1. QUANTITATIVE ASPECTS OF DRUG ACTIONS DR. SHABANA ALI

2. QUANTITATIVE ASPECTS OF DRUG ACTIONS Quantitative aspects are important for mode of use e.g. dose-response relationship Dose-Response Relationship of agonists  Relationship between amount of drug administered in plasma and magnitude of desired response cont.

3.  A given dose of drug produces measurable degree of action in a biological system (sm.muscle or whole animal) Types of DRC  Two types 1) Graded Dose-Response 2) Quantal Dose-Response

4. 1) GRADED DOSE-RESPONSE  When dose of drug response also e.g., contraction or relaxation of muscles, ∆ BP, ∆ blood sugar etc.  Studied in vitro on a piece of small intestine  Relationship b/w dose & response can be plotted on curve (x-axis=dose; y-axis=response)  Conc./dose on arithmetic scale, curve is hyperbolic (not linear relationship)  Conc./dose on log scale, curve is sigmoid-shaped (semi log dose-response curve)

5. Effect of various conc. of ACh on isolated small intestine of rabbit showing graded response

6. GRADED DOSE-RESPONSE CURVE

7. Advantages of semi log Dose-Response Curve  Wide range of drug doses is depicted  Easy comparison between agonists  Easy study of antagonists  The middle portion (25-75%)  of curve is linear; direct  relationship between dose  and response can be obtained

8. GRADED DOSE-RESPONSE CURVE Following valuable data can be drawn Threshold dose: dose which produces first noticeable response ED 50 /EC 50 (median effective dose or concentration): Dose or conc. which produces 50% of maximal response Cont.

9.  Drugs with same action at a receptor but with d/f potency show parallel DRC  Potencies of two drugs can be compared by ED 50 ED 100 /EDmax (ceiling effect): Conc. which produces maximal response

10. 2) QUANTAL DOSE-RESPONSE  Response follow all or none phenomenon ( e.g., analgesics, convulsants, anticonvulsant activity, death etc )  Dose of drug evokes a fixed pharmacological response  Studied in whole animal (in vivo); data derived from group of animals or population

11.  Results can be plotted as Log dose- percentage curve  Gaussian Distribution Curve (sigmoid > graded response) is obtained by keeping log doses on horizontal-axis and % response on vertical-axis

12. QUANTAL DOSE-RESPONSE CURVE

13. Following valuable data can be drawn from Quantal Dose Response curve A) Median Effective Dose (ED 50 ) Dose of a drug required to produce 50% of maximum response B) Median lethal dose (LD 50 ) Dose of a drug required to kill 50% of experimental animals; measurement of toxicity

14. C) Median toxic dose (TD50) Dose producing toxicity in 50% animals or humans D) Therapeutic Index Ratio of the median lethal dose to median effective dose CONT.

15. Therapeutic Index (TI) =LD 50 / ED 50 e.g. digoxin & warfarin have  TI; Penicillin =  TI Based on median doses; not about slope of DRC for therapeutic or toxic doses Approximate assessment of safety of the drug  TI safer is drug &vice versa

16. THERAPEUTIC INDEX

17. E) Margin of safety Ratio of LD 0.1 / ED 99.9 LD 0.1 =min. lethal dose for 0.1 % of population; ED 99.9 %=minimum effective dose for 99.9 % of population

18. STRUCTURE-ACTIVITY RELATIONSHIP  Study of chemical structure of drug and its relationship with its pharmacological action  Both affinity & efficacy of drug r determined by its chemical structure  Minor change in drug molecule  major change in pharmacological property cont.

19. Significance of structure-activity relationship  Synthesis of 1. Valuable therapeutic agent from parent compound 2. Drug with wide margin of safety 3. Drug with  selectivity for tissues  Useful therapeutic antagonist of hormone or neurotransmitter  Improvement of PK property  Drug designing, identification of receptors, size, shape, position, orientation of charged groups or H + bond donors

20. Improved affinity and selectivity for receptors E.g., Chlorpromazine (antipsychotic)  trifluoperazine Procaine (antiarrhythmic)  procainamide (resistant to hydrolysis) Benzyl pencillin (antibiotic)  phenoxymthylpencillin, ampicillin, amoxycillin (resistant to HCl) Atropine ( mydriatic)  Homatropine (less lasting effect)