THERAPEUTIC INDEX :AN INDEX OF SAFETY

DR RAHULASSOCIATE PROFESSOR

PHARMACOLOGY

THERAPEUTIC INDEX• Ratio of median

lethal dose to median effective dose.

LD50/ED50

• This is the dose (mg/kg)which would kill one half of limited population of the same species & strain.

MEDIAN LETHAL DOSE

LD50-• This is the dose (mg/kg) which produces desired response in 50% of test population

MEDIAN EFFECTIVE

DOSE

ED50-

THERAPEUTIC INDEX

Margin of safety is the difference between therapeutic and lethal dose

of the drug.

IMPORTANCELarger the therapeutic index safer the drug.

ex. Penicillin has high therapeutic index while digitalis has much less.

Drugs with low TI

• Digitalis• Gentamicin• Lithium• Quinine

FEATURES

TI not reliable guide for safety.

Therapeutic index varies from species to species.

Reliable only when LD50 & ED50 is determined in same strain of same species.

ED50 is determined from DRC.

No drug produces single effect but spectrum of effect aswellas differs in selectivity.

• ex. Antihistaminic , Aspirin

FACTORS MODIFYING DRUG ACTION

Factors modifying effects of drugs

Individual differ in degree and character of drug response and therefore the optimum dose of drug that produces therapeutic effect varies from person to person.

Causes of Variability in Drug Response

Those related to the biological system

1. Body weight and size2. Age and Sex

3. Species and race4. Genetics – pharmacogenetics

5. Condition of health6. Placebo effect

Those related to the conditions of administration

7. Route of administration. 8. Drug interactions

• Pharmacokinetic drug interactions• Pharmacodynamic Drug interactions

9. Resulting from repeated administration of drug: • Drug Tolerance-Tachyphylaxis;• Drug dependence

BODY WEIGHT

• Average dose is mentioned in mg/kg or as total single dose (50-100kg)• Do not apply for:

ObeseEdemaDehydratedEmaciationIndividual dose= BW/70 X average

adult dose

AGE Neonates, infants & childrenPk factors-Gastric Emptying , Liver & Renal FunctionsPd factors-Teratogenicity , Adverse Effects

Old-Absorption , Metabolism , Excretion, Sensitivity, Half Lives Of Drugs.

SEX

FEMALES MALES• BODY SIZE SEXUAL FUNCTIONS•MENSTRUATION GYANACOMASTIA• PREGNANCY • LACTATION

SPECIES AND RACE

• SPECIES –Some drugs resistant with some species•Rats- Digitalis•Rabbits-Atropine

• RACE-•Blacks require higher and Mongols require lower conc. of Ephedrine and Atropine for pupilary dilatation.• Indians- chloramphenicol

GENETIC FACTORS

Genetically mediated variations in drug responses

Different rates of metabolismEx.•Pseudocholinestrases•G6PD defeciency•Acetylation & hydroxylation

Condition of health : Pathological states

Gi diseases- Malabsorption syndrome, Achlorhydria,…….

Liver diseasesHigh first pass metabolism,Decrease -ppb, drug metabolism, Prodrug less effective

Renal disease-Decrease clearence

PLACEBO

• Inert substance•Psychological effect•Pts. Belief, attitude, expectations

Those related to the conditions of administration

7. Route of administration. 8. Drug interactions

• Pharmacokinetic drug interactions• Pharmacodynamic Drug interactions

9. Resulting from repeated administration of drug: • Drug dependence• Drug Tolerance-Tachyphylaxis;

Causes of Variability in Drug Response• Those related to the conditions of

administration1. Route of administration.2. Resulting from repeated administration of

drug: drug tolerance-tachyphylaxis;

drug dependence3.Drug interactions GI absorption;

protein binding/distribution; metabolism (stimulation/inhibition); excretion (ph/transport processes); receptor (potentiation/antagonism); changes in pH or electrolytes.

ROUTE OF ADMINISTRATION

• Governs speed and intensity of drug response. drugs may have different uses with diff.routes• Iv doses •Smaller than oral•Quick onset of action•More chances of toxicity

DRUG DEPENDENCE

•Repeated administration of drug may induce habit and dependence.Psychic dependencePhysical dependence

Drug tolerance• Requirement of large dose of a drug to

elicit an effect ordinarily produced by normal therapeutic dose of the drug• Types- a. Pseudo tolerance b. True tolerance Natural Acquired

(repeated)1.Species 1.Tissue tolerance2.Racial 2.Cross tolerance

TACHYPYLAXIS• Decrease in pharmacological

response of a drug after repeated administration at very short interval (occurs rapidly)EphedrineTyramineAmphetamine serotonin