Pharmacology Introduction - PDF

INTRODUCTION TO PHARMACOLOGY Prof. Marta Marín Vázquez, PhD. [email protected] Dept. of Pharmacy Office 324 (3rd floor, Health Sciences Building) Tutorials: Upon request by email   1. Introduction to Pharmacology  2. Pharmacokinetics 1....

INTRODUCTION TO PHARMACOLOGY Prof. Marta Marín Vázquez, PhD. [email protected] Dept. of Pharmacy Office 324 (3rd floor, Health Sciences Building) Tutorials: Upon request by email   1. Introduction to Pharmacology  2. Pharmacokinetics 1. GENERAL  3. Pharmacodynamics PHARMACOLOGY:  4. Drug interactions  5. Factors modifying dosage and drug action  6. Adverse effects METABOLISM (Biotransformation) Chemical transformation of a drug in vivo Sites of biotransformation: liver (main), GI tract, lung, plasma, kidney Goal is to make compounds more hydrophilic to enhance renal elimination As a result of the process of biotransformation: a pro-drug may be activated to an active drug (e.g. tamoxifen to endoxifen) a drug may be changed to another active metabolite (e.g. diazepam to oxazepam) a drug may be changed to a toxic metabolite (e.g. meperidine to normeperidine) a drug may be inactivated (e.g. procaine to PABA) Can turn a nontoxic molecule into a poisonous one (toxification). And an inactive drug to an active one. METABOLISM (Biotransformation) Drug Metabolizing Pathways In the endoplasmic reticulum or cell cytoplasm *Phase I reactions usually precede Phase II, but not necessarily. (CYT P450) (increase its water solubility)  METABOLISM (Biotransformation) Factors Affecting Drug Biotransformation: Genetic polymorphism of metabolizing enzymes  Individuals may metabolize drugs faster or slower depending on their genotype → poor, intermediate, extensive or ultrarapid metabolizers  May lead to toxicity or ineffectiveness of a drug at a normal dose e.g. codeine is a prodrug activated by 2D6 (nonfunctional alleles reduce effectiveness), while warfarin metabolized by 2C9 (nonfunctional alleles lead to lower dose requirements) Enzyme inhibition → A drug can inhibit the metabolism of another drug if it uses the same enzyme or metabolism cofactors. e.g. erythromycin, ketoconazole and indinavir inhibit CYP3A4 and predispose a patient to drug toxicity from other drugs metabolized by it → concentrations of the drug can ↑ over the MTC level METABOLISM (Biotransformation) Factors Affecting Drug Biotransformation: Enzyme induction  Certain drugs ↑ gene transcription → ↑ activity of a metabolizing enzymes – A drug may induce its own metabolism by inducing the P450 enzyme system – A single drug may stimulate multiple P450 isoenzymes simultaneously Liver dysfunction caused by disease (hepatitis, alcoholic liver, biliary cirrhosis or hepatocellular carcinoma) may ↓ drug metabolism Renal disease often results in ↓ drug clearance if it is cleared by the kidneys Extremes of age (neonates or elderly) have ↓ biotransformation capacity, and doses should be adjusted accordingly METABOLISM (Biotransformation) Factors Affecting Drug Biotransformation: Nutrition  Insufficient protein and fatty add intake ↓ P450 biotransformation  Vitamin and mineral deficiencies may also impact metabolizing enzymes Alcohol: - acute alcohol ingestion inhibits P450 2E1 - chronic consumption can induce P450 2E1 → ↑ the risk of hepatocellular damage from acetaminophen (by ↑ [acetaminophen's toxic metabolite]) Smoking can induce P450 1A2 (CYP1A2) → ↑ metabolism of some drugs (e.g. smokers may require higher doses of theophylline, which is metabolized by CYP1A2) ELIMINATION Removal of drug from the body Routes of Drug Elimination: Kidney (main organ of elimination): 3 mechanisms 1. GLOMERULAR FILTRATION (passive process → ONLY the free drug fraction can be filtered) 2. TUBULAR SECRETION (an active process that is saturable → protein-bound and free drug fractions are excreted) – two distinct transport mechanisms for weak acids and weak bases – drugs may competitively block mutual secretion if both use the same secretion system 3. TUBULAR REABSORPTION: drugs can be passively reabsorbed back to the systemic circulation, countering elimination mechanisms  DRUG CLEARANCE BY THE KIDNEY ELIMINATION Removal of drug from the body Routes of Drug Elimination: Kidney (main organ of elimination) Elimination rate depends on renal function → ↓ with age and is affected by many disease states Avoid toxicity from drug or metabolite accumulation bv adjusting a drug’s dosage according to the eliminaltion characteristics of the patient (e.g. in renal impairment). Renal function is assessed clinically using serum creatinine (cr) levels  ELIMINATION Removal of drug from the body Routes of Drug Elimination: Stool: some drugs and metabolites are actively excreted in the bile or directly into the intestinal tract from systemic circulation enterohepatic circulation – some glucuronic acid conjugates that are excreted in the bile will be hydrolyzed in the intestines by bacteria; this results in the drug being converted back to its original form and allows for systemic reabsorption – counteracts stool elimination→ can substantially prolong the drug's duration in the body Lungs elimination of anesthetic gases and vapors by exhalation Saliva salivary concentration represents the free drug concentration in plasma: 'salivary recycling' (e.g. caffeine, phenytoin, and theophylline)  DRUG CLEARANCE BY THE KIDNEY ELIMINATION Removal of drug from the body Routes of Drug Elimination: Kidney (main organ of elimination) Excretion kinetics Allow the precise adjustment of the dosage intervals to the patient. Three main pharmacokinetic parameters must be considered: » Clearance (CL) » Bioavailability (F) » Volume of distribution (Vd) ELIMINATION Clearance (CL) A quantitative measurement of the rate of removal of a substance from the body Body fluid volume (L) from which a substance is removed per unit time (h) → L/hr, ml/min, etc. Consider: clearance from a specific part of the body, and total body clearance  ELIMINATION Zero-order kinetics (least common, associated with toxicities, Elimination Kinetics e.g. alcohol) First-order kinetics (most common type) – non-linear kinetics that leads to a constant RATE (a constant amount) of drug eliminated regardless of – Linear and predictable relationship that concentration leads to a constant FRACTION (%) of drug eliminated per unit time – clearance slows as [drug] rises – The amount of drug eliminated is based on the [drug] present ELIMINATION Elimination Kinetics Half-Life (t1/2): time taken for the serum drug level to fall to 5O% during elimination for drugs with first order kinetics, takes 4-6 t1/2 to reach STEADY STATE with repeated dosing, or for drug ELIMINATION once dosing is stopped only applies when drug exhibits first order kinetics