Master Pharmacokinetics, Dynamics & OmpathStudy

1. PHARMACOKINETICS (PK) — "what the body does to the drug" ADME: A bsorption – drug enters systemic circulation D istribution – drug moves from blood into tissues M etabolism – chemical alteration, mainly in the liver E xcretion – removal of drug/metabolites, mainly via kidneys Key PK parameters: Bioavailability (F) – fraction of dose reaching systemic circulation unchanged. IV = 100%; oral usually lower (absorption losses + first-pass metabolism) Half-life (t½) – time for plasma concentration to fall by 50%. Determines dosing interval; steady state reached in ~4–5 half-lives Clearance (CL) – volume of plasma cleared of drug per unit time (reflects renal + hepatic elimination) Volume of distribution (Vd) – theoretical volume needed to account for total drug amount at observed plasma concentration. High Vd = lipophilic/tissue-bound; Low Vd = stays in plasma, hydrophilic Factors affecting absorption/bioavailability: Route of administration, GI pH/motility, presence of food Drug formulation (solubility, particle size) First-pass metabolism P-glycoprotein efflux pumps Disease states (e.g. malabsorption) First-pass metabolism: Oral drugs metabolized by gut wall/liver before reaching systemic circulation → reduces bioavailability Clinical relevance: choosing sublingual/IV/transdermal routes to bypass it Phase I vs Phase II metabolism: Phase I – oxidation, reduction, hydrolysis (mainly Cytochrome P450); may create active or toxic metabolites Phase II – conjugation (glucuronidation, sulfation, acetylation); makes drug inactive + water-soluble for excretion Organ dysfunction effects: Renal impairment → accumulation of renally-cleared drugs → reduce dose/extend interval Hepatic impairment → reduced metabolism → ↑ drug levels, especially high first-pass drugs Dosage regimen design: Loading dose ≈ (Vd × target concentration) / F Maintenance dose ≈ (CL × target concentration × interval) / F Adjust for organ impairment; use therapeutic drug monitoring for narrow-therapeutic-index drugs 2. PHARMACODYNAMICS (PD) — "what the drug does to the body"- PD = mechanism & effect of drug; PK = drug movement/concentration over time Drug-receptor interactions: Agonist – binds & fully activates receptor Partial agonist – binds receptor, produces submaximal effect even at full occupancy Competitive antagonist – binds same site, reversible; overcome by ↑ agonist dose (shifts curve right) Non-competitive antagonist – binds allosteric site or irreversibly; cannot be overcome by more agonist (↓ maximal effect) Dose-response relationships: Potency – amount of drug needed for a given effect (EC50) Efficacy – maximum effect achievable (Emax) Graded curve (single subject) vs quantal curve (population, % responding) Therapeutic index (TI): TI = LD50/ED50 (or TD50/ED50) High TI = safer (wide margin); Low TI = narrow margin, needs monitoring (e.g. warfarin, digoxin, lithium) Tolerance & dependence: Tolerance – diminished response over time, needing higher doses Physical dependence – withdrawal symptoms on stopping Psychological dependence – craving/compulsive use Mechanisms: receptor downregulation, desensitization, metabolic tolerance 3. ANTIMICROBIAL PHARMACOLOGY Classification by mechanism: Cell wall synthesis inhibitors – β-lactams (penicillins, cephalosporins, carbapenems), vancomycin Protein synthesis inhibitors – aminoglycosides & tetracyclines (30S); macrolides, clindamycin, chloramphenicol, linezolid (50S) DNA synthesis inhibitors – fluoroquinolones (gyrase/topoisomerase), metronidazole, rifampin (RNA polymerase) Antimetabolites – sulfonamides + trimethoprim (folate synthesis) Antivirals – nucleoside analogs (acyclovir), neuraminidase inhibitors (oseltamivir), protease/integrase inhibitors Hallmark adverse effects: β-lactams – hypersensitivity reactions Aminoglycosides – nephrotoxicity, ototoxicity Vancomycin – nephrotoxicity, "red man syndrome" Fluoroquinolones – tendon rupture, QT prolongation Tetracyclines – photosensitivity, teeth discoloration (avoid in pregnancy/children) Macrolides – GI upset, QT prolongation Chloramphenicol – aplastic anemia, gray baby syndrome Metronidazole – disulfiram-like reaction with alcohol Resistance mechanisms: Enzymatic inactivation (e.g. β-lactamases) Altered target site (e.g. PBP mutation) ↓ permeability / efflux pumps Bypass/alternative metabolic pathways Rational combination therapy (why combine antibiotics): Broaden empiric coverage before culture results back (e.g. meningitis: ceftriaxone + vancomycin ± ampicillin) Achieve synergy against tough organisms (e.g. beta-lactam + aminoglycoside for endocarditis) Prevent resistance emergence (classic: TB → rifampin + isoniazid + pyrazinamide + ethambutol) Treat polymicrobial infections where one agent won't cover all organisms Antimicrobial stewardship: Right drug, right dose, right duration; de-escalate once cultures/sensitivities available Avoid unnecessary broad-spectrum use to limit resistance pressure Patient education on adherence (completing full