2.5 mgInjection 50 mg/ml

Mitomycin-C* T Injection 10 mgPaclitaxel* T Injection 30 mg/5 mlProcarbazine* T Capsules 50 mgVinblastine Sulphate* T Injection 10 mgVincristine T Injection 1 mg/ml

8.3 Hormones and antihormonesPrednisolone* S, T Tablets 5 mg

Injection 20 mg 25 mg (as sodiumphosphate or succinate)

Raloxifene* T Tablets 60 mgTamoxifen Citrate* T Tablets 10 mg, 20 mg

8.4 Medicines used in palliative careMorphine Sulphate* T Tablets 10 mgOndansetron* S, T Tablets 4 mg, 8 mg

Injection 2 mg/mlSyrup 2 mg/5 ml

9. ANTIPARKINSONISM MEDICINES

Bromocriptine Mesylate S, T Tablets 1.25 mg, 2.5 mgLevodopa+ Carbidopa U Tablets 100 mg + 10 mg,

250 mg + 25 mg, 100 mg + 25 mgTrihexyphenidyl HCl U Tablets 2 mg

10. MEDICINES AFFECTING BLOOD

10.1 Antianemia medicinesCyanocobalamin U Injection 1 mg/mlFerrous Salt U Tablets Equivalent to 60 mg elemental

ironOral solution 25 mg elementaliron (as sulphate)/mlFolic Acid U Tablets 1 mg, 5 mgIron Dextran S, T Injection 50 mg iron/mlPyridoxine U Tablets 5 mg

* Complementary

Appendix IV 271

10.2 Medicines affecting coagulationAcenocoumarol 4 mgHeparin Sodium S, T Injection 1000 IU/ml 5000 IU/mlMenadione Sodium Sulphite S, T Tablets 10 mgProtamine Sulphate S, T Injection 10 mg/mlPhytomenadione S, T Injection 10 mg/mlWarfarin Sodium S, T Tablets 5 mg

11. BLOOD PRODUCTS AND PLASMA SUBSTITUTES

11.1 Plasma substitutesDextran-40 U Injection 10%Dextran-70 U Injection 6%Fresh Frozen Plasma* T InjectionHydroxyethyl Starch (Hetastarch)

S, T Injection 6%Polygeline S, T Injection 3.5%

11.2 Plasma fractions for specific useAlbumin S, T Injection 5%, 20%Cryoprecipitate S, T InjectionFactor VIII Concentrate* S, T Injection DriedFactor IX Complex (Coagulation Factors II,VII, IX, X)

* S, T Injection DriedPlatelet Rich Plasma S, T Injection

12. CARDIOVASCULAR MEDICINES

12.1 Antianginal medicinesAcetyl Salicylic Acid* U Tablets 75 mg, 100 mg, 350 mgDiltiazem S, T Tablets 30 mg, 60 mgGlyceryl Trinitrate U Sublingual Tablets 0.5 mg,

Injection 5 mg/mlIsosorbide 5 Mononitrate/Dinitrate

U Tablets 10 mg, 20 mgMetoprolol* U Tablets 25 mg, 50 mg

Injection 1 mg/ mlPropranolol U Tablets 10 mg, 40 mg

Injection 1 mg/ml

* Complementary


12.2 Antiarrhythmic medicinesAdenosine* S, T Injection 3 mg/mlAmiodarone S, T Tablets 100 mg, 200 mg

Injection 150 mgBretylium Tosylate* T Injection 1 mg, 2 mg 4 mg/mlDiltiazem S, T Tablets 30 mg, 60 mgDiltiazem T Injection 5 mg/mlEsmolol* T Injection 10 mg/mlIsoprenaline HCl* T Injection 2 mg/mlLignocaine HCl S, T Injection 1%, 2%Mexiletine HCL S, T Capsules, 50 mg,150 mg

Injection 25 mg/mlProcainamide HCl T Tablets 250 mg

Injection 100 mg/ml*Quinidine T Tablets 100 mgVerapamil S, T Tablets 40 mg, 80 mg

Injection 2.5 mg/ml12.3 Antihypertensive medicines

Amlodipine U Tablets 2.5 mg, 5 mg,10 mgAtenolol U Tablets 50 mg, 100 mgChlorthalidone* U Tablets 25 mg, 50 mgClonidine HCl* S, T Tablets 100 mg, 150 mgEnalapril Maleate U Tablets 2.5,5,10 mg

Injection 1.25 mg/mlLosartan Potassium* S, T Tablets 25, 50 mgMethyldopa U Tablets 250 mgNifedipine S, T Capsules 5, 10 mgtablets 10 mg, 20 mg, Sustained release capsules 10 mg, or tablets 20 mg,Propranolol U Tablets 10 mg, 40 mgSodium Nitroprusside* T Injection 50 mg/ 5 mlTerazosin* S, T Tablets 1, 2, 5 mg

12.4 Medicines used in heart failureDigoxin S, T Tablets 0.25 mg

Injection 0.25 mg/mlElixir 0.05 mg/ml

Dobutamine* S,T Injection 50 mg/mlDopamine HCl S,T Injection 40 mg/ml

* Complementary

Appendix IV 273

12.5 Antithrombotic medicinesAcetyl Salicylic Acid U Tablets 75, 100 mgHeparin Sodium* S, T Injection 1000, 5000 IU/mlStreptokinaseST Injection 750,000,15,00,000IU,Urokinase T Injection 500,000 IU/ml

10,00,000 IU/ml

13. DERMATOLOGICAL MEDICINES (TOPICAL)

13.1 Antifungal medicinesBenzoic Acid + Salicylic Acid U Ointment or Cream 6% + 3%Miconazole U Ointment or Cream 2%

13.2 Antiinfective medicinesAcyclovir S, T Cream 5%Framycetin Sulphate U Cream 0.5%Methylrosanilinium Chloride (Gentian Violet)

U Aqueous solution 0.5%Neomycin+Bacitracin U Ointment 5 mg + 500 IUPovidone Iodine U Solution or Ointment 5%Silver Nitrate U Lotion 10%Silver Sulphadiazine U Cream 1%

13.3 Antiinflammatory and antipruriticBetamethasone Dipropionate U Cream/Ointment 0.05%Calamine U Lotion

13.4 Astringent medicinesZinc Oxide U Dusting Powder

13.5 Medicines affecting skin differentiation and proliferationCoal Tar U Solution 5%Dithranol* T Ointment 0.1-2%Glycerin U SolutionSalicylic Acid U Solution 5%

13.6 Scabicides and pediculicidesBenzyl Benzoate U Lotion 25%Gamma Benzene Hexachloride

U Lotion 1%

* Complementary


14. DIAGNOSTIC AGENTS

14.1 Ophthalmic medicinesFluorescein S, T Eye drops 1%Lignocaine S, T Eye drops 4%Tropicamide S, T Eye drops 1%

14.2 Radiocontrast mediaBarium Sulphate S, T Suspension 100% w/v 250% w/vCalcium Ipodate S, T Injection 3 gIopanoic Acid S, T Tablets 500 mgMeglumine Iothalamate S, T Injection 60% w/v

(iodine = 280 mg/ml)Meglumine Iotroxate S, T Solution 5-8 g

iodine in 100-250 mlPropyliodone S, T Oily, suspension 500-600 mg/mlSodium Iothalamate S, T Injection 70% w/v

(Iodine = 420 mg/ml)Sodium Meglumine Diatrizoate

S, T Injection 60% w/v(Iodine conc. = 292mg/ml) 76% w/v

(Iodine conc. = 370 mg/ml)

15. DISINFECTANTS AND ANTISEPTICS

15.1 AntisepticsAcriflavin+Glycerin U SolutionBenzoin Compound U TinctureCetrimide U Solution 20% (conc. for dilution)Chlorhexidine U Solution 5% (conc. for dilution)Ethyl Alcohol 70% U SolutionGentian Violet U Paint 0.5%, 1%Hydrogen Peroxide U Solution 6%Povidone Iodine U Solution 5%, 10%

15.2 DisinfectantsBleaching Powder U PowderFormaldehyde IP U SolutionGlutaraldehyde S,T Solution 2%Potassium Permanganate U Crystals for solution

Appendix IV 275

16. DIURETICS

Furosemide U Injection, 10 mg/ ml,Tablets 40 mg

Hydrochlorothiazide U Tablets 25 mg, 50 mgMannitol* U Injection 10%, 20%Spironolactone U Tablets 25 mg

17. GASTROINTESTINAL MEDICINES

17.1 Antacids and other antiulcer medicinesAluminium Hydroxide + Magnesium Hydroxide

U Tablet SuspensionOmeprazole U Capsules 10, 20, 40 mgRanitidine HCl U Tablets 150, 300 mg

Injection 25 mg/ml17.2 Antiemetics

Domperidone U Tablets 10 mgSyrup 1 mg/ml

Metoclopramide U Tablets 10 mgSyrup 5 mg/mlInjection 5 mg/ml

Prochlorperazine U Tablets 5, 25 mgPromethazine U Tablets 10 mg, 25 mg

Elixir or Syrup 5 mg/5 mlInjection 25 mg/ml

17.3 Antihaemorrhoidal medicinesLocal Anaesthetic, Astringent and Antiinflammatory Medicines

U Ointment/suppository17.4 Antiinflammatory medicines

Sulfasalazine T Tablets 500 mg17.5 Antispasmodic medicines

Dicyclomine HCl U Tablets 10 mgInjection 10 mg/ml

Hyoscine Butyl Bromide U Tablets or 10 mgInjection 20 mg/ml

17.6 LaxativesBisacodyl U Tablets/suppository 5 mgIsphaghula U Granules

* Complementary


17.7 Medicines used in diarrhoea17.7.1 Oral rehydration salts

U Powder for solution As per IP17.7.2 Antidiarrhoeal medicinesFurazolidone S, T Tablets 100 mg

Syrup 25 mg/5 mlLoperamide* S, T Capsules 2 mg(Contraindicated for paediatric use)

18. HORMONES, OTHER ENDOCRINE MEDICINES AND CONTRACEPTIVES

18.1 Adrenal hormones and synthetic substitutesDexamethasone S, T Tablets 0.5 mg

Injection 4 mg/mlHydrocortisone Sodium Succinate

U Injection 100 mg/mlMethylprednisolone S, T Injection 40 mg/ mlPrednisolone U Tablets 5 mg, 10 mg

18.2 AndrogensTestosterone T Capsules 40 mg (as undecanoate)

T Injection 25 mg/ml (as propionate)18.3 Contraceptives

18.3.1 Hormonal contraceptivesEthinylestradiol + Levonorgesterol

U Tablets 0.03 mg + 0.15 mgEthinylestradiol + Norethisterone

U Tablets 0.035 mg + 1.0 mgHormone Releasing IUD T Levonorgesterol Releasing IUD

18.3.2 Intrauterine devicesIUD containing Copper U

18.3.3 Barrier mMethodsCondoms U

18.3.4. Non hormonal contraceptivesCentchroman U Tablets 30 mg

18.4 EstrogensEthinylestradiol U Tablets 0.01, 0.05 mg

* Complementary

Appendix IV 277

18.5 Antidiabetics and hyperglycaemics18.5.1 Insulins and other antidiabetic AgentsGlibenclamide U Tablets 2.5 mg, 5 mgInsulin Injection (Soluble) U Injection 40 IU/mlIntermediate Acting Insulin (Lente/NPHInsulin)

U Injection 40 IU/mlMetformin U Tablets 500 mg

18.5.2 HyperglycaemicsGlucagon* T Injection 1 mg/ml

18.6 Ovulation inducersClomiphene Citrate* T Tablets 25, 50, 100 mg

18.7 ProgestogensMedroxy Progesterone Acetate

U Tablets 5, 10 mgNorethisterone U Tablets 5 mg

18.8 Thyroid and antithyroid medicinesCarbimazole S, T Tablets 5 mg, 10 mgLevothyroxine S, T Tablets 0.1 mgIodine S, T Solution 8 mg/5 ml

19. IMMUNOLOGICALS

19.1 Diagnostic agentsTuberculin, Purified Protein Derivative

U Injection19.2 Sera and Immunoglobulins

Anti-D S, Immunoglobulin(Human)T Injection 250, 300 mg

Antisnake Venom U Injection 10 mlAntitetanus Human Immunoglobin

U Injection 250 IU, 500 IUDiphtheria Antitoxin S, T Injection 10,000 IURabies Immunoglobulin U Injection 150 IU/ml

19.3 Vaccines19.3.1 For universal immunisationBCG Vaccine U InjectionDPT Vaccine U InjectionHepatitis B vaccine U Injection

* Complementary


Measles Vaccine U InjectionOral Poliomyelitis Vaccine (Live Attenuated)

U Solution19.3.2 For Specific group of individualsRabies Vaccine U InjectionTetanus Toxoid U Injection

20. MUSCLE RELAXANTS (PERIPHERALLY ACTING) AND CHOLINESTERASEINHIBITORS

Atracurium Besylate* S, T Injection 10 mg/mlNeostigmine S, T Tablets 15 mg

Injection 0.5 mg/mlPancuronium Bromide S, T Injection 2 mg/mlPyridostigmine Bromide S, T Tablet 60 mg

Injection 1 mg/mlSuccinyl Choline Chloride S , T Injection 50 mg/ml

21. OPHTHALMOLOGICAL PREPARATIONS

21.1 Antiinfective AgentsChloramphenicol U Drops/Ointment 0.4%, 1%Ciprofloxacin HCl U Drops/Ointment 0.3%Gentamicin U Drops 0.3%Miconazole U Drops 1%Povidone Iodine S, T Drops 0.6%Sulphacetamide Na U Drops 10%, 20%, 30%Tetracycline HCl U Ointment 1%

21.2 Antiinflammatory agentsPrednisolone Acetate U Drops 0.1%Prednisolone Sodium Phosphate

U Drops 1%Xylometazoline U Drops 0.05%, 0.1%

21.3 Local anaestheticsTetracaine HCl U Drops 0.5%

21.4 Miotics and antiglaucoma medicinesAcetazolamide S, T Tablets 250 mgBetaxolol HCl S, T Drops 0.25%, 0.5%Physostigmine Salicylate* S, T Drops 0.25%

* Complementary

Appendix IV 279

Pilocarpine S, T Drops 2%, 4%Timolol Maleate S, T Drops 0.25%, 0.5%,

21.5 MydriaticsAtropine Sulphate U Drops/Ointment 1%Homatropine U Drops 2%Phenylephrine U Drops 5%

21.6 Ophthalmic Surgical AidsMethyl Cellulose* T Injection 2%

22. OXYTOCICS AND ANTIOXYTOCICS

22.1 OxytocicsMethyl Ergometrine U Tablets 0.125 mg

Injection 0.2 mg/mlMifepristone T Tablets 200 mgOxytocin S, T Injection 5, 10 IU/ml

22.2 AntioxytocicsIsoxsuprine HCl S, T Tablets 10 mg

Injection 5 mg/mlTerbutaline Sulphate S, T Tablets 2.5 mg

Injection 0.5 mg/ml

23. PERITONEAL DIALYSIS SOLUTION

Intraperitoneal Dialysis Solution (of approximate composition)

24. PSYCHOTHERAPEUTIC MEDICINES

24.1 Medicines used in psychotic disordersChlorpromazine HCl U Tablets 25, 50, 100 mg

Syrup 25 mg/5 mlInjection 25 mg/ml

Haloperidol S, T Tablets 1.5, 5, 10 mgInjection 5 mg/ml

Trifluoperazine S, T Tablet 5 mg, 10 mg24.2 Medicines used in mood disorders

24.2.1 Medicines used in depressive disordersAmitriptyline U Tablets 25 mgFluoxetine HCl U Capsules 20 mgImipramine U Tablets 25 mg, 75 mg

* Complementary


24.2.2 Medicines used in bipolar disordersLithium Carbonate T Tablets 150 mg

24.3 Medicines used for generalized anxiety and sleep disordersAlprazolam U Tablets 0.25, 0.5 mgDiazepam U Tablets 2, 5, 10 mgNitrazepam U Tablets 5 mg, 10 mg

24.4 Medicines used for obsessive compulsive disorders and panics attacksClomipramine HCl S, T Tablets 10, 25 mg

25. MEDICINES ACTING ON THE RESPIRATORY TRACT

25.1 Antiasthmatic medicinesAminophylline U Injection 25 mg/mlBeclomethasone Dipropionate U Inhalation 50 mg, 250 mg/doseHydrocortisone Sodium Succinate

U Injection 100, 200, 400 mgSalbutamol Sulphate U Tablets 2 mg, 4 mg

Syrup 2 mg/5 mlInhalation 100 mg/dose

Theophylline Compounds U Tablets 100, 200 mg25.2 Antitussives

Codeine Phosphate U Tablets 10 mgSyrup 15 mg/5 ml

Dextromethorphan U Tablets 30 mg

26. SOLUTIONS CORRECTING WATER, ELECTROLYTE AND ACID-BASEDISTURBANCES

26.1 OralOral Rehydration Salts U Powder for Solution

As per IP26.2 Parenteral

Glucose U Injection 5% isotonic50% hypertonic

Glucose with Sodium ChlorideU Injection 5% + 0.9%

Normal Saline U Injection 0.9%N/2 Saline S, T InjectionN/5 Saline S, T InjectionPotassium Chloride U Injection 11.2% Sol.

Appendix IV 281

Ringer Lactate U InjectionSodium Bicarbonate U Injection

26.3 MiscellaneousWater for Injection U Injection 2, 5, 10 ml

27. VITAMINS AND MINERALS

Ascorbic Acid U Tablets 100, 500 mgCalcium salts U Tablets 250, 500 mgMultivitamins U Tablets

(Having composition as per schedule v of drugs and cosmetics act, 1940)

Nicotinamide U Tablets 50 mgPyridoxine U Tablets 25 mgRiboflavine U Tablets 5 mgThiamine U Tablets 100 mgVitamin A U Tablets 5000 IU,

Capsules 10,000 IU 50,000 IUInjection 50,000 IU/ml

Vitamin D 3 (Ergocalciferol) S, T Capsules 0.25 mg, 1 mg

Terminologies Used in Pharmacology

PHARMACOLOGY

Pharmacology is the science that deals with study of drugs and their action on livingorganisms. It consists of detailed study of drugs, including their actions on living animals,organs or tissues. The actions may be beneficial or harmful.

Pharmacology is combination of two words:Pharmacon = an active principle (drug)Logos = a discourse or treatise

DRUG

The name is derived from Drogue, a French word (means Dry herb). The name is derivedfrom the fact that most of the drugs earlier were obtained by drying plant or animal parts.

Definition of Drug

According to WHO “A drug is any substance/product that is used/ intended to be used tomodify/explore physiological systems/pathological states for benefit of the recipient.”

Drug is also defined as any chemical substance which is used for prevention, treatmentor diagnosis of a disease.

Examples:• Antibiotics for treatment of infection• Vaccines for prevention of disease• Radioactive iodine for diagnosis of thyroid cancer.Branches of Pharmacology: Pharmacology has expanded to much wider areas, so now it

has a number of branches or subdivisions.

PHARMACY

It is the art of preparing, compounding and dispensing drugs in such a way so as to make themedication suitable for easy, effective and palatable administration in the treatment of adisease.


Experimental Pharmacology

It is the study of drugs in animals. It usually involves research on animals using drugs.

Clinical Pharmacology

It is the scientific study of drugs in human being. It includes clinical trials/studies of newdrugs in human beings, identifying and reporting adverse drug reactions, rational drug useand essential drug concept. This area of pharmacology is most demanding these days. Withthe shift of a number of clinical trials of new drugs to India, the training, demand andrecruitment has increased tremendously in clinical pharmacology.

CLINICAL PHARMACY

It deals with patient care with particular emphasis on drug therapy. In practice it is patientoriented and includes not only the dispensing of required drug but also giving advice to thepatient on the proper use of all drugs, both prescribed and over the counter drugs. It usuallyutilizes the services of a pharmacist as an information source for members of the medical andother health professions on all matters pertaining to drugs and their dosage forms. Thispractice is quite common and also mandatory in developed countries. In India it has juststarted in few metropolitan cities. A number of good pharmacy stores have come up inmajor cities in India, which are following all aspects of clinical pharmacy.

Molecular Pharmacology

It deals with study of actions of drugs at molecular level.

Pharmacodynamics

It is the study of action of drugs on the body (what the drug does to the body).

Pharmacokinetics

It is the study of absorption, distribution, metabolism and excretion (ADME) of drugs (whatthe body does to the drug).

Pharmacognosy

It is the study of identification of source and physical properties of natural medicinalsubstances, i.e. drugs obtained from plants.

Pharmacotherapeutics

It is a branch of medicine concerned with the cure of disease or relief of symptoms usingdrugs. (It deals with the use of drugs in clinical practice). It is also called Drug therapy orpharmacotherapy.

Poison

A poison is a substance which when absorbed or ingested into the body may alter physiologyto a mild or a critical extent by damaging body tissues or cells.

Terminologies Used in Pharmacology 285

TOXICOLOGY

It is the science of poisons dealing with their detection, measurement and management ofpoisons. (Poisons are substances that cause harmful, dangerous or fatal symptoms in animalsand human beings.)

Pharmaceutics

It is an adjective which means pertaining to pharmacy. It deals in technique of calculation,preparation and dispensing required dosage forms.

Pharmaceutical chemistry

It is the application of organic and inorganic chemistry to pharmaceutics and relation ofthese principles to drug use.

Pharmacoeconomics

It involves the cost of drug therapy, including those of purchasing, dispensing (e.g. salariesof pharmacists, pharmacy technicians), storage, administration (e.g. salaries of nurses, costsof supplies), laboratory, other tests used to monitor client responses and losses fromexpiration. Length of illness or hospitalization is also considered.

Pharmacovigilance

It involves adverse drug event monitoring, detection, reporting and remedial measures.

AAcute abdomen 126Acute asthma 120Acute attack of migraine 128Acute gouty arthritis 137Acute severe asthma 121Adverse drug reaction (ADR) 178

types 178augmented 178bizarre 178continues use 178delayed 179end of dose 179

Adverse effects of drugs on miceusing rota rod apparatus 96

Allergic conjunctivitis 129Analgesic effect of drugs on rats

using tail flick method 94Anemia (microcytic hypochromic)

118Angina pectoris 119Animal toxicity studies 98Antidepressant effect of drugs

on mice 95Antipsychotics and tricyclic

antidepressants 197Aphthous ulcer 154Aspirate drug from ampoule

into syringe 41requirements 41technique 41

Aspirate drug from vial intosyringe 42requirements 42technique 42

AUC 106Autonomic nervous

system pharmacology 74

BBipolar disorder 148

Index

CCalculation of drug doses and

dilutions 223Cerebral malaria 143Chloroquine resistant malaria 142Chloroquine sensitive malaria 141Chronic simple glaucoma 153Clark’s rule 195Clearance 109

clinical significance 110salient features 109

Commercial preparations of drugs 13Common errors in prescription

writing 157Conversion between systems 8Creams 61

advantage 61disadvantage 61

Cytochrome P450 isoenzymes 165

DDepression 147Dilator pupillae 75Dissolve dry medicine in vial aspirate

drug solution into syringe 43requirements 43technique 43

Domestic weights and measures 8Dosage adjustment and plasma level

monitoring 200Dosage forms for injections 40Drug characteristics 36Drug interaction 162

pharmaceutical 162pharmacokinetic 163

Drug nomenclature 16Drug schedules 18Drugs and solutions used in dog BP

experiment 91

Drugs and solutions used in rabbit

intestine experiment 87

Drugs classified into various

categories 14

over-the counter (OTC)

drugs 14

prescription-only drugs 14

Drugs on the rabbit eye 75

drugs and solutions 76

procedure 76

corneal reflex 77

light reflex 77

size of pupil 76

requirements 76

Drugs schedules and acts 17

Dusting powder 59

advantages 60

disadvantages 60

Dysmenorrhoea 127

EEar drops 55

advantage 55

disadvantage 55

procedure 56

Effect of drugs on dog BP 92

Effect of drugs on frog heart 80

Effect of drugs on rabbit intestine 88

Effect of drugs on rats using hole

board test 97

Erectile dysfunction 152

Essential drug concept 234

implementation 234

purpose 234

selection criteria 234

Essential drug list (India) 2003 262

anaesthetics 262

general anaesthetics and

oxygen 262

local anaesthetics 262


analgesics, antipyretics, NSAIDs,medicines in gout and

rheumatoid disorders263

disease modifying agentsused in rheumatoid

disorders 263medicines used to treat

gout 263non-opioid analgesics,

antipyretics andnonsteroidal anti-

inflammatory medicines 263

opioid analgesics 263antiallergics and medicines used

in anaphylaxis 264antidotes and other substances

used in poisonings 264antiepileptics 264antiinfectives 264antimigraine medicines 269antineoplastic immuno-

suppressives and medicinesin palliative care 269

antiparkinsonism medicines 270blood products and plasma

substitutes 271cardiovascular medicines 271dermatological medicines

(topical) 273diagnostic agents 274disinfectants and antiseptics 274diuretics 275gastrointestinal medicines 275hormones, other endocrine

medicines andcontraceptives 276

immunologicals 277medicines acting on the

respiratory tract 280medicines affecting blood 270muscle relaxants (peripherally

acting) and cholinesteraseinhibitors 278

ophthalmological preparations278

oxytocics and antioxytocics 279

peritoneal dialysis solution 279psychotherapeutic medicines

279

solutions correcting water,

electrolyteand acid-base

disturbances 280

vitamins and minerals 281

Ethical criteria for drug promotion

211

Ethics 238

principles 238

Ethics and humans 238

Evaluation of drug formulations 232

Eye drops 54

advantages 54

disadvantages 54

procedure 54

Eye ointment 55

advantage 55

disadvantage 55

procedure 55

FFactors affecting drug disposition in

children 194

Factors affecting oral route of

administration 35

Facts about frog heart 81

FDA (USA) schedules 18

Food-drug interactions 167

Formulations 10

Fried’s rule 195

GGeneralized tonic clonic and partial

seizures 146

Genetic variations 204

Golden rules in treatment of

elderly 198

HHalf-life 108

clinical significance 109

salient features 108

Hepatic amoebiasis 133

Hepatic disease 201

first pass metabolism 201

hepatic blood supply 201

prodrugs 201

Herpes zoster 130

Hypertension (essential

hypertension with no

associated disease) 122

IImperial system 7

apothecary system (UK)/troysystem 8

avoirdupois system 7Importance of ethics 100Inject drugs subcutaneously 47

procedure 48requirements 48

Injection by intramuscular route 46procedure 46requirements 46

Injections by intramuscular route inan orange model 46procedure 46requirements 46

Injections by intravenous route 43procedure 43requirements 43

Inscription 113Insomnia 151Instruments in pharmacy 4

containers 5dispensing balance 4measuring cylinders and flask 4mortar and pestle 4pill tile 5spatulas 5wash bottle 5weights 4

Intestinal amoebiasis 134

LLabel 19

primary label 19secondary label 19

Liniments 60advantage 60disadvantage 60procedure 60

Loading dose 110maintenance dose 111

Local anaesthetics (Las) 79Local-inhalation 62

advantages 63care of for the rotahaler 64

Index 289

disadvantages 63procedure (for rotahaler) 64procedure for correct use

(for MDI) 63Local-oral 64

gargles and mouthwashes 64advantage 65disadvantage 65procedure 65

Lotions 60advantage 60

disadvantage 60procedure 60

MMedical journals 210Metabolism 164Metric system 7Miotics and mydriasis 78

classification 78indications 78

Model for IV injections for studentsin laboratory 44general principles 44requirements 44

Multibacillary leprosy 138Myasthenia gravis 150

NNaranjo algorithm 179Nasal drops 56

advantage 56disadvantages 56procedure 56

Nasal sprays 56advantages 56disadvantage 56procedure 57

NDDS-oral 66advantages 66prodrugs 66

New drug development 219New techniques for drug delivery 65NIDDM 125

OObjective structured practical

examination (OSPE) 253Ointments 60

advantages 61

disadvantages 61procedure 61

Oral candidiasis (thrush) 131Oral-capsules 32

advantages 33disadvantages 33type 32

hard gelatin type 32soft gelatine type 32

Oral-liquids 34advantages 34disadvantages 34

Oral-pills 33advantages 33disadvantages 33

Oral-powder 33advantages 33disadvantages 33

Oral-special preparations 36coated preparations 36sustained release (SR)

preparations 37advantages 37disadvantages 37

Oral-tablets 31disadvantages 32

Organization of ADR monitoringsystem in India 183

PPaints 61


Parameters of prescription audit 159Parenteral 40

intravenous injections (IV)advantages 41disadvantages 41

Parenteral-IM 45intramuscular injections 45

advantages 45disadvantages 45

precautions 45Parenteral-intradermal injection 48

epidural injections 48intra-arterial injections 48intra-articular injections 49intra-thecal injections 48

Parenteral-SC 46advantages 47disadvantages 47

Parenteral-sublingual 49advantages 49disadvantages 49

Parenteral-transdermal 49advantages 51disadvantages 51types 50

matrix controlled 50membrane controlled 50sandwich type 50

Parkinsonism 149Patient consent document 240Paucibacillary leprosy 139Peptic ulcer 124Pharmaceutical calculations 8

percent calculation 8percent by volume (%v/v) 9percent by weight (%w/w) 9percent weight in volume

(%w/v) 8proportion calculation 9

Pharmaceutical containers 6Pharmacopoeia 16Poisoning with drugs 246

aspirin and other salicylates 248clinical features 248management 248

methanol 249clinical features 249management 249

OPC poisoning 251clinical features 251management 251

opioid poisoning 247clinical features 247management 248

paracetamol poisoning 246clinical features 246management 246

tricyclic antidepressants (TCAs)250clinical features 250management 250

Postmarketing methods 180case control studies

(retrospective) 181case reports 181cohort studies 181prescription event monitoring

181spontaneous reporting-yellow

card system 181Premarketing clinical trails 180


Prepare and dispense 1:5000 solutionof potassium permanganate 24adverse effects 26labeling 25pharmacological actions 25procedure 24storage conditions 25therapeutic uses 25

Prepare and dispense 25 ml ofMandle’s throat paint 23labeling 23pharmacological actions 24

iodine 24potassium iodide 24

precautions 24procedure 23therapeutic uses 24

Prepare and dispense 50 ml ofcalamine lotion 21labeling 22pharmacological actions 22

bentonite 22calamine 22glycerine 22liquefied phenol 22sodium citrate 22zinc oxide 22

precautions 23procedure 21therapeutic uses 23

Prepare and dispense one dose of oralrehydration powder for 1000 ml

of oral rehydrationsolution (ORS) 26

home made ORS 28new WHO ORS 29objective of ORS 26pharmacological action of

salts 27glucose 27sodium chloride 27

pharmacological actions 27precautions 29procedure 26reduced osmolarity ORS 29super-ORS 28therapeutic uses 28WHO formula (for 1 litre ORS)

26Prescription 112

Primary syphilis 135Principles of ethics 100Process of pharmacokinetics 104

absorption of drugs 104distribution of drugs 104elimination of drugs 104

bioavailability 104clinical significance 105salient features 105

metabolism of drugs 104

RRational drug 233Rectal 37

advantages 37disadvantages 38

Renal diseases 202Routes of drug administration 11

SSource of drug information 208Sources of drugs 30

animals 30biosynthetic 30microorganisms 30minerals 30plants 30semisynthetic 30synthetic 30

Special need for ADR monitoringin India 182

Special toxicity studies 99Sphincter pupillae 75Sprays 61


Starling heart lever 80Status epilepticus 123Subscription 113Suppositories 57

advantages 57disadvantages 57procedure 58

Suspected adverse drug reactionreporting form 260

Sustained vs. controlled release 66Syme’s cannula 80Symposia/conferences 210

TTerminologies used in pharmacology

283

Therapeutic drug monitoring (TDM)

187characteristics 187

cost-effective 192indications 188

steps 188dosage adjustment 190

drug estimation methods 189

interpretation of plasmaconcentration data 189

time of sampling 188TDM procedure 191

antiepileptic drugs

(AED) 191carbamazepine 192

phenobarbitone 192phenytoin 191

Therapeutic follow-up cases/problems 215

Time of drug administration 10

Tips for writing a good prescription159

Tuberculosis 140Typhoid 136

UUpper respiratory tract infection 144

VVaginal candidiasis (vulvovaginitis)132

Vaginal pessaries 58advantages 58

disadvantages 58

procedure 58Volume of distribution (VD) 106

WWritten informed consent 240

YYoung’s formula 195

Badyal - Practical Manual of Pharmacology

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