Untitled Quiz

General Pharmacology

• Lecturer: Nabil Mahmoud
• Faculty of Medicine, Mansoura University

Learning Objectives

• Define pharmacological terminology
• Understand drug sources
• Understand pharmacodynamics
• Understand pharmacokinetics

Introductory Definitions

• Clinical pharmacology: Science of rational, safe, and effective drug use
• Drug: Any chemical interacting with body systems at the molecular level to produce an effect

Source of Drugs

• Minerals: e.g., magnesium sulfate, magnesium trisilicate
• Animals: e.g., insulin, heparin
• Plants: e.g., morphine, atropine
• Synthetic Sources: e.g., aspirin
• Micro-organisms: e.g., penicillin
• Genetic Engineering: e.g., human insulin

Drug-Body Interactions

• Pharmacodynamics: The effect of the drug on the body (mechanism of drug action and its effects)
• Drug-Body interactions: Process of interaction
• Pharmacokinetics: The effect of the body on the drug (absorption, distribution, metabolism, excretion)

Pharmacodynamics

• Drugs exert effects by interacting with:
  • Receptors
  • Ion channels
  • Enzymes
  • Carrier molecules
• Ligand: A molecule that combines with receptors
• Affinity: The receptor's empathy for a ligand; determines the number of receptors the drug occupies

Receptors

• Protein macromolecules
• Combine with drugs to become activated or blocked
• Types:
  • Ion channel-linked receptors (fast, short duration, e.g. Nicotinic Ach receptors)
  • G-protein-linked receptors (slower than ion channels; longer duration; e.g., a-adrenergic receptors)
  • Tyrosine kinase-linked receptors (e.g., insulin receptors)
  • Intracellular receptors (slow response; synthesis of new proteins)

Drug Receptor Relationship

• Agonist: Drug combines with receptor to produce a response
• Antagonist: Drug combines with receptor but doesn't cause a response; blocks other drugs from binding; can be competitive (reversible) or noncompetitive (nonreversible)

Dose-Response Relationship Curves

• Graded response: Response increases proportionally to the dose (e.g., heart response to adrenaline)
• Quantal response: All-or-none response, not proportional to the dose (e.g., prevention of convulsions by antiepileptic drugs)

Effectiveness and Safety

• Efficacy: Ability of a drug to produce a response after binding to a receptor; measured by Emax (maximum response at full concentration)
• Full agonist: A drug that produces the maximum response at full concentration
• Partial agonist: A drug that produces a submaximal response even at full dose
• Potency: ED50 (effective dose that produces 50% of maximal response) by smaller doses is potent

Safety

• TD50 (Toxic Dose): Dose of a drug causing harmful effects on 50% of a test population
• LD50 (Lethal Dose): Dose of a drug causing death in 50% of a test group; experimental term measured in animals

Therapeutic Index (TI)

• Ratio between LD50 and ED50
• High TI indicates a safer drug; vice versa

Factors Affecting Dose-Response Relationship

• Drug related: Drug shape, Molecular weight, Time of administration (Chronopharmacology) adjusting to circadian rhythm, Drug cumulation
• Patient related: Age, sex, weight (mg/kg per dose or day or body surface area mg/m2 per day), Pathological status (liver or kidney diseases significantly alter drug response by altering drug metabolism/excretion)
• Pharmacogenetic: Abnormal response due to genetic abnormality (e.g., choline esterase deficiency, glucose-6-phosphate dehydrogenase deficiency, Acetylation of INH, Resistance to vit D). and others.

Drug Combination

• Summation (Addition): Combined effect equals sum of individual effects (e.g., 1+1=2)
• Synergism: Combined effect is greater than the sum of individual effects (e.g., 1+1=3); different mechanisms of action
• Potentiation: Effect of one drug is increased by the intake of another drug without notable effects (e.g., 1+0=2)
• Antagonism: One drug abolishes the effect of the other (e.g., 1+1 =0 )

Hypo Reactivity

• Tolerance (progressive decrease), Tachyphylaxis(acute), Hyper susceptibility (overshot/intolerance)

Pharmacokinetics

• Journey of drug inside the body
• 4 processes: Absorption, Distribution, Metabolism, Excretion

Absorption of Drugs

• Definition: Pass of drug from administration to plasma
• Routes:
  • Enteral: Buccal Cavity(e.g. Nitrates), Oral (Stomach-e.g. aspirin; Intestine-most of drugs), Rectum (e.g.suppositories)
  • Parenteral: Intradermal(e.g. B.C.G vaccine), Subcutaneous (e.g. insulin, heparin), Intramuscular (e.g. multivitamins, streptomycin), Intravenous(e.g. glucose, saline & blood), Intrathecal (spinal anaesthetics), Intraperitoneal (antibiotics), Intra-articular (e.g. hydrocortisone)
  • Transcutaneous (patches-e.g. scopolamine for motion sickness, nitroglycerin for angina)
  • Topical/local (e.g. dusting powder, paste, lotion, drops, ointment, suppository for vagina and rectum)
  • Inhalation (e.g., salbutamol, volatile general anesthetics)
• Factors affecting absorption:
  • Drug related: Molecular size; Dose; Formulations (sustained release); Local effects (e.g., drugs producing vasoconstriction); Drug combinations (e.g., Vit C ↑ iron absorption); Lipid solubility; ionization; pKa.
  • Surface related: Route of administration(iv Fastest, rectal slowest); Integrity; Specific factors (e.g., ferritin for iron.)

Distribution of Drugs

• Definition : apparent volume of water drug is distributed in after equilibrium
• Clinical significance
  • Vd <5L : confined to vascular compartment; can be removed through dialysis
  • Vd 5-15 L: restricted to ECF
  • Vd >41L : mainly bound to tissue proteins; Not removable by dialysis;
• Binding of drugs to plasma proteins
  • Clinical Significance : free VS bound part, prolongs effects of drugs, site of drug interactions, affected by diseases.

Excretion and Elimination of Drugs

• Clearance: amount of plasma cleared of drug per minute
• Routes: Kidney (major); Bile; Liver; Lungs; Intestine; Milk; Saliva; Sweat
• Clinical significance: Adjust dose to avoid accumulation; Avoid drugs eliminated by diseased organs; Targeting therapy
• First-order elimination: Rate proportional to plasma concentration; Constant ratio of the drug eliminated per unit time; Constant t1/2
• Zero-order elimination: Constant amount eliminated per unit time; Variable t1/2; Greater liability to toxicity & drug interactions
• Plasma half-life(t1/2): Time taken for drug concentration to fall to half its original value
• Steady-state plasma concentration(CPSS): Steady level of drug in plasma when the rate of administration = elimination rate

Metabolism of Drugs

• Site of drug metabolism : Liver mainly
• Drugs are converted to water-soluble form for excretion
• Metabolism can result in:
  • Inactive metabolites
  • Active metabolites
  • Toxic metabolites
• First-pass metabolism (pre-systemic elimination) in gut or liver before systemic circulation
  • e.g. the liver after oral administration; the lung after inhalation; topical on skin
• Factors e.g., bioavailability; Inducing or Inhibiting CYP P450 enzymes and other enzymes, first-pass metabolism;

Adverse Drug Reactions (ADR)

• Type A (Augmented): Predictable, exaggerated response (e.g., hypotension from an antihypertensive drug)
• Type B (Bizarre): Less common, less predictable, may be severe (e.g., penicillin allergy, genetic haemolysis, idiosyncratic malignant hyperthermia)
• FDA Pregnancy Categories: A (no risk), B (no risk to animals/women), C (risk to animals, unknown to women), D (risk to humans; benefits may outweigh risk), X(risk to women; does not outweigh risks)

Drug-Drug Interactions

• Pharmacokinetic: Interactions affecting absorption, distribution, metabolism, or excretion (e.g., tetracycline complexing with metal ions)
• Pharmacodynamic: Interactions affecting the drug's effect through mechanisms like antagonism, synergism, or potentiation (e.g., alcohol potentiating opioid CNS depression)