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

2. Learning Objectives 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

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

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

5. Antagonism Combined effect of the two drugs is less than the sum of their individual effects –Types of antagonism Pharmacological (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 effects i.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 drug with 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 or receptor signaling pathway. Example: agonist binds to the beta-receptor then beta- 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 fewer available 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 in most of the population (various toxicities) to the minimum concentration that is effective in most of the population (e.g., theophylline 10 - 20 µg/ml) (avg.TD/ED in the ninth edition of Goodman & 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. Drugs Commonly Associated with Adverse Reactions In hospitalized patients: digoxin heparin hydrochlorothiazide spironolactone Leading to hospitalization: aspirin digoxin hydrochlorothiazide prednisone warfarin

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 physical dependence 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