General Principles in Pharmacology

1. General Principlesin Pharmacology Ma. Victoria M. Villarica M.D.

2. Basic Principles: • Pharmacology – study of substances that interact with living systems to produce an effect • Pharmacotherapeutics – drugs used in the diagnosis, treatment and prevention of diseases • Toxicology – toxic effects of drugs • Pharmacognosy – drugs in their unaltered state

3. Pharmacogenetics • Pharmacoeconomics • Drug – substance that brings about change through its’ chemical action • Physical properties of a drug: a. physical nature of a drug b. drug size c. chemical forces – covalent, electrostatic, hydrophobic

4. Basic Pharmacologic concepts: • Pharmacokinetics – body → drug - “ drug-concentration” relationship 4 processes: A. absorption – rate → circulating fluids factors: drug solubility, drug concentration, local conditions, blood flow, surface area

5. Routes of drug administration: a. enteral – oral , rectal b. parenteral – IV, IM, SC, intraperitoneal, intrathecal, intraarterial, inhalational, otic, optic c. topical B. distribution – site of administration →site of action factors: size of the organ, blood flow, solubility, binding

6. Permeation – how a drug transverses the plasma membrane • Passive diffusion, active transport, facilitated diffusion, pinocytosis C. metabolism – biotransformation; liver 2 phases: 1. phase I – introduce or expose a functional group e.g. dealkylation, oxidation, reduction, hydrolysis, deamination, cytochrome p450

7. 2. Phase II – formation of covalent linkage between the functional group on the parent compound; cytosol e.g. glucoronidation, sulfation, acetylation Factors Inducer Inhibitor D. excretion – elimination; kidneys Factors

8. 2 Basic Parameters of Pharmacokinetics • Volume of distribution (Vd) – amount of apparent space in the body able to contain a drug Vd = amt of drug in body / concentration (C) 2. Clearance (Cl) – ability of the body to eliminate a drug Cl = rate of elimination / C

9. Clearance: • capacity-limited elimination – varies, depending upon concentration of the drug that is achieved; saturable; dose/concentration dependent e.g. phenytoin, ethanol, aspirin rate of elimination = Vmax x C Km x C Vmax – maximum elimination capacity Km – drug conc. at w/c rate of elimination is 50% of Vmax “pseudo-zero order kinetics” – elimination is independent of concentration

10. b. Flow dependent elimination – dependent on the rate of delivery of the drug to the organ “high extraction” drugs “first order kinetics” – a constant fraction of drug is eliminated/unit of time; not saturated “zero-order kinetics” – a constant amount of drug is eliminated/unit of time; saturable

11. Other parameters: • Half-life (t ½) – time required to change the amount of drug by ½ t ½ = 0.7 x Vd Cl • Drug accumulation – drug interval is shorter than 4 t ½ , accumulation is detectable Accumulation factor = 1/ 1 – fraction remaining before next dose

12. Bioavailability – fraction of unchanged drug reaching the circulation; extent of absorption varies first pass elimination ER = C liver Q (hepatic blood flow) • Steady state – achieved when rate of elimination = rate of administration rate in = rate out • Area under the curve (AUC) – 1st order elimination; time concentration profile after a dose; C is constant

13. Minimum effective concentration • Loading dose = Vd x desired plasma conc. bioavailability - initial dose that is given • Maintenance dose = Cl x desired plasma conc. bioavailability • Therapeutic index (TI) – dose to produce desired effect • Intermittent dose: peak – high pts. of fluctuations (toxic effects) troughs – low pts. of fluctuations (lack drug of effects)

14. 2. Pharmacodynamics – drug →body • Receptors inert binding site – binds with a drug w/out initiating events leading to any of the drug’s effects; buffers concentration gradient that drives diffusion active site – recognition site

15. Principles: • Concentration effect curve – response to low dose increases in direct proportion to dose; however, as dose increases, the response increment diminishes that finally, doses may be reached at w/c no further increase in response can be achieved • Receptor-effector coupling – transduction process that occurs between occupancy of the receptors and drug response

16. Spare receptor • Receptor antagonists – prevent agonist from binding and activating receptors • 2 classes: a. competitive antagonist b. irreversible antagonist – unavailable chemical antagonist – protamine and warfarin or heparin Physiologic antagonist – steroids and insulin • Receptor agonist – full agonist and partial agonist

17. Signaling mechanism and drug action • Intracellular receptors for lipid soluble agents – NO, hormones, corticosteroids, sex hormones, vit D, thyroid hormone • Ligand regulated transmembrane enzymes – insulin, growth factor • Cytokine receptor – JAK enzyme, STAT; growth hormone, erythropoietin, interferon • Ligand-gated channels – ACTH, GABA • G-proteins and 2nd messengers – cAMP, Ca, cGMP

18. Relation between drug dose and clinical response A. Graded dose response pharmacologic potency – EC50 and ED50 maximal efficacy – extent or degree of an effect that can be achieved by the patient B. Quantal dose effect responsemargin of safety; indicates variability of responsiveness; ED50, LD50, TD50, TI = TD50 ED50

19. Variations in drug responsiveness: - mechanisms involve alteration in concentration of a drug and changes in the receptor • Hyporeactive • Hyperreactive • Tolerance - ↓ responsiveness due to continued drug administration • Tachyphylaxis – rapid, diminishing responsiveness

20. Basic and Clinical Evaluation of a New Drug • 1st step – discovery of a potential molecule (chemical modification, random screening of natural products, rational drug design, biotechnology and cloning) • 2nd step – drug screening → LEAD compound • 3rd step – preclinical and toxicity testing; limitations (acute and chronic toxicity, teratogenicity, carcinogenicity, mutagenicity, investigative toxicology) • 4th step – evaluation in humans ; factors

21. Phases of clinical trial: • Phase 1 – 25-50 healthy volunteers • Phase 2 – 10-200 patients with target disease • Phase 3 – larger population; difficult phase; NDA is submitted and approval takes place 3 yrs or more • Phase 4 post-marketing surveillance; apply for a patent (20 yrs.)

22. Maraming Salamat