General Pharmacology - Mansoura University - PDF

General pharmacology Nabil Mahmoud Lecturer of Clinical Pharmacology Faculty of Medicine, Mansoura University Learning Objectives Define various terminologies used in Pharmacology. Know about sources of drugs. Understand pharmacodynamics. Understand theoretical pharmac...

General pharmacology Nabil Mahmoud Lecturer of Clinical Pharmacology Faculty of Medicine, Mansoura University Learning Objectives Define various terminologies used in Pharmacology. Know about sources of drugs. Understand pharmacodynamics. Understand theoretical pharmacokinetics. Introductory definitions Clinical pharmacology Is the science concerned with the rational, safe and effective use of drugs The drug Is any chemical molecule that can interact with body systems at the molecular level and produce effect. Source of Drugs ▪ Minerals: magnesium sulfate, magnesium trisilicate etc. ▪ Animals: Insulin, heparin, etc. ▪ Plants: Morphine, atropine, etc. ▪ Synthetic source: Aspirin, …. etc. ▪ Micro organisms: Penicillin, etc. – ▪ Genetic engineering: Human insulin, etc. The drug-body interactions Pharmacodynamics A drug may produce its effects through interaction with: 1. Receptors 2. Ion channels 3. Enzymes 4. Carrier molecules: antidepressant Ligand: ▪ is any molecule that can combine with the receptors. Affinity: ▪ It is the empathy of the receptor to the ligand. ▪ It determines the number of receptors occupied by the drug.  Receptors ▪ They are protein macromolecules. ▪ When they combine with a drug, they may be activated or blocked. Ion channel-linked receptors G-protein-linked receptors Tyrosine kinase (TK)- Intracellular (direct ligand-gated ion linked receptors receptors channels) ▪ very fast ▪ slower than ion channel ▪ e.g., insulin receptors ▪ Their response is ▪ very short. receptors slow (time is ▪ e.g., Nicotinic Ach receptors ▪ duration is longer. required for ▪ e.g., α adrenergic synthesis of new receptors proteins Drug receptor relationship Agonist effect: ▪ The drug combines with the receptor and gives response. Antagonist effect: ▪ The drug combines with the receptor but gives NO response. ▪ It prevents the receptor from binding to another drug. ▪ It may be competitive (reversible) or noncompetitive (nonreversible) Dose-response relationship curves there are 2 types of responses to drugs: Graded response Quantal response ▪ The response is increased ▪ The response does not increase proportionally to the dose of the proportionally to the agonist but it agonist is all-or-none response ▪ e.g. the response of the heart to ▪ e.g. prevention of convulsions by adrenaline. antiepileptic drugs Effectiveness and safety Efficacy ▪ It is the ability of a drug to produce response (effect) after binding to the receptor. ▪ It is measured by the Emax (the maximal response that a drug can elicit at full concentration): ✓Full agonist is the drug that gives maximal response at full concentration (at full occupancy). ✓Partial agonist is that agonist gives submaximal response even at full dose Potency ▪ ED50 (Effective Dose) is the dose of the drug that gives 50% of the Emax Or ▪ The dose that gives the desired effect in 50% of a test population of subjects. ▪ A drug that gives ED50 by smaller doses is described as “potent” drug. Safety ▪ TD50 (Toxic Dose) is the dose of the drug needed to cause a harmful effect in 50% of a test population of subjects. ▪ LD50 (Lethal Dose) is the dose needed to cause death in 50% of a test group of animals. It is experimental term that can be determined in animals. Therapeutic index (TI) LD50 ▪ The ratio between the LD50 and the ED50 ED50 ▪ If there is a large difference between theses two doses it is said that the drug has a large TI. ▪ Drugs with high TI are safer for clinical use, and vice versa ▪ e.g. warfarin has a narrow TI and requires careful therapeutic monitoring). Factors affecting dose-response relationship Factors related to the drug ▪ Drug shape (stereoisomerism) ▪ Molecular weight (MW): ▪ Time of drug administration (Chronopharmacology) Chronopharmacology is the science dealing with tailoring drug medication according to the circadian rhythm of the body to get better response and/or to avoid possible side effects. ▪ Drug cumulation: ▪ occurs when the rate of drug administration exceeds the rate of its elimination.  Drug combination Summation or Synergism potentiation Antagonism addition ▪ The combined effect of ▪ The combined effect ▪ The effect of one drug ▪ One drug abolishes two drugs is equal to the of two drugs is is increased by intake the effect of the sum of their individual greater than the of another drug other i.e. 1+1=0). effects (i.e. 1+1=2). sum of their individual without notable effect effects (i.e. 1+1=3). (i.e. 1+0=2) ▪ drugs having the same ▪ The two drugs usually mechanism have different ▪ for E.g., mechanisms of action Phenobarbitone has ▪ E.g., the use of two simple ▪ E.g., the use of no analgesic action analgesics together. penicillin with but it can potentiate aminoglycosides to the analgesic action of exert bactericidal aspirin. effect. Factors related to the patient ▪ Age, sex, and weight; ▪ The pediatric doses are expressed in terms of body weight (mg/kg per dose or day) or in terms of body surface area (mg/m 2 per day). ▪ Pathological status; Liver or kidney diseases ▪ significantly alter the response to drugs due to altered metabolism or excretion of drugs. Pharmacogenetic factors (idiosyncrasy) ▪ It is abnormal response to drugs due to genetic abnormality in drug metabolism. Examples: ▪ choline esterase deficiency ▪ administration of succinylcholine leads to apnea. ▪ Glucose -6 phosphate dehydrogenase deficiency. ▪ Drugs like primaquine, sulfonamides and dapsone may cause haemolysis in patients with glucose -6 phosphate dehydrogenase deficiency. ▪ Acetylation of INH: ▪ Slow acetylator develops peripheral neuropathy ▪ Rapid acetylator develops hepatotoxicity. ▪ Resistance to coumarin (warfarin) anticoagulants. ▪ Resistance to vit D (vit D-resistant rickets). ▪ Hypo reactivity to drugs: (Tolerance; tachyphylaxis; drug resistance) ▪ Tolerance: ▪ Progressive decrease in drug response with successive administration. ▪ The same response could be obtained by higher doses. ▪ It occurs over long period. ▪ Tachyphylaxis: ▪ it is an acute type of tolerance that occurs very rapidly. ▪ Hyper susceptibility (overshot phenomenon; intolerance) ▪ It is an exaggerated response occurs on sudden stopping of a drug taken for long time. Mechanism: ▪ up-regulation: ▪ increase number of receptors due to prolonged exposure to the antagonist or prolonged deficiency of the natural agonist. ▪ When the antagonist is suddenly withdrawn, severe reaction occurs in the form of rebound or withdrawal effects ▪ Drug dependence: (habituation and addiction) Pharmacokinetics Definition ▪ it is the journey of the drug inside the body It includes 4 processes: ✓ Absorption ✓ Distribution ✓ Metabolism ✓ Excretion Absorption of Drugs Definition ▪ it is the passage of drug from the site of administration to the plasma. Routes of administration: A- Enteral (from the alimentary tract): 1. Buccal cavity: e.g., nitrates 2. Oral: ▪ Stomach: e.g., aspirin ▪ Intestine: e.g. most of drugs 3. Rectum: e.g. rectal suppositories Absorption of Drugs Routes of administration: B- Parenteral route 1. Intradermal: e.g. B.C.G. vaccine 2. Subcutaneous: e.g. insulin, heparin 3. Intramuscular: e.g. multivitamins, streptomycin, etc. 4. Intravenous route: e.g: glucose, saline & blood 5. Intrathecal: e.g. spinal anaesthetics. 6. Intraperitoneal: e.g. antibiotics 7. Intra-articular: e.g. hydrocortisone. Absorption of Drugs Routes of administration: C- Transcutaneous route: Transdermal Adhesive patches: e.g. scopolamine for motion sickness, nitroglycerine for angina. D- Topical/ local route: e.g., dusting powder, paste, lotion, drops, ointment, suppository for vagina and rectum. E- Inhalation: e.g., salbutamol spray used in bronchial asthma and volatile general anesthetics. Absorption of Drugs Factors affecting drug absorption: A. Factors related to the drug ▪ Molecular size ▪ Dose: ▪ Drug formulations: ✓e.g. sustained-release tablets are slow in absorption. ▪ Local effects of the drug: ✓ e.g. drugs producing VC ↓ their own absorption. ▪ Drug combination: ✓e.g. vit C ↑ absorption of iron. ▪ Lipid solubility, drug ionization, and the pKa of the drug. The pKa and drug ionization ▪ Ionized (polar; charged) drugs are poorly absorbed, ▪ Unionized (non-polar, non-charged) drugs are more absorbed. ▪ pKa of a drug: is the pH at which 50% of the drug is ionized and 50% is non-ionized. Clinical significance of pKa Treatment of drug toxicity: - Toxicity with acidic drugs (e.g. aspirin) could be treated by alkalinization of urine, which renders this drug more ionized in urine and less reabsorbable. - Toxicity with basic drugs (e.g. amphetamine) could be treated by acidification of urine, which renders this drug more ionized in urine and less reabsorbable. Absorption of Drugs Factors affecting drug absorption: B. Factors related to the absorbing surface: ▪ Route of administration: ✓ i.v. route is the fastest while rectal is the slowest. ▪ Integrity of the absorbing surface: ▪ -Specific factors: ✓ e.g. apoferritin system for iron, etc. Distribution of Drugs Volume of distribution (Vd) ▪ Definition: The apparent volume of water into which the drug is distributed in the body after distribution equilibrium. ▪ Clinical significance: the site of drug distribution ▪ Vd < 5 L: means that the drug is confined to the vascular compartment and can be removed by dialysis. ▪ Vd 5-15 L: means that the drug is restricted to the ECF. ▪ Vd > 41 L: means that the drug is highly bound to tissue proteins and cannot be removed by dialysis. Distribution of Drugs Binding of drugs to plasma proteins Clinical significance: ▪ free part Vs bound part. ▪ Binding of drugs to plasma proteins prolongs their effects. ▪ Site of drug interactions ▪ Affected by diseases Excretion and Elimination of Drugs A- First- order elimination: B- Zero-order elimination ▪ Most drugs. ▪ Limited number of drugs ▪ E.G prednisolone, theophylline ▪ The rate of elimination is ▪ The rate of elimination is not proportional to plasma conc. I.E. proportional to plasma conc. I.E. Constant ratio (%) of the drug is Constant amount of the drug is eliminated per unit time. eliminated per unit time ▪ The t1/2 of the drug is constant. ▪ The t 1/2 of the drug is not constant ▪ More liable to toxicity and drug- drug interaction. Excretion and Elimination of Drugs Plasma half-life (t1/2) Definition: It is the time taken for the concentration of a drug in blood to fall half its original value. Clinical significance: ▪ Inter-dosage interval ▪ Time to reach Cpss: 4-5 t1/2. ▪ Time-course of drug elimination: 4-5 t1/2. ▪ Drugs having long t1/2 could be given once daily to improve patient compliance. Excretion and Elimination of Drugs Steady-state plasma concentration (Cpss) Definition: the steady level of drug in plasma achieved when the rate of administration equals the rate of elimination Excretion and Elimination of Drugs Clearance as a channel of elimination : Definition: ▪ The amount of plasma cleared from the drug per minute. Routes of elimination: ▪ Kidney (the major route). ▪ Bile and liver. ▪ Lungs, intestine, milk, saliva and sweat. Clinical importance of knowing the route of elimination: ▪ Adjust the dose to avoid accumulation. ▪ Avoid drugs eliminated by a diseased organ. ▪ Targeting therapy: e.G., Drugs eliminated by the lung could be used as expectorants. Metabolism of Drugs (biotransformation) ▪ Site of drug metabolism? ▪ Drugs are converted into a water-soluble form (polar) to be excreted. ▪ Some drugs are excreted unchanged (hard drugs). Metabolism of drugs may lead to: conversion of active drug into: ▪ Inactive metabolites ▪ Active metabolites (e.g. Codeine to morphine). ▪ Toxic metabolites (e.g. Paracetamol to n-acetylbenzoquinone). ▪ Conversion of inactive drug into active metabolites (prodrugs) (e.g. Enalapril to enalaprilat). Metabolism of Drugs (biotransformation) Phase I reactions Phase II reactions (conjugation) ▪ Oxidation, reduction, and hydrolysis. Glucuronic acid ▪ Cytochrome p450 (cyp450) enzyme Enterohepatic circulation Genetic polymorphism Some drugs can induce (increase activity) or inhibit certain CYP450 enzymes leading to significant drug interactions; Microsomal enzyme induction Microsomal enzyme inhibition ▪ ↑ Rate of metabolism of some drugs ▪ ↓ Rate of metabolism of some drugs leading to ↓ their serum levels and leading to ↑ their serum levels and therapeutic failure. toxicity. ▪ Examples of inducing agents: ▪ Examples of inhibiting agents: ▪ Phenytoin, phenobarbitone, ▪ Macrolide antibiotics (e.G. Erythromycin), carbamazepine, rifampicin, smoking, ciprofloxacin, cimetidine, ketoconazole, chronic alcohol intake, st john's wort, ritonavir, grapefruit juice. ▪ Clinical examples: ▪ Clinical examples: - ▪ Rifampicin accelerates metabolism of ▪ Ciprofloxacin inhibits metabolism of contraceptive pills leading to failure of warfarin (anticoagulant) leading to contraception. accumulation of warfarin and bleeding. Metabolism of Drugs (biotransformation) First-pass metabolism (pre-systemic elimination) metabolism of drugs at the site of administration before reaching systemic circulation e.g. the liver after oral administration, the lung after inhalation, the skin after topical administration, etc. ▪ Gut first-pass metabolism: ▪ Gastric acidity: benzyl penicillin. ▪ Digestive enzymes: insulin. ▪ Hepatic first-pass metabolism: ▪ Complete: lidocaine. ▪ Partial: propranolol, morphine, nitroglycerine ▪ None: atenolol and mononitrates ▪ How to avoid? ▪ By increasing the dose of the drug. ▪ By giving the drug through other routes e.g. sublingual, inhalation, or i.v. Metabolism of Drugs (biotransformation) Bioavailability Definition: ▪ it is the fraction of the drug become available for systemic effect after administration. ▪ The bioavailability of drugs given i.v. is 100%. ▪ Factors affecting bioavailability: ▪ Factors affecting absorption. ▪ Factors affecting metabolism. ▪ First-pass metabolism. Adverse drug reactions (ADR) Type A (Augmented) Type B (Bizarre) ▪ Predictable ▪ Less common ▪ Exaggerated response (e.g. ▪ Less predictable Hypotension from an ▪ May be severe. antihypertensive). Examples ▪ Immunologic: penicillin allergy ▪ Genetic: haemolysis in G6PD deficiency ▪ Idiosyncratic: malignant hyperpyrexia in anesthesia. Adverse drug reactions (ADR) ADR on pregnancy Drug-drug interactions Pharmacokinetic Interactions Drug interactions in vitro: ▪ e.g. penicillins and aminoglycosides form complexes in the infusion fluid. Drug interactions in vivo: Absorption ▪ Tetracycline forms complexes with Ca2+, Mg2+ and Al3+ Distribution ▪ Sulfonamides displace bilirubin from pl pr in premature infants → kernicterus. Metabolism ▪ Inhibition or induction of microsomal metabolism. Excretion Alkalinization of urine (e.g. sodium bicarbonate) ↑ excretion of weak acids drug-drug interactions Pharmacodynamic Interactions Antagonism: ▪ competitive, non-competitive, chemical, physical Synergism: ▪ e.g. MAO inhibitors can cause toxic synergism with TCA. Potentiation: ▪ e.g. ethanol can enhance CNS depression caused by opioids Thank You