Pharmacodynamics : Drug Interaction

1. Topic 11 Pharmacodynamics: Drug Interaction 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana Faculty of Veterinary Medicine, Khon Kaen University

2. Topics on Drug Interactions • Definition • Effects of drug interaction • Types of drug interaction • Pharmaceutical interaction • Pharmacodynamic interaction • Pharmacokinetic interaction

3. Definition • Drug interactioncan be defined as the modifications of the effects of one drug by the prior or concomitant of another drug (poly-pharmacy) • A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own.

4. Effects of drug interaction • Drug interaction can result in • Increased effect – Additive or Synergistic effect • Increased therapeutic effect good • Increased toxic or adverse effect bad • Decreased effect – Antagonistic effect • Decreased therapeutic effect bad • Decreased toxic effect good • Drug interactions usually happen unexpectedly and result in adverse drug reactions • Drug interactions for good therapeutic effects are usually used intentionally and their results are already known by physicians

5. Drug-Drug interaction may alter drug effect by • Additive effect : 1 + 1 = 2 • Synergistic effect : 1 + 1 > 2 • Potentiation effect : 1 +0 = 2 • Antagonism : 1 - 1 = 0 or 0.5

6. Effect of Drug interaction Therapeutic drug interaction could be used in 2 objectives • To produce synergistic therapeutic effects • Examples are found by several antibiotic combinations • Penicillin-Sreptomycin • Penicillin-Probenecid • Sulfa-trimethoprim • To detoxify or lower toxic effects • Examples are those antidotes of certain toxic agents • Xylazine-Yohimbine

7. Types of drug interaction There are at least 3 types of drug interaction • Pharmaceutical interaction minor • Pharmacodynamic (PD) interaction major • Pharmacokinetic (PK) interaction major

8. Pharmaceutical interaction • Interactions that occur prior to systemic administration • At manufacturing process • At clinical process by mixing 2 or more drugs in the same container • Drug incompatibility having drug interaction • Drug compatability no interaction • Chemical or Physical interactions • Usually result in pharmacological loss

9. Pharmacodynamic interaction • Definition – interaction that one drug may cause changes in another drug action, effect or response without PK alteration • Pharmacodynamic interaction could result in either • Additive effect • Synergistic effect • Antagonistic effect • Pharmacodynamic interaction can happen at these levels • Level of drug action • Level of drug effect • Level of drug response • At this level, it could be called Physiological interaction

10. Pharmacokinetic interaction • Pharmacokinetic (PK) interactions sometimes are also referred to as dispositional interactions. • These interactions are characterized by the alteration of the PK or disposition (ADME) of one drug by another. • Change in absorption • Change in distribution • Change in Metabolism • Change in Excretion • Important PK interactions are those associated with • Altered drug metabolism • Drug transporters • Protein binding

11. PK interaction associated with altered drug metabolism • Altered phase I metabolism • CYP induction • CYP inhibition • Altered phase II metabolism • Induction of phase II enzyme UDP-glucuronyl transferases (UGTs) • Inhibition of phase II enzyme • Competitive use of conjugate molecules

12. PK interaction associated with drug transporters • Transporters Playing Key Roles in Drug Absorption and Excretion • Important drug transporters • P-glycoproteins (PgP) • very important for excretion processes • Other transporters • Interaction usually result in • Inhibit function of transporters • And inhibit drug excretion • And finally cause AUC of a drug to increase or more drug in the body

13. Examples of Clinically Significant Drug interactions Associated with Inhibition of Transporters Other Than PgP

14. PK interaction associated with Protein binding • The major plasma proteins to which most drugs bind are albumin and a1-acid glycoprotein; the former typically binds acidic, anionic drugs whereas the latter typically favors basic drugs • Competitive protein binding by another drug will result in increase concentration of free drug, and that will yield more drug response