1. Distribution & Fate Lesson 5

2. Distribution n Drug disperses throughout system l does not reach target l silent receptors n Distributes in l Blood & extracellular fluid l organs & tissues ~

3. Redistribution n Drug releases re-enters circulatory system from l Depot binding l Protein binding l Ion trapping n Bound / unbound drug l Ratio maintained l Prolongs drug effects ~

4. Depot Binding n Unable to cross membranes n Slow drug effects l or prevent n Prolong drug effects l not metabolized n Termination of drug effects n Redistribution ~

5. TA Blood Brain CTZCTZ Organs & Tissues Protein Binding Depot Binding

6. Protein Binding n Large blood proteins l albumin most abundant n Nonselective binding l Prevents drug from reaching target l multiple drugs  compete u higher effective dose for 1 u Seldom clinical implications n Valium 99% bound, 1% free n Redistribution ~

7. Drug Fate n Immediate & long-term drug disposal n Determines duration of drug effects l drug in system  drug effects n Terminates drug effects ~

8. Half-life - t ½ n After complete absorption n Plasma half-life l time blood levels drop by half l distribution half-life l elimination half-life u metabolism & excretion ~

9. Biotransformation n Metabolism l structure altered  metabolite n By enzymes l site of action l blood plasma l liver n Inactivation n Some metabolites active l e.g., valium, codeine ~

10. Liver n Main site of metabolism l nutrients l detoxification n 1st pass metabolism l GI tract  liver ~

11. Cytochrome P-450 n Main detoxification enzyme l liver and intestine l enzyme induction u contributes to tolerance n Inhibited by… l grapefruit juice u 6',7'-dihydroxybergamottin? l red wine to lesser extent ~

12. Excretion: Kidneys n Filtration of blood l Excretion in urine n Ionization required l ion-trapping n Active & inactive form l Koryak tribesmen (Siberia) l Amanita muscaria ~

13. Excretion: Kidneys n Smoking cessation diet   alkalinity of urine stress   excretion n Antidiuretic Hormone (ADH) l regulation of water l alcohol, caffeine inhibit l dehydration ~

14. Excretion: Other routes n Lungs l alcohol breath n Breast milk l acidic  ion traps alkaloids l alcohol: same concentration as blood l antibiotics n Also bile, skin, saliva ~~