Principles of Pharmacology Pharmacokinetics & Pharmacodynamics

1. Principlesof PharmacologyPharmacokinetics &Pharmacodynamics

2. Pharmacokinetics • Movement of drugs in the body • Four Processes • Absorption • Distribution • Metabolism • Excretion • Drug concentration at sites of action influenced by several factors, such as: • Route of administration • Dose • Characteristics of drug molecules (e.g., lipid solubility)

3. Drug Absorption • Routes of Drug Administration • Oral (per os, p.o.) • Inhalation • vapors, gases, smoke • Mucous membranes • intranasal (sniffing) • sublingual • rectal suppositories • Injection (parenteral) • intravenous (IV) • intramuscular (IM) • subcutaneous (SC) • intraperitoneal (IP; nonhumans only) • Transdermal

4. DRUG ABSORPTION • Lipid solubility • pKa = pH at which 50% of drug molecules are ionized (charged) • Only uncharged molecules are lipid soluble. • The pKa of a molecule influences its rate of absorption through tissues into the bloodstream. • pH varies among tissue sites • e.g., stomach: 3-4, intestines: 8-9

5. pKa and Lipid Solubility Image from McKim, 2007, p. 14

6. Routes of Drug Administration • Oral Drug Administration • Advantages: • relatively safe, economical, convenient, practical • Disadvantages: • Blood levels are difficult to predict due to multiple factors that limit absorption. • Some drugs are destroyed by stomach acids. • Some drugs irritate the GI system.

7. Routes of Drug Administration • Advantages of Injection Routes • Absorption is more rapid than with oral administration. • Rate of absorption depends on blood flow to particular tissue site (I.P. > I.M. > S.C.). • Advantages specific to I.V. injection • No absorption involved (inject directly into blood). • Rate of infusion can be controlled. • A more accurate prediction of dose is obtained.

8. Routes of Drug Administration • Disadvantages/Risks of Injection • A rapid onset of action can be dangerous in overdosing occurs. • If administered too fast, heart and respiratory function could collapse. • Drugs insoluble in water or dissolved in oily liquids can not be given I.V. • Sterile techniques are necessary to avoid the risk of infection.

9. Drug Distribution • Cell Membranes • Capillaries • Drug affinities for plasma proteins • Bound molecules can’t cross capillary walls • Blood Brain Barrier • Tight junctions in capillaries • Less developed in infants • Weaker in certain areas, e.g. area postrema in brain stem • Cerebral trauma can decrease integrity • Placenta • Not a barrier to lipid soluble substances.

10. Termination of Drug Action • Biotransformation (metabolism) • Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products. • Cytochrome P450 enzyme family

11. Termination of Drug Action • Elimination • Two-stage kidney process (filter, absorption) • Metabolites that are poorly reabsorbed by kidney are excreted in urine. • Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e.g., pro-drugs) • Other routes of elimination: lungs, bile, skin

12. Termination of Drug Action • Kidney Actions • excretes products of body metabolism • closely regulates body fluids and electrolytes • The human adult kidney filters approx. 1 liter of plasma per minute, 99.9% of fluid is reabsorbed. • Lipid soluble drugs are reabsorbed with the water.

13. Termination of Drug Action • Factors Influencing Biotransformation • Genetic • Environmental (e.g., diet, nutrition) • Physiological differences (e.g., age, gender differences in microsomal enzyme systems) • Drug Interactions • Some drugs increase or decrease enzyme activity • e.g., carbamazepine stimulates CYP-3A3/4 • e.g., SSRIs inhibit CYP-1A2, CYP-2C

14. Drug Time Course • Time Course Studies important for • predicting dosages/dosing intervals • maintaining therapeutic levels • determining time to elimination • Elimination Half-Life • time required for drug blood levels to be reduced by 50% • Approx. 6 half-lives to eliminate drug from body • With repeated regular interval dosing, steady-state concentration reached in approx. 6 x half-life

15. Therapeutic Drug Monitoring • TDM important for clinical decisions • Plasma levels rough approximation of tissue/receptor concentrations • TDM goals • assess medication compliance • avoid toxicity • enhance therapeutic response

16. Tolerance & Dependence • Mechanisms of Tolerance • Metabolic (Pharmacokinetic, Dispositional) • Cellular-Adaptive (Pharmacodynamic) • Behavioral Conditioning • Dependence • Abstinence Syndrome • Not all addictive drugs produce physical dependence. • Some nonaddictive therapeutic drugs (e.g. SSRIs) can produce physical dependence.

17. Pharmacodynamics • Drug actions at receptor sites and the physiological/chemical/behavioral effects produced by these actions • Studies of drug mechanisms of action at the molecular level • Provides basis for rational therapeutic uses and the design of new, superior therapeutic agents

18. Drug-Receptor Interactions • Receptors found on membrane spanning proteins • Continuous series of amino acid loops • Ligands (neurotransmitters, drugs) attach inside spaces between coils, held by ionic attractions • Reversible ionic binding of ligand activates receptor by changing protein structure. • Intensity of transmembrane signal is determined by percentage of receptors occupied. • Drugs may influence transmembrane signal by binding to neurotransmitter receptor or to nearby site.

19. Drug-Receptor Interactions • Drug/Receptor Binding • Mimic actions of neurotransmitter at same site (agonist) • Bind to nearby site and facilitate neurotransmitter binding (agonist) • Block actions of neurotransmitter at same site (antagonist)

20. Receptor Structures • Ion Channel Receptors • Carrier Proteins • G Protein-Coupled Receptors • Enzymes

21. Drug-Receptor Specificity • Alterations to a drug’s chemical structure may influence potency • e.g., amphetamine vs. methamphetamine • Many drugs have multiple sites of action • Some sites of action are responsible for side effects • e.g., tricyclic antidepressants: sedation, dry mouth, blurred vision

22. Dose-Response Relationships • Potency • Efficacy

23. Dose-Response Functions • Efficacy (ED50 = median effective dose) • Lethality (LD50 = median lethal dose) • Therapeutic Index = LD 50 /ED 50