Drug Dosage and Clinical Responses

1. Drug Dosage and Clinical Responses September 12, 2007 Frank F. Vincenzi

2. Antagonism Potency Clinical efficacy Slope of D-R curve Quantal response ED50, LD50, TI Synergism Summation Tolerance Tachyphylaxis Idiosyncrasy Drug allergy Therapeutic/side effects Adverse effects Toxicology Learning Objectives

3. Factors Modifying Drug Responses(The Big Three) • Drug (pharmacodynamics) • Dose (pharmaco/dynamics/kinetics) • Route of Administration (pharmacokinetics)

4. Tolerance Dependence Age Weight Sex Pharmacogenetics Set Setting Dosing errors Non-compliance Drug interactions Disease! Attitude! Factors Modifying Drug Responses (cont):The ‘big many’

5. Antagonism • Combined effect of the two drugs is less than thesum of their individual effects • Types of antagonismPharmacological (agonist/antagonist)(pure antagonist + full agonist) (i.e., 0 + 6 = 1) (partial agonist + full agonist) (i.e., 2 + 6 = 4) • Chemical • direct chemical interaction (e.g., chelation) • Physiological • Two drugs produce opposite effects on the same system(epinephrine in the treatment of histamine-induced bronchospasm)

6. Synergism • The combined effect of two drugs is greater than the sum of their individual effectsi.e., 1 + 1 = 6 or 0 + 4 = 10(often called ‘potentiation’)

7. Potency and Clinical Efficacy/Efficiency • Potency refers to the amount of drug necessary to produce a certain effect. A drug which produces a certain effect at 5 mg dosage is ten times more potent than a drug which produces the same effect at 50 mg dosage. • Clinical efficacy (or simply efficacy) refers to the maximal clinical response that can be obtained by a particular drug (morphine is more clinically efficacious than aspirin as an analgesic) * • Clinical efficiency is the bottom line of how well an intervention actually works (includes compliance)

8. Healthy Volunteers (Medical Students?) and Intravenous Sodium Amytal (n = 55) Adapted from Clark’s Applied Pharmacology

9. Clinical Responses to Drugs are Often Expressed Quantally: Quantal Dose-Response Curve

10. Medical Students (?) and Intravenous Sodium Amytal (n = 55) Adapted from Clark’s Applied Pharmacology

11. Population Quantal Dose-Response Curve • Position is a reflection of drug potency. Drugs that produce a certain effect at a low dose are more potent than drugs that produce the same effect at a higher dose. • Slope is a reflection of the dispersion of sensitivity to the drug among members of the population. The steeper the slope the more homogeneous the population.

12. Therapeutic Effect of Prazosin: Lowering of Blood Pressure by 10 mm Hg

13. Isoniazid levels in patients subjected to a standard dose - an example of pharmacokinetically determined tolerance/sensitivity

14. Therapeutic and Side Effects of Drugs • Therapeutic effect: the desired clinical effect • Side effects: any other clinical effects(may include neutral or adverse events)

15. Frequency distribution and cumulative % responses of a population to a drug

16. Calculation of Median Therapeutic Index

17. Different therapeutic indices of a given drugwith more than one therapeutic effect

18. Several measures of relative drug safety • Median Therapeutic Index, TI = LD50/ED50 • ‘Conventional Index’ = LD1/ED1 • ‘Standard Safety Margin’ = ([LD1/ED99 - 1])*100 • ‘Standard Safety Margin’ = ([LD0.1/ED99.9 - 1])*100

19. Examples of relative toxicities of some psychotropic drugs

20. Changes in therapeutic index of a chronically administered barbiturate:dispositional and cellular tolerance

21. Tolerance • A condition produced by repeated or continued exposure to a drug that produces decreased responses to that drug when given at a certain dosage - or that increased doses are needed to maintain a certain level of response. • (Cross tolerance refers to the same phenomenon involving chemically or mechanistically related drugs).

22. Subsets of Tolerance • Tachyphylaxis(e.g., indirectly acting sympathomimetic amines) • Tolerance • Dispositional • Cellular • Behavioral

23. Receptor Desensitization: One Potential Mechanism of Cellular Tolerance Reversible decrease in the sensitivity to agonist(s)of responses mediated by a particular receptor orreceptor signaling pathway. Example: agonist binds to the beta-receptor thenbeta-adrenoceptor kinase (ARK), phosphorylates the beta-adrenoceptor protein - this promotes the binding of beta-arrestin and decreases interaction of the receptor with the G protein, Gs. Removal of agonist allows phosphatases to ‘reset’ the receptor.

24. Down Regulation of Receptors: Another potential mechanism of cellular tolerance Agonist-induced decrease in the number of available receptors of a particular type. This decreases the sensitivity of the system to responses mediated by the receptor in question.Example: altered receptor turnover that results in feweravailable receptors for activation in chronic opiate usage, etc. (basis of tissue tolerance).

25. Up Regulation of Receptors Antagonist- or ‘dis-use’-induced increase in the number of available receptors of a particular type. This increases the sensitivity of the system to responses mediated by the receptor in question (increased number of spare receptors). Example: ‘denervation supersensitivity’

26. The ‘Therapeutic Window’ Ratio of the maximum concentration that is non-toxic inmost of the population (various toxicities) to the minimumconcentration that is effective in most of the population (e.g., theophylline 10 - 20 µg/ml) (avg.TD/ED in the ninth edition ofGoodman & Gilman’s = 2.79 ± 3.2 (0.23 - 15) THEREFORE: A decimal point is a potentially lethal weapon!! You MUST know pg, ng, µg, mg, g, kg, etc.

27. Practical limitations on clinical dosing: Therapeutic and side effects of digitoxin

28. Adverse Drug Reactions • Overdosage (includes interactions, genetics, suicide) • Side effects (most are predictable) • Secondary effects (e.g., overgrowth) • Idiosyncrasy (unpredictable, by definition) • Drug allergy (also called hypersensitivity)

29. In hospitalized patients: digoxin heparin hydrochlorothiazide spironolactone Leading to hospitalization: aspirin digoxin hydrochlorothiazide prednisone warfarin Drugs Commonly Associated with Adverse Reactions

30. Adverse Drug Reactions Associated with Multiple Drugs

31. Mortality Associated with Multiple Drugs

32. Dependence • “A cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues use of the substance despite significant substance-related problems.” (DSM-IV) • Psychological - withdrawal mainly psychological • Physical - the hallmark of physicaldependence is ‘physical’ withdrawal. May have cross dependence.

33. Substance Abuse • “…a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances.”(DSM IV) (Note: The criteria do not include tolerance, withdrawal or a pattern of compulsive use. Also note, DSM IV never uses the term ‘addiction’) • Curiously: The category of substance abuse does not apply to caffeine and nicotine - at least according to DSM IV.

34. ADDICTION: A more ‘official’ view “Uncontrollable, compulsive drug seeking and use, even in the face of negative health and social consequences” • Alan L. Leshner, Ph.D., Director of NIDA in: The Brain: Understanding Neurobiology Through the Study of Addiction