General Principles of Drug Actions – The Foundation of Drug Actions in the CNS

1. General Principles of Drug Actions – The Foundation of Drug Actions in the CNS Kim Edward Light, Ph.D. Professor, College of Pharmacy University of Arkansas for Medical Sciences

2. Objectives • Identify the various perspectives for understanding drug actions. • Describe the pharmaceutical and pharmacokinetic phases of drug actions. • Describe the pharmacodynamic, therapeutic, and toxic phases of drug actions. • Identify ADME and the important aspects of each. • List the major routes of drug administration and elimination. • Identify the role of distribution and biotransformation in drug actions. • What is the importance of dose-response relationships in drug action?

3. Objectives • Identify the difference between quantal and graded dose-responses. • Differentiate between potency and efficacy in regards to drug actions? • Define agonists, antagonists, partial agonists and how their presence in combination impacts the resulting drug effects. • Identify the difference between competitive and non-competitive antagonist drug actions. • Identify the importance of signal transduction and how the type of receptor determines the transduction process.

4. Aspects of Drug Actions • Pharmaceutical • Pharmacokinetic • Pharmacodynamic • Therapeutic • Toxic

5. Pharmaceuticalaspects • Drug absorption. • Routes of administration • Oral • Injection (iv, im, ia) • Topical • Inhalation • Rectal

6. Metabolism Biotransformation Pharmacokinetic Aspects Distribution Absorption ADME Elimination

7. Absorption TRANSDERMAL CAPSULE AEROSOL SUB-LINGUAL SYRUP TABLET IM IV SUPPOSITORY

8. Distribution • Delivery of the drug to tissues • Blood flow • Most drugs “like” fat (lipophilic) • Plasma protein binding • Apparent “barriers” • Blood-Brain Barrier • Synovial barrier • Placental Barrier • Breast milk

9. X + O2 + X-O + H2O CYP + 2NADPH CYP + 2NADP+ MetabolismBiotransformation • To render the drug more water-soluble • Liver, GI tract, lungs, kidneys, brain • Cytochrome P450 (CYP) / mixed function oxidases • Split molecular O2 to oxidize drug

10. MetabolismBiotransformation • Specialized forms of CYP enzymes • CYP3A4 >50% of drugs • CYP2D6 many CNS and cardiovascular drugs • Other enzyme systems: • alcohol dehydrogenase • plasma esterase enzymes

11. Elimination or Excretion • Filtration by the kidneys • Eliminated in urine • Some passed into the bile • After liver metabolism • Other important routes: • breath, • sweat, • saliva, • milk, • hair, • finger/toe nails

12. Plasma Concentration Time Course of Drug Actions

13. Pharmacokinetic Terminology • Clearance • the total time to completely eliminate the drug from the body • Half-life (T½) • the amount of time for the concentration to decrease by half

14. One half-life Two half-lives Three half-lives Four half-lives Five half-lives Half-Lives • For example, for a drug with an T½ of 6 hours • @ 0 hours = 100 mg/ml in the plasma • @ 6 hours = 50 mg/ml • @ 12 hours = 25 mg/ml • Note: each T½ decreases the previous concentration by half • This type of elimination is called FIRST-ORDER since the amount of drug eliminated per unit time is dependent on one variable – concentration

15. Pharmacodynamics • Dose-Response Relationships • Drug actions are related to dose • More drug = more actions • Two perspectives • response of a population of subjects to a given drug (i.e. how many respond) • The response magnitude (or graded response)

16. Dose Responses in Populations • Relates the number (or %) of subjects that respond in a specific manner (i.e. sleep). • Large numbers of individuals increases accuracy. • Clinical trials in new drug testing • If tested population is too small or not diverse then the results will not be translatable to all individuals.

17. Graded Dose Responses Dose that produces 50% of Maximal Response

18. Receptor Drug Interactions • Affinity • How well the receptor and drug are attracted to each other • Efficacy • How much response is produced by drug-receptor interaction • Potency • Comparative measure of how much drug is required to produce a certain magnitude of response

19. Graded Dose Responses • Types of drug actions • Agonist = bind and produce a response • Affinity and efficacy (Drug A or B) • Antagonist= bind but don’t produce response (block agonist, however) • Affinity but no efficacy (Drug D) • Partial Agonist = bind and produce weak response • Affinity and weak efficacy (Drug C)

20. Understanding Drug Actions • A fundamental principle of pharmacology is that drugs do not produce effects that are new or novel to the physiological system. • Drugs act within the physiological system to alterresponses • How drug actions are produced is essentially a question of how physiological systems are designed.

21. Drug Mechanisms • Agonist • direct = a drug that binds to and activates specific receptors • affinity and efficacy • indirect = a drug that results in an increase in the presence and ability of the endogenous transmitter’s binding to the receptor

22. Drug Mechanisms • Antagonist • direct = a drug that binds to but does not activate specific receptors • Affinity no efficacy • indirect = a drug that results in a decrease in the presence or ability of the transmitter to bind with the receptor

23. Drug Mechanisms Partial Agonist • Affinity and weak efficacy • Therefore, it may sometimes act as an agonist or antagonist. If no agonist is present, then partial agonist produces some response. If agonist and partial agonist are present then less agonist can bind so total response is less – like antagonist

24. Pharmacodynamic Principles • Tolerance • the ability of the body to adapt to the presence of a drug that alters physiological functioning. • subsequent exposure will require higher doses to produce the same magnitude of response

25. Pharmacodynamic Principles • Withdrawal • adverse physiological symptoms produced by the absence of a drug • physiological alterations to oppose drug actions • removal of the drug results in the expression of the physiological alterations

26. Pharmacodynamic Principles • Dependence • physiological state characterized by the presence of adverse signs and symptoms that occur when the drug or treatment is withdrawn.

27. drug Pharmacodynamic Principles • Drug effects to alter the system • System responds to oppose drug effects (tolerance) • Absence of drug results in expression of the system’s adaptations (withdrawal) • Drug presence is necessary to balance the system’s adaptations (dependence) adaptation withdrawal Homeostasis (balance) adaptation dependence drug

28. Summary • Perspectives of drug actions • Pharmaceutics, kinetics, dynamics, etc. • ADME • Dose-response relationships • Drug Actions • agonists, partial agonists, antagonists • Pharmacodynamic principles • (affinity, efficacy, tolerance, dependance, etc.)