General Principles of Pharmacology

Targets for drug action

* A drug is a chemical that affects physiological function in specific way

* Most drugs are effective because they bind to particular target protein including receptors

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• TEXT BOOK

• PHARMACOLOGY BY

• RANG & DALE

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TYPES OF RECEPTORS

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TYPES OF RECEPTORS1- Channel-linked receptors- coupled directly to an ion channel such acetylcholine, GABA & Glutamate receptors

2- G-protein-Coupled receptors- it produces second massenger as well as opening channel

-stimulated by adrenergic drugs, muscarinic & hormones

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Continue TYPES OF RECEPTORS

3- Kinase-linked receptors- insulin & growth hormone receptors- this type also linked to guanylate cyclase*** ALL PREVIOUS TYPES OF RECEPTORS ARE MEMBRANE BOUND

4- Receptors that regulate gene transcription* They are soluble receptor usualy inside the cell (cytosol or intranuclear protein)* Steroid , thyroid, retinoic acid & vit D

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* Drug binds only to certain targets

* Individual targets recognise only certain class of drug

* There are no drugs completely specific in action

* Increase the dose will affect other targets in cell

Drug Specificity

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Binding of Drugs to Receptors* Binding of drugs to receptors obeys the law of mass action (the rate of chemical reaction is proportional to the product concentrations of reactants)

*At equilibrium, receptor occupancy is related to drug concentration

* The higher the affinity of drug for receptor, the lower the concentration needed for occupancy

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Agonist & antagonist(blocker)* drug acting on receptor may be agonist or antagonist

A- Agonist initiates changes in cell function

* Full agonist: has high efficacy

* Partial agonist

- it produces submaximal effects

- it has intermediate efficacy

* Partial agonist:

What is is the efficacy ?

It is the ability of drug to initiate biochemical changes leads to the effect of drug

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Inverse Agonists

The actions of an inverse agonist may also be blocked by an antagonist of that receptor.

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BLOCKER* it binds with receptor without initiating biochemical changes

* it has zero efficacy

* it binds with any state of receptor (active & inactive)

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Types Drug Antagonist

A- Chemical antagonist

B- Pharmacokinetic antagonist

* one drug affecting other drug via:

- Absorption

- Metabolism

- Excretion

C- Competitive antagonism(BLOCKER)

* Reversible & * Irreversible

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Continue Types Drug Antagonist

D- Non-Competitive antagonism

- interrupts receptor-effector linkage

- e.g. calcium channel blocker prevents the effects epinephrine on the heart and blood vessels

E- Physiological antagonism

- Two drugs producing opposite effects

- Omeprazole blocks histamine in gastric acid secretion

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Desensitization and Tachyphylaxis

* They are synonymous which describe RAPID loss in the

effect of drug despite an increase in the dose of drug

* Due to depletion of endogenous neurotransmitters

TOLERANCE* It is a decrease in effects of drug as a result of repeated use of drug

* It take few days or weeks to develop

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Mechanism of Tolerance, Tachyphylaxis & desensitisation etc..

1- Change in Receptors

- (agonist failure to induce biochemical changes)

2- Loss of Receptors

3- Exhaustion of mediators (depletion)

4- increased metabolic degradation5- Physiological adaptation (kidney & antihypertensive)

6- Active extrusion of drug from cells

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DOSE RESPONSE RELATIONSHIP

It is a relationship between the drug amount (concentration) and pharmacological effects

• Types of responses

a- Graded response

- response increases by increase the dose

b- All or none response such as

anti-convulsant.

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Therapeutic index

* it is a measure of drug safety

* How to calculate ?

- LD50/ED50

Potency of drug* It is the minimum dose required to cause maximum response

* Potency of drug is not important clinically

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HOW DRUGS MEDIATE THEIR ACTIONS ?

* Via interacting with its target(s) leading to:

1- activation or blocking of receptors

2- block endogenous mediators (counterfeit)

3-open or close ionic channels (Benzodiazepine &L.A. )

4- compete with uptake system (carrier)

- imipramine, cocaine, proton pump inhibitor, digoxin, probenecid

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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?

5- Enzymes (dihydrofolate reductase targeted by methotrexate & trimethoprim, cyclooxygenase, xanthine oxidase, MAO, Dopa decarboxylase, ACE etc…..)

6- Other targets such as

* Immunophilins in lymphocyte targeted by immunosuppresants such as Cyclosporin & Tacrolimus

* Tubulin of phagocytes and other cells including cancerous cells

- Targeted by Colchicine, Vincristine & Taxol

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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?

7- Physical means

- Osmotic diuretics

- inhalational anesthesia

8- Chelating agent

* reacts with DNA or ions

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Examples on the mechanisms of drugs action

1- activation of muscarinic receptor in the heart(M2) * ACTIVATE Gi-protein which lead to decrease in Camp

* This leads to decrease in calcium influx

* This causeS bradycardia

2- Activation of muscarinic receptor in smooth muscle (M3)

* This leads to activate Gs-protein leads which leads to increase calcium influx which causes contraction

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Examples on the mechanisms of drugs action

3- activation of alpha-1 receptor in the blood vessels * ACTIVATE Gi-protein which lead to increase in IP3(Inositol triphosphate VIA activation of G-protein

* This leads to an increase in calcium influx and vasoconstriction

4- Activation of beta-1 receptor in heart * This leads to activate Gs-protein leads which leads to activate adenylate cyclase which causes phosphorylation of calcium channel

* calcium influx which causes contraction(Tachycardia & increase in the force of cardiac muscle contraction (+ve inotropic

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Examples on the mechanisms of drugs action

5- Activation of beta-2 receptor in smooth muscle * This causes to activate Gs-protein and to activate adenylate cyclase

•CAMPactives protein kinase which leads to series of phosphorylation of various protein

•phosphorylation either activates or inhibits target enzyme or channel

* in smoth muscle , CAMP dependent protein kinase phosphoryate myosin-light chain kinase which required for contraction (relaxation occurred)

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Classification of adverse effects

1- TYPE A- It is dose related

- It depends on therapeutic index

2- Type B- Non-dose related

- immunological reactions

- Pharmacogenetic

3- Long-Term effects- Adaptive changes

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Classification of adverse effects

- Rebound Phenomena

- It depends on therapeutic index

4- Delayed effects- Non-dose related

- Carcingenesis

- impair fertility

- Teratogenicity

- drug in breast milk

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Pharmacokinetic of drugs

1- ABSORPTION OF DRUG

- From the site of administration

2- Distribution- To reach the site of action

3- metabolism- to inactivate or activate

4- Excretion

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ROUTE OF DRUG ADMINISTRATION

1- Oral administration (P.O.)

2- Subcutaneous (S.C.)

3- Intradermal

4- Intramuscular (I.M.)

5- Intravenous (I.V.)

6- Sublingual

7- Rectal

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ROUTE OF DRUG ADMINISTRATION

8- Intrathecal & epidural

9- Inhalation

10- Topical

* skin

* eye

* mucous membrane

-nasal, vaginal, oropharynx

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ORAL ADMINISTRATION

1- PROS• Convenient• Safe ?• Economical (does not need sterilization)

2- CONS• Requires patient compliance• Drugs irritant to stomach• Drugs not stable in GIT• Drugs extensively metabolize by the liver

• Drugs NOT absorb from GIT

• Leads to food drug interaction

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INTRAVENOUS ADMINISTRATION

1- PROS• Rapid action• Delivered the desired amount

• irritant drug can be given only I.V. but NOT S.C.

2- CONS• Increase the risk of adverse effects

• Must inject slowly in order to minimize the effects of drug on the heart

• It needs constant monitoring the reponse of patient

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SUBCUTANEOUS ADMINISTRATION

1- PROS• It provides sustain effects because of slow absorption• Addition of vasoconstrictor decreases further the rate of absorption from the site of injection• It is suitable for insoluble drugs such as pellets

and suspension

2- CONS• can not inject large volume

• can not inject irritant drug

• repeated injection leads to necrosis (atrophy of skin)

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INTRAMUSCULAR ADMINISTRATION

1- PROS• Suitable for oily vehicle and irritant drug• The rate of absorption is very high because of high blood flow in the muscle

2- CONS• It is not recommended in patient taking Anti-coagulant

• Increase CPK

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PULMONARY ADMINISTRATION

1- PROS• Rapid absorption• Local administration into the lung is beneficial in bronchial asthma•Avoid hepatic effects•Can absorb fine droplets (aerosol), prticle size, gaseous and volatile drugs

2- CONS• Difficult to regulate & administered the dose• some drugs cause lung irritation

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TOPICAL ADMINISTRATION

1- Mucous membrane

• Rapid absorption such as local anesthetic & ADH

2- Skin

• Lipophilic drugs absorb rapidly from skin such as nitroglycerin skin batch, scopolamine batch• Inflammed, burned, abraded skin absorb drug faster

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TOPICAL ADMINISTRATION

3- Ophthalmic absorption• it is used for local effectss• systemic absorption occurs through NASOLACRIMAL CANAL such as β-adrenergic blockers eye drops

•Ointment and suspension minimized systemic absorption•Ocular insert provides continous delivery of drug with minimum systemic absorption

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SUBLINGUAL ADMINISTRATION

• Excellent absorption for non-ionized drug Example Nitroglycerin, apomorphine (Uprima)

• It has high absorption rate close to intravenous injection

• Avoid hepatic first pass metabolism

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RECTAL ABSORPTION

• It is used when oral route is warranted such as vomiting or coma

• It has erratic, irregular and incomplete absorption (50%)

• It goes in partial hepatic first pass metabolism

•Some drugs may cause rectal irritation

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DRUGS DISTRIBUTION

Factors influence drug distribution1- Permeability of drug to biological membranes•Blood brain barrier

•Testicular barrier

•Placental barrier

- LIPID SOLUBLE DRUGS

-They have large Vd (volume of distribution)

2- Extent of plasma protein

- Highly protein bound stay in circulation & also have large Vd

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DRUGS DISTRIBUTION

Factors influence drug distribution-Drugs with large Vd have the following properties

•High protein binding

•High lipid solubility

•High affinity to other tissues such as bone & liver

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DRUGS DISTRIBUTION

Factors influence drug distribution3- Availability of transport mechanism - passive diffusion: The drug must be in unionized form

- Active transport: require ATP

- Facilitative diffusion: it requires carrier but without energy such vit B12, glucose and amino acid

- ion pair transport: the ionic compound combines reversibly with endogenous compound such as MUCIN in GIT

4- Regional pH - breast milk more acidic than blood: Weak base drugs accumulate in breast milk

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DRUGS DISTRIBUTION

Factors influence drug distribution4- Rate of blood flow to tissues - Skeletal muscles have high blood flow

5- Regional pH - breast milk more acidic than blood: Weak base drugs accumulate in breast milk

6- Tissues mass

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DRUG METABOLISM

OBJECTIVES OF METABOLISM

1- To make the drug more water soluble in order to facilitate its excretion

2- To activate or inactivate the drug

* Some drugs become highly toxic or carcinogenic

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Factors influence Metabolism

1- Drugs- inducer: rifampicin, dilantin, barbiturate

- inhibitors: cimetidine, macrolide & antifungal drugs

2- Liver diseases

3- Diet- grape fruit, vitamins deficeincy such vit B6 is cofactor for decarboxylation

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Types of reactions in metabolism

* Phase-I reaction- consist of oxidation (dealkylation & deamination) , reduction or hydrolysis

- the product is reactive such as hydroxyl

-Some time highly toxic

- the product ready to enter other phase of metabolism

* Phase-II- Normally results to inactive compound

- involve conjugation of glucuronyl, sulfate Play a role

in enterohepatic cycle

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EXCRETION OF DRUGS

1- TYPES OF EXCRETION

• Renal excretion

• Biliary excretion

• Pulmonary excretion

• Excretion via other body fluids

- Saliva

-Breast milk

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RENAL EXCRETION OF DRUGS

Some drugs mainly excreted via kidney such as metformin & sotalol etc…

•Factors influence renal excretion•GFR• Interference with renal active transport of drug such as probenecid

• Altering passive diffusion by change PH, lipid solubility

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RENAL EXCRETION OF DRUGS

•Altering passive diffusion by change PH

- When pH of urine acidic, weak base drug will not be reabsorb from renal tubule

-When pH of urine alkaline, weak acid drugs will not reabsorb from renal tubule

•Lipid water solubility

- Highly lipid soluble drug stay in circulation for longer time

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BILIARY EXCRETION & ENTEROHEPATIC CYCLE OF DRUGS

Liver cells transfer various drug from plasma to bile by

• Transport system similar to renal tubule

• conjugates drugs and concentrate these drugs in bile and the delivered into the intestine

• Some conjugate drugs which is delivered into the intestine hydrolyzed to unconjugated drug (free drug)

• The free drug reabsorb back into circulation

• This called enterhepatic cycle.

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BILIARY EXCRETION & ENTEROHEPATIC CYCLE OF DRUGS

• This creates a reservoir of recirculating drugs which represent around 20% of total drug in the body

• This cycle maintains drug blood levels leading to prolongs the drug action

• Examples of drugs go through enterohepatic cycle:

- Digoxin

- morphine

- steroids including sex hormones

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PULMONARY EXCRETION OF DRUGS

Pulmonary excretion does not require metabolism

• Factors influence pulmonary excretion 1- Rate of respiration

2- Cardiac output

3- solubility of gas in blood - High blood solubility decreases gases loss from lung

- In contrast less blood soluble, leads to faster loss of gas via lung such nitrous oxide

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Excretion of drugs via other body fluids

1- Sweat

- Drugs or its metabolite may be responsible for induction of dermatitis or other skin reactions

2- Saliva - change in taste or induction metallic taste

3- Milk- The PH of milk is 6.5, therefore the weak base drugs will concentrate in milk

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