Pharmacodynamics : Drug Action

1. Topic 8 Pharmacodynamics: Drug Action 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana Faculty of Veterinary Medicine, Khon Kaen University

2. Drug Action Topics in Drug action • Sequences of Drug action • Primary Responses • Action, effect and response • Secondary Responses • Classification of Drug action • Based on receptor • Receptor mediated • Agonist or Antagonist • Non-receptor mediate • Based on time course of drug action • Immediate, Delayed, Accumulation

3. Sequences of Drug action • Primary response • Direct effect and consequences of a drug • Action - > Effect - > Response • e.g. Drug A activate beta receptor on heart muscle • Effect -> increased heart rate, increased cardiac output • Secondary response • Any response of the body system that is induced by primary response • It may either enhance or diminish the primary response • e.g. Primary response of Drug A (Increased cardiac output) • Effect - > Increased GFR Increased rate of excretion

4. Sequences of Drug actionPrimary Response • Drug Action (Mechanism of action) • on a receptor • Drug Effect • observable consequence of drug action (“biomarker”, “surrogate endpoint”) • Drug Response • clinical outcome

5. Example:Thiopentonean ultra-short iv anesthetic agent • Drug Action • Potentiation of GABA receptor activation • Drug Effect • Slowing of EEG activity • Drug Response • Anesthesia

6. Classification of Drug actionBased on Receptors • Receptor mediated Drug action • Receptors • Ligands (Drugs) • Ligand-receptor interaction  effect • Non-receptor mediated Drug action • Physical property  effect • Chemical property  effect

7. Non-receptor mediated drug action • For a minority of drugs • PD properties are determined by some physico-chemicalproperty • The mechanisms are characterized by a lack of requirement for highly specific chemical structure • Examples • Bulk or Osmotic laxatives • Osmotic diuretics • Volatile liquids • Emollient creams • Antacids

8. Examples of Non-receptor mediated drug action • Bulk or Osmotic laxatives • MgSO4 draw fluid into GI tract • Osmotic diuretics • Mannitol increase osmotic pressure in urine • Volatile liquids • Ethyl Chloride – sprayed on skin – evaporate - cool

9. Examples of Non-receptor mediated drug action • Emollient creams • Physical protective barrier • Antacids • Sodium bicarbonate neutralize excess acid in the stomach

10. Receptor-mediated Drug action • For majority of drugs, Drug action will be either • Mimic or inhibit normal physiological / biochemical processes or inhibit pathological processes in animals • Inhibit vital processes of endo- or ectoparasites and microbial organisms • (Theactions will give results asPharmacological effects) • The action is mediated by • the interaction or chemical binding between drug and molecules (receptors) in body tissues, parasites, or microorganisms.

11. Receptor-mediated Drug action • The actions are produced by mechanisms • Which are similar or identical to those mechanisms • By which enzymes interact with substrate or • By which neurotransmitters or hormones produce their biological effects • The action can be either increase, decrease, or inhibit the physiological process • Depending on the type and quantity of ligands or drugs • Agonist • Partial agonist • Antagonist

12. Example ofReceptor-mediated Drug actionCardiovascular effect of the catecholamines The catecholamines (Epinephrine, Norepinephrine) • Molecular level • Interact with 1-receptor • -> increase cAMP • -> increase slope of the depolarization potential • Cellular level • The action potential generated • -> Wave of electrical conduction • -> increase rate of firing of the sinus node cells • -> increase contractility of the myocardial cells

13. Example ofReceptor-mediated Drug actionCardiovascular effect of the catecholamines • Tissue level • Increase heart rate • Increase heart contractility • -> increase cardiac output • System level • Increase blood supply to the heart, brain and muscle

14. Classification of Drug actionTime Course of Drug Action • Immediate Drug Effects • Delayed Drug Effects • Cumulative Drug Effects

15. Immediate Drug EffectsThiopentone Distribution to Effect Site in Brain • Drug Action • Potentiation of GABA receptor activation • Drug Effect • Slowing of EEG activity • Drug Response • Anesthesia • Response in Minutes

16. Thiopentone Time Course

17. Delayed Drug Effects • Distribution to Effect Site • pharmaco-kinetics • “effect compartment model” • Physiological Intermediate • physio-kinetics • “indirect effect model”

18. Delayed Drug EffectsWarfarin Physiological Intermediate • Drug Action • inhibition of Vit K recycling • Drug Effect • decreased synthesis of clotting factors • Drug Response • prolonged coagulation time

19. Physiokinetic Delayed ResponseWarfarin and The Vitamin K Cycle

20. Warfarin Delayed Response • IC50 for synthesis is 1.5 mg/L • Synthesis is reduced 50% at the IC50 • [prothrombin complex] is reduced 50% • Critical parameter is • Half-life of prothrombin complex • about 14 h • Takes 4 half-lives to reach SS • 2 to 3 days

21. Physiokinetic Delayed Responses • Angiotension Converting Enzyme Inhibitors (enalapril) • Delayed effect on blood pressure (1 week) • Half-life of Na+ is about 2 days • Anti-Depressants (amitriptyline) • Delayed effect on depression (2 weeks) • Unidentified mediator • A protein with a 4 day half-life?

22. Cumulative Drug Response • Response is related to drug exposure • Exposure Indicators • Single Dose • Daily Dose Rate • Cumulative Dose • Average Steady State Conc (Css) • Area under Time vs Conc Curve (AUC) • Area under Time vs Effect Curve (AUCe)

23. Cumulative Drug EffectsAcid Pump Inhibitors • Action • inhibition of gastric acid pump • Effect • decreased acid secretion and increased pH • Response • ulcer healing

24. Cumulative Drug EffectsUlcer Healing Response • Takes several weeks of acid inhibition to heal an ulcer • Acid inhibition Effect is constant but the Response continues to develop (e.g. smaller size of ulcer) • Response time course is (almost) independent of drug dose/concentration when inhibition is nearly 100%

25. Cumulative Drug EffectsDiuretics and Heart Failure • Diuretics are used to treat heart failure • with digoxin and ACE inhibitors • Symptoms are produced by excess fluid • Ascites, edema, breathlessness, ankle swelling, (dropsy) • Benefit is related to net reduction in fluid

26. Cumulative Drug EffectsDiuretic Action/Effect/Response • Action • Inhibition of Na+ reabsorption • Effect • Increased Na+ and H2O excretion • Cumulative fluid loss • Response • Reduced ankle swelling • Decreased breathlessness

27. Cumulative Drug EffectsSchedule Dependence • Response is NOT proportional to cumulative diuretic doseor AUC • Response IS proportional to cumulative diuretic effector AUCe • Phenomenon is known as • “Schedule Dependence”

28. Furosemide Response • 40 mg x 3 • AUCe = 540 mmol Na+/12h • 120 mg x 1 • AUCe = 400 mmol Na+ /12h • Response is increased 35% • using 40 mg x 3

29. Cumulative Drug EffectsAnti-Cancer Agents • Schedule Dependence is common • Large intermittent doses are often more toxic and less effective than smaller repeated doses • Response is related to cumulative dose as well as Schedule • AUC may be used to guide individual treatment • Action • Irreversible binding to cell structure • Effect • Block of cell division/cell death • Slowing or reversal of tumour growth • Response • Decreased morbidity (e.g. Pain) • Postponement of death