Pharmacology: Basic Principles

• Pharmacology is the study of drugs and their effects on living systems.
• It encompasses how drugs are absorbed, distributed, metabolized, and excreted (ADME), as well as their mechanisms of action and therapeutic and toxic effects.

Core Principles

• Pharmacokinetics: What the body does to the drug (ADME).
• Pharmacodynamics: What the drug does to the body (mechanism of action and effects).
• Therapeutics: The use of drugs to diagnose, prevent, or treat disease.
• Toxicology: The study of the adverse effects of drugs and other chemicals.

Pharmacokinetics (ADME)

• Absorption: The process by which a drug enters the bloodstream.
  • Routes of administration affect absorption (e.g., oral, intravenous, intramuscular, subcutaneous, transdermal).
  • Bioavailability: The fraction of the administered dose of a drug that reaches the systemic circulation.
• Distribution: The process by which a drug spreads throughout the body.
  • Factors affecting distribution: blood flow, tissue permeability, protein binding, and tissue binding.
  • Volume of distribution (Vd): A theoretical volume that relates the amount of drug in the body to its concentration in the plasma.
• Metabolism: The process by which a drug is chemically altered in the body.
  • Primarily occurs in the liver.
  • Phase I reactions: Oxidation, reduction, and hydrolysis (often involving cytochrome P450 enzymes).
  • Phase II reactions: Conjugation (e.g., glucuronidation, sulfation).
  • Prodrugs: Inactive compounds that are metabolized into active drugs.
• Excretion: The process by which a drug is removed from the body.
  • Primarily occurs via the kidneys (urine) and liver (bile/feces).
  • Clearance: The rate at which a drug is removed from the body.
  • Half-life (t1/2): The time it takes for the plasma concentration of a drug to decrease by half.

Pharmacodynamics

• Receptors: Proteins that bind drugs and mediate their effects.
  • Agonists: Drugs that activate receptors.
  • Antagonists: Drugs that block receptors.
    • Competitive antagonists bind reversibly to the same site as the agonist.
    • Noncompetitive antagonists bind irreversibly or to a different site.
  • Partial agonists: Drugs that activate receptors but produce a submaximal response.
  • Inverse agonists: Drugs that bind to receptors and produce an effect opposite to that of an agonist.
• Dose-response relationship: The relationship between the dose of a drug and the response.
  • Efficacy: The maximum effect a drug can produce.
  • Potency: The amount of drug required to produce a certain effect.
  • Therapeutic index (TI): A measure of drug safety (TD50/ED50).
    • TD50: The dose that produces a toxic effect in 50% of the population.
    • ED50: The dose that produces a therapeutic effect in 50% of the population.
• Signal transduction: The process by which a drug's binding to a receptor leads to a cellular response.
  • G protein-coupled receptors (GPCRs)
  • Ion channels
  • Enzyme-linked receptors
  • Intracellular receptors

Drug Classes

• Cardiovascular drugs:
  • Antihypertensives (e.g., ACE inhibitors, beta-blockers, calcium channel blockers)
  • Antiarrhythmics (e.g., sodium channel blockers, potassium channel blockers)
  • Antianginals (e.g., nitrates, beta-blockers, calcium channel blockers)
  • Heart failure drugs (e.g., ACE inhibitors, diuretics, beta-blockers, digoxin)
  • Lipid-lowering drugs (e.g., statins, fibrates)
• Central nervous system (CNS) drugs:
  • Antidepressants (e.g., SSRIs, SNRIs, TCAs, MAOIs)
  • Antipsychotics (e.g., typical, atypical)
  • Anxiolytics (e.g., benzodiazepines, SSRIs)
  • Hypnotics (e.g., benzodiazepines, non-benzodiazepines)
  • Antiepileptics (e.g., phenytoin, carbamazepine, valproic acid)
  • Antiparkinsonian drugs (e.g., levodopa, dopamine agonists)
  • Analgesics (e.g., opioids, NSAIDs)
• Endocrine drugs:
  • Antidiabetic drugs (e.g., insulin, metformin, sulfonylureas)
  • Thyroid hormones (e.g., levothyroxine)
  • Antithyroid drugs (e.g., methimazole, propylthiouracil)
  • Corticosteroids (e.g., prednisone, hydrocortisone)
  • Sex hormones (e.g., estrogens, progestins, androgens)
• Anti-inflammatory drugs:
  • NSAIDs (e.g., ibuprofen, naproxen)
  • Corticosteroids (e.g., prednisone)
  • Disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate)
• Antimicrobial drugs:
  • Antibiotics (e.g., penicillins, cephalosporins, macrolides, tetracyclines)
  • Antivirals (e.g., acyclovir, oseltamivir)
  • Antifungals (e.g., azoles, amphotericin B)
  • Antiparasitics (e.g., metronidazole, mebendazole)
• Chemotherapeutic drugs:
  • Alkylating agents (e.g., cyclophosphamide)
  • Antimetabolites (e.g., methotrexate)
  • Topoisomerase inhibitors (e.g., doxorubicin)
  • Microtubule inhibitors (e.g., paclitaxel)
  • Targeted therapies (e.g., tyrosine kinase inhibitors)

Factors Influencing Drug Response

• Age: Infants and elderly individuals often have altered drug metabolism and excretion.
• Genetics: Genetic variations can affect drug metabolism and receptor sensitivity.
• Disease: Liver or kidney disease can affect drug metabolism and excretion.
• Drug interactions: Drugs can interact with each other, altering their effects.
  • Additive effects: The combined effect is equal to the sum of the individual effects.
  • Synergistic effects: The combined effect is greater than the sum of the individual effects.
  • Antagonistic effects: One drug reduces the effect of another.
• Tolerance: Decreased response to a drug with repeated use.
• Dependence: Physiological or psychological need for a drug.
• Placebo effect: A response to a drug that is not due to its pharmacological effect.

Drug Development

• Preclinical testing: In vitro and in vivo studies to assess drug safety and efficacy.
• Clinical trials: Studies in humans to evaluate drug safety and efficacy.
  • Phase I: Small number of healthy volunteers to assess safety and pharmacokinetics.
  • Phase II: Small number of patients with the target disease to assess efficacy and dose-ranging.
  • Phase III: Large, randomized, controlled trials to confirm efficacy and monitor adverse effects.
  • Phase IV: Post-marketing surveillance to monitor long-term safety and effectiveness.

Toxicology

• Adverse drug reactions (ADRs): Undesirable effects of drugs.
  • Type A reactions: Predictable and dose-dependent (e.g., side effects).
  • Type B reactions: Unpredictable and not dose-dependent (e.g., allergic reactions).
• Drug interactions: Can lead to increased toxicity.
• Overdose: Excessive dose of a drug, leading to toxic effects.
• Treatment of poisoning:
  • Supportive care (e.g., airway, breathing, circulation).
  • Decontamination (e.g., activated charcoal, gastric lavage).
  • Antidotes (e.g., naloxone for opioid overdose).

Special Populations

• Pediatric Pharmacology:
  • Differences in drug absorption, distribution, metabolism, and excretion.
  • Dosing often based on weight or body surface area.
• Geriatric Pharmacology:
  • Age-related changes in organ function.
  • Increased risk of adverse drug reactions and drug interactions.
  • Polypharmacy: The use of multiple medications.
• Pregnancy and Lactation:
  • Drugs can cross the placenta and affect the fetus.
  • Some drugs can be excreted in breast milk and affect the infant.
  • Risk-benefit ratio must be carefully considered.

Routes of Administration

• Enteral:
  • Oral: Simplest, but absorption can be variable.
  • Sublingual: Rapid absorption, avoids first-pass metabolism.
  • Rectal: Useful for patients who cannot swallow.
• Parenteral:
  • Intravenous (IV): Rapid onset, precise control of drug concentration.
  • Intramuscular (IM): Slower absorption than IV, but faster than subcutaneous.
  • Subcutaneous (SC): Slower absorption than IM.
  • Transdermal: Slow, sustained release through the skin.
• Other:
  • Inhalation: Rapid absorption for respiratory drugs.
  • Topical: Local effects on the skin or mucous membranes.

Drug Regulation

• Regulatory agencies:
  • Food and Drug Administration (FDA)
  • European Medicines Agency (EMA)
• Drug scheduling:
  • Controlled substances are classified based on their potential for abuse.

Precision Medicine

• Pharmacogenomics: The study of how genes affect a person's response to drugs.
• Personalized medicine: Tailoring drug therapy to an individual's genetic makeup, lifestyle, and environment.