Pharmacokinetics and Drug Administration: Understanding Drug Action in the Body

1. Definitions • Pharmacokinetics • The process by which a drug is administered, absorbed, distributed, bound,inactivated,metabolized and eliminated by the body • Pharmacodynamics • The interactions of a drug and the receptors responsible for its action in the body and CNS

2. Drug Administration • Orally (swallowed) • through Mucus Membranes • Oral Mucosa (e.g. sublingual) • Nasal Mucosa (e.g. insufflated) • Rectally (suppository)

3. Drug Administration (cont.) • Parenterally (injection) • Intravenous (IV) • Intramuscular (IM) • Subcutaneous (SC) • Intraperitoneal (IP) • Inhaled (through lungs)

4. Drug Administration (cont.) • Topical/Transdermal (through skin) • Directly into CNS • Intracranial or intracerebral (into brain tissue) • Intracerebroventricular (into brain ventricles)

5. Drug Administration Summary • Pharmacokinetics relates to bioavailability • The fraction of an administered dose of a drug that reaches the blood stream • How quickly a drug reaches its site of action relates to “addictiveness.”

6. Distribution: Solubility • Water-soluble • Ionized (have electrical charge) • Crosses through pores in capillaries, but not cell membranes • The extent of ionization of a drug is expresses as the pKa of the drug • Lipid(fat)-soluble • Non-ionized (no electrical charge) • Crosses pores, cell membranes, blood-brain-barrier

8. Distribution: Blood Brain Barrier

10. Depot Binding • Drugs bind to “depot sites” or “silent receptors” • Deposits slow elimination, can increase drug detection window

11. Metabolism & Elimination • Liver • Enzymes transform drugs into more water-soluble metabolites • Kidneys • Traps water-soluble compounds for elimination via urine

12. Metabolism and Elimination (cont.) • Half-lives and Kinetics • Half-life: • Plasma half-life: Time it takes for plasma concentration of a drug to drop by 50%. • Whole body half-life: Time it takes to eliminate half of the body content of a drug. • Factors affecting half-life • age • renal excretion • liver metabolism • protein binding

13. First order kinetics A constant fraction of drug is eliminated per unit of time. When drug concentration is high, rate of disappearance is high.

14. Zero order kinetics Rate of elimination is constant. Rate of elimination is independent of drug concentration. Constant amount eliminated per unit of time. Example: Alcohol

15. The Dose-Response Curve • X-axis = Dose • Y-axis = Response, measured as either • magnitude of response in individual • number/percentage of individuals responding at a given level

16. Therapeutic Index • ED50 = dose at which 50% population shows response • LD50 =dose at which 50% population dies • TI = LD50/ED50, an indication of safety of a drug (higher is better)

17. Potency • Relative strength of response for a given dose • accessability, affinity, and efficacy • D-R curve shifts left with greater potency

18. Efficacy(% of maximal change elicited) • Maximum possible effect • Indicated by peak of D-R curve

19. Tolerance(desensitization) • Decreased response to same dose with repeated exposure • or more drug needed to achieve same effect • Right-ward shift of D-R curve • Sometimes occurs in an acute dose (e.g. alcohol) • Can develop across drugs (cross-tolerance) • Caused by compensatory mechanisms that oppose the effects of the drug

20. Tolerance • Physical • User requires more of the drug to achieve the same effect, and the same amount will produce a lesser effect. • Psychological • As the user becomes familiar with the drug’s effects, s/he learns tricks to hide or counteract the effects. • Metabolic • The user is able to break down and/or excrete the drug more quickly due to repeated exposure.

21. Sensitization • Increased response to same dose with repeated exposure • or less drug needed to achieve same effect • Left-ward shift in D-R curve • Sometimes occurs in an acute dose (e.g. amphetamine) • Can develop across drugs (cross-sensitization)

22. Mechanisms of Tolerance and Sensitization • Pharmacokinetic • changes in drug availability at site of action; metabolic changes • Pharmacodynamic • changes in drug-receptor interaction (G-protein uncoupling; down regulation) • Conditioning • automatic physiological change in response to cues • Motivational • change in organism’s behavior to attenuate/increase effect

23. Pharmacodynamics • Receptor • target/site of drug action (e.g. genetically-coded proteins embedded in neural membrane, cytoplasm, nucleus) • Lock and key model • Drug acts as key, receptor as lock, combination yields response

24. Pharmacodynamics continued • Affinity • propensity of a drug to bind with a receptor • Selectivity • specific affinity for certain receptors (vs. others)

25. Agonism and Antagonism Agonists facilitate receptor response Antagonists inhibit receptor response (direct ant/agonists)

26. Agonists • Full Agonist • Partial Agonist • Direct/Competitive Agonist • Indirect/Noncompetitive Agonist

27. Antagonists • Direct/Competitive Antagonist • Indirect/Noncompetitive Antagonist • Inverse Agonist

28. Important implications ofdrug-receptor interaction • drugs can potentially alter rate of any bodily/brain function • drugs cannot impart entirely new functions to cells • drugs do not create effects, only modify ongoing ones • drugs can allow for effects outside of normal physiological range