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DOSAGE OFDRUGS,CALCULATION AND

CLINICAL APPLICATION LEARNING OBJECTIVES

At the end of lecture student should be able to know,

MAINTENANCE DOSE LOADING DOSE PEDIATRIC DOSE EFFECTIVE DOSE MEDIAN EFFECTIVE DOSE LETHAL DOSE MEDIAN LETHAL DOSE DOSAGE REGIMENS

DOSE Quantity of a drug given to the patient at one time to produce

certain therapeutic effect.

DIFFERENT DOSES

MAINTENANCE DOSE LOADING DOSE PEDIATRIC DOSE EFFECTIVE DOSE MEDIAN EFFECTIVE DOSE LETHAL DOSE MEDIAN LETHAL DOSE MAINTENANCE DOSE:

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o In most clinical conditions, drugs are administered in a

series of repetitive doses or as a continuous infusion inorder to maintain a steady state concentration of thedrug in the body i.e. just enough drug is given in each

dose to replace the drug eliminated since the precedingdose.

Therefore calculation of maintenance dose is essential.

To maintain a chosen target concentration (Css), rate ofdrug input (maintenance dose) is equal to rate of drugclearance.

Dosing Rate = Rate of clearance at specified targetconcentration.

o Dosing rate (I/V) = Cl TC (Target Concentration) If the desired target concentration is known, clearance of

drug will determine dosing rate. If the drug is given by routethat has bioavailability less than 100% (oral route) dosingrate is predicted b

Dosing rate (oral) = dosing rate (I/V)

F (oral)

F is the bioavailability OR

Dosing rate = Cl TCo F

If intermittent doses are given maintenance dose iscalculated as

Maintenance dose = Dosing rate Dosing interval.o Example:

A target plasma theophylline concentration of 10 mg/L isneeded to relieve acute bronchial asthma. Mean clearanceof theophylline is 2.8 L/h/70Kg.

Since the drug is given intravenously,o dosing rate is = Cl TC

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= 2.8 L/h/70Kg 10mg/L

= 28 mg/h/70Kg

Therefore, in this patient proper infusion rate would be 28

mg/h.

When acute attack is relieved drug can be given orally atevery 12 hours. The oral bioavailability of drug is 0.96, thesize of each maintenance dose is calculated as:

Maintenance dose = Dosing rate Dosing interval.o As Dosing rate (oral) = dosing rate (I/V)o Therefore F (oral)

o Maintenance dose = dosing rate (I/V) Dosing interval. F (oral)

o = 28 mg/h 12 h

0.96

= 350 mg.

LOADING DOSE:

Loading dose is one or series of doses that may be given atonset of therapy to achieve target concentration quickly, it is

calculated as Loading dose = TC Vd

Fo Loading dose may be desirable if time required to attain

steady state concentration by the administration of drugat constant rate is long relative to demands of thecondition being treated.

For example half-life of Lignocaine is one hour. Arrhythmias

following myocardial infarction are usually rapidly fatal, andone can not wait for 46 hours to achieve therapeuticconcentration of lignocaine by infusion of drug at the raterequired to maintain this concentration.

Therefore loading dose of Lignocaine is usually given incoronary care unit.

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Disadvantages of loading dose:

Patient may be exposed abruptly to toxic concentration of adrug.

If drug has long half-life, it will take long time for theconcentration to fall, if plasma level of drug is high.

Loading dose is usually given intravenously, this isparticularly dangerous if loading dose is large and drug isadministered rapidly.

PEDIATRIC DOSE:

Because of the differences in pharmacokinetics in infantsand children, they require small doses as compared toadults. The approximation of pediatric doses can be madeby methods based on age, weight and surface area.

These approximations are not precise and should not beused if manufacturer provides a pediatric dose.

YOUNGS RULE: Pediatric dose = Age of child adult dose

Age + 12

FRIED RULE: Pediatric dose = Age (in months) adult dose

150

CLARKS RULE: Pediatric dose = Weight (in Kg) adult dose

70 Pediatric dose = Weight (in Lbs) adult dose

150o Based on surface area:

o Pediatric dose = Surface area (in sq. m) adult dose

1.7

Dosage calculation based on surface area is moreappropriate than age and body weight.

Determination of Drug DoseCalculate Body Surface Area

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Height (cm) x Weight (kg)o 3600

THERAPEUTIC INDEX

It is the ratio of median lethal dose (LD50) to medianeffective dose (ED50).

OR

It is the measurement that describes the relationshipbetween doses of drugs required to produce undesired anddesired effects.

o LD50

T I =

ED50

Median lethal dose is the minimum amount of drug in mg/Kg

body weight that kills 50% of test animals.

Median effective dose is the minimum amount of drug inmg/Kg body weight that produces desired effects in 50% oftest animals.

ED50 is the measure of potency of the drug, lower the dosemore potent is drug and vice versa.

Therapeutic index is used to evaluate safety and usefulnessof a drug, higher the therapeutic index safer will be drug. For

safe application of a drug its therapeutic index should bemore than one.

Penicillins and benzodiazepines have high therapeutic index.

Digitalis, G.Anesthetics and Anticancer drugs have lowtherapeutic index.

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Depending upon therapeutic utility, a drug may have morethan one therapeutic indices.

Ideally a drug should have LD50 much higher than ED50.

STANDARD MARGIN OF SAFETY:

Therapeutic index may be misleading if the log doseresponse curve for effectiveness and toxicity have differentslopes i.e. are not parallel.

Therefore, standard margin of safety may be more useful. Standard margin of safety shows the percentage by which

ED99 (Dose effective in 99% of population) must beincreased to cause toxic effects in 1% of population.

Formula for standard margin of safety is:

o LD1

------ x 100o ED99

Therapeutic IndexTD50/ED50

Dose-Response FunctionED50

Dose-Response FunctionTD5o

Dose-Response FunctionLD50

Dose-Response FunctionED50 ,TD50 ,LD50

Efficacy & Potency

Efficacy & Potency

Efficacy & Potency

Summation

Potentiation

Causes of Variability in Drug Response

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Those related to the biological system

Body weight and size

Age and Sex

Genetics - pharmacogenetics

Condition of health

Placebo effect

Causes of Variability in Drug Response

Those related to the conditions of administration

Dose, formulation, route of administration. Resulting from repeated administration of drug:

o drug resistance; drug tolerance-tachyphylaxis;

o

drug allergy Drug interactions:

o Chemical or Physical;

o GI absorption;

o Protein binding/distribution;

o Metabolism (stimulation/inhibition);

o Excretion (ph/transport processes);

o Receptor (potentiation/antagonism);

o Changes in pH or electrolytes. DOSE RESPONSE RELATIONSHIP

Two basic types of dose response relationships have beenobserved, these are:

QUANTAL OR ALL & NONE DOSE RESPONSERELATIONSHIP:o In this type of relationship a single dose of the drug

either produces no effect or produces maximum effect.

DOSE RESPONSE RELATIONSHIPo GRADED OR QUANTITIVE DOSE RESPONSE

RELATIONSHIP:

In this type of relationship as the dose administered to asingle subject is increased, the pharmacological responsealso increases in a gradual fashion.

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The degree of effect produced by increasing the dose ofdrug eventually reaches steady level. This phenomenon iscalled ceiling effect and dose at which it occurs is calledceiling dose.

Increasing the dose beyond this dose produces undesirableeffect.

o EFFICACY:

Maximal effect that can be elicited by a drug is calledefficacy, it is measured by Emax. Efficacy is more importantthan potency in selecting drug for clinical use.

o POTENCY: Concentration (EC50) or dose (EC50) of a drug that produces

50% of the maximal effect of that drug is called potency, it ismeasured by ED50, and lower the ED50 more potent is thedrug.

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