Pharmacology: Basic Principles and Pharmacokinetics

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

Basic Principles

• A drug is any substance that, when absorbed into a living organism, alters normal bodily function.
• Drugs can be synthesized chemically, derived from plants or animals, or produced through biotechnology.
• The study of how drugs affect the body is called pharmacodynamics.
• The study of how the body affects the drug is called pharmacokinetics.

Pharmacokinetics

• Absorption is the process by which a drug enters the bloodstream.
• Distribution is the process by which a drug spreads throughout the body.
• Metabolism (or biotransformation) is the process by which the body chemically modifies a drug.
• Excretion is the process by which the body eliminates a drug.
• These processes determine the concentration of a drug at its sites of action.

Drug Absorption

• The route of administration affects the rate and extent of drug absorption.
• Common routes include oral, intravenous, subcutaneous, intramuscular, transdermal, and inhalation.
• Bioavailability refers to the fraction of an administered dose of drug that reaches the systemic circulation unchanged.
• Factors affecting absorption include the drug's physical properties, formulation, and the route of administration.
• Drugs given intravenously have 100% bioavailability.
• The first-pass effect can significantly reduce the bioavailability of orally administered drugs.

Drug Distribution

• Drug distribution is affected by blood flow, tissue permeability, and binding to plasma proteins and tissues.
• Only unbound (free) drug can exert a pharmacological effect.
• The volume of distribution (Vd) is a measure of the apparent space in the body available to contain the drug.
• A high Vd indicates that the drug is extensively distributed into tissues.
• The blood-brain barrier restricts the passage of many drugs into the central nervous system.

Drug Metabolism

• Drug metabolism primarily occurs in the liver.
• Phase I reactions (e.g., oxidation, reduction, hydrolysis) introduce or expose a functional group on the drug molecule.
• Phase II reactions (e.g., glucuronidation, sulfation, acetylation) conjugate the drug with a polar molecule, increasing its water solubility.
• Cytochrome P450 (CYP) enzymes are a major family of enzymes involved in drug metabolism.
• Genetic variations in CYP enzymes can affect drug metabolism and response.
• Prodrugs are inactive compounds that are metabolized into active drugs.

Drug Excretion

• The kidneys are the primary organs for drug excretion.
• Drugs can be excreted in urine via glomerular filtration, active tubular secretion, or passive tubular reabsorption.
• Liver excretes drugs into the bile, which are then eliminated in feces.
• Clearance is a measure of the rate at which a drug is removed from the body.
• Half-life (t1/2) is the time it takes for the plasma concentration of a drug to decrease by 50%.

Pharmacodynamics

• Pharmacodynamics describes the effects of a drug on the body, including its mechanism of action.
• Drugs typically exert their effects by binding to receptors, enzymes, ion channels, or transporters.
• Receptors are proteins that bind signaling molecules and initiate a cellular response.
• Agonists activate receptors, while antagonists block receptor activation.
• Affinity is a measure of how tightly a drug binds to its receptor.
• Efficacy is a measure of a drug's ability to produce a maximal response.
• Potency refers to the amount of drug needed to produce a given effect.
• A dose-response curve illustrates the relationship between drug dose and effect.
• The therapeutic index (TI) is a measure of a drug's safety, calculated as the ratio of the toxic dose to the therapeutic dose.
• A higher TI indicates a safer drug.

Drug Receptors

• Drug receptors are typically proteins located on the surface or inside of cells.
• Major receptor families include ligand-gated ion channels, G protein-coupled receptors (GPCRs), enzyme-linked receptors, and intracellular receptors.
• Ligand-gated ion channels open or close in response to ligand binding, altering ion flow across the cell membrane.
• GPCRs activate intracellular signaling pathways via G proteins.
• Enzyme-linked receptors activate intracellular enzymes upon ligand binding.
• Intracellular receptors bind to ligands that can diffuse across the cell membrane, such as steroid hormones.

Drug Interactions

• Drug interactions can occur when one drug alters the effects of another drug.
• Interactions can be pharmacokinetic (affecting ADME) or pharmacodynamic (affecting the drug's action).
• Enzyme inducers increase the expression of drug-metabolizing enzymes, potentially decreasing the effects of other drugs.
• Enzyme inhibitors decrease the activity of drug-metabolizing enzymes, potentially increasing the effects of other drugs.
• Additive effects occur when two drugs with similar actions produce a combined effect equal to the sum of their individual effects.
• Synergistic effects occur when two drugs produce a combined effect greater than the sum of their individual effects.
• Antagonistic effects occur when one drug reduces or blocks the effect of another drug.

Adverse Drug Reactions

• Adverse drug reactions (ADRs) are unintended and undesirable effects of drugs.
• ADRs can range from mild to severe, including allergic reactions, organ damage, and death.
• Side effects are predictable and often unavoidable ADRs that occur at therapeutic doses.
• Toxic effects result from excessive drug doses or prolonged use.
• Allergic reactions are immune-mediated responses to drugs.
• Idiosyncratic reactions are unpredictable and rare ADRs that occur in a small percentage of patients.

Special Populations

• Pediatric patients may require different drug doses due to differences in ADME compared to adults.
• Geriatric patients may be more susceptible to ADRs due to age-related changes in organ function.
• Pregnant women require special consideration due to the potential effects of drugs on the fetus.
• Patients with renal or hepatic impairment may require dose adjustments to prevent drug accumulation.
• Genetic factors can influence drug response and metabolism.

Drug Development

• Drug development involves preclinical research, clinical trials, and regulatory review.
• Preclinical research includes in vitro and in vivo studies to assess drug efficacy and safety.
• Clinical trials are conducted in phases (I-IV) to evaluate drug safety and efficacy in humans.
• Phase I trials assess safety and tolerability in a small number of healthy volunteers.
• Phase II trials evaluate efficacy and dose-response in a larger group of patients with the target disease.
• Phase III trials compare the new drug to standard treatments in a large, randomized, controlled trial.
• Phase IV trials are post-marketing studies to monitor long-term safety and efficacy.
• Regulatory agencies (e.g., the FDA in the United States) review clinical trial data and approve new drugs for marketing.