USMLE (Fach) / Pharmacology (Lektion)
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- Michaelis-Menten kinetics Km is inversely related to the affinity of the enzyme for its substrate. Vmax is directly proportional to the enzyme concentration. Most enzymatic reactions follow a hyperbolic curve (ie, Michaelis-Menten ...
- Lineweaver-Burk plot ↑ y-intercept, ↓ Vmax. The further to the right the x-intercept (ie, closer to zero), the greater the Km and the lower the affinity. Competitive inhibitors cross each other on the y-axis (same Vmax), ...
- Enzyme inhibitors Competitive inhibitors, reversible:- Resemble substrate: Yes- Overcome by ↑ [S]: Yes- Bind active site: Yes- Effect on Vmax: Unchanged- Effect on Km: ↑- Pharmacodynamics: ↓ potency Competitive ...
- Bioavailability (F) Part of the pharmacokinetics. Fraction of administered drug reaching systemic circulation unchanged. For IV dose, F = 100%.Orally: F typically <100% due to incomplete absorption and first-pass metabolism. ...
- Volume of distribution (Vd) Part of the pharmacokinetics. Theoretical volume occupied by the total amount of drug in the body relative to its plasma concentration. Apparent Vd of plasma protein-bound drugs can be altered by liver ...
- Clearance (CL) Part of the pharmacokinetics. The volume of plasma cleared of drug per unit time. Clearance may be impaired with defects in cardiac, hepatic, or renal function. CL = rate of elimination of drug/plasma ...
- Half-life (t1/2) Part of the pharmacokinetics. The time required to change the amount of drug in the body by 1/2 during elimination. In first-order kinetics, a drug infused at a constant rate takes 4-5 half-lives to ...
- Dosage calculations Loading dose = (Cp x Vd)/F Maintenance dose = (Cp x CL x τ)/F Cp = target plasma concentration at steady stateτ = dosage interval (time between doses), if not administered continuously In renal or ...
- Types of drug interactions Additive: Effect of substance A and B together is equal to the sum of their individual effects- Example: Aspirin and acetaminophen Permissive: Presence of substance A is required for the full effects ...
- Receptor binding Competitive antagonist: Shifts curve right (↓ potency), no change in efficacy. Can be overcome by ↑ the concentration of agonist substrate.- Example: Diazepam (agonist) + flumazenil (competitive antagonist) ...
- Zero-order elimination Capacity-limited elimination. Rate of elimination is constant regardless of Cp (ie, constant amount of drug eliminated per unit time). Cp ↓ linearly with time. Examples of drugs – phenytoin, ethanol, ...
- First-order elimination Flow-dependent elimination. Rate of first-order elimination is directly proportional to the drug concentration (ie, constant fraction of drug eliminated per unit time). Cp ↓ exponentially with time. ...
- Urine pH and drug elimination Ionized species are trapped in urine and cleared quickly. Weak acids: Phenobarbital, methotrexate, aspirin. Trapped in basic environments. - Treat overdose with sodium bicarbonate to alkalinize urine. ...
- Drug metabolism Phase I: Reduction, oxidation, hydrolysis with cytochrome P-450 usually yield slightly polar, water-soluble metabolites (often still active).- Geriatric patients lose phase I first. Phase II: Conjugation ...
- Efficacy vs potency Efficacy: Maximal effect a drug can produce. ↑ Vmax = ↑ efficacy. Unrelated to potency (ie, efficacious drugs can have high or low potency). Partial agonists have less efficacy than full agonists. ...
- Therapeutic index Measurement of drug safety. Therapeutic index (TI) = TD50/ED50 = median toxic dose/median effective dose Therapeutic window – dosage range than can safely and effectively treat disease. Safer drugs ...
- Acethylcholine receptors Nicotinic ACh receptors are ligand-gated Na+/K+ channels. - NN (found in autonomic ganglia, adrenal medulla) - NM (found in neuromuscular junction of skeletal muscle) Muscarinic ACh receptors are G-protein-coupled ...
- α1 Gq ↑ vascular smooth muscle contraction↑ pupillary dilator muscle contraction (mydriasis)↑ intestinal and bladder sphincter muscle contraction
- α2 Gi ↓ sympathetic (adrenergic) outflow↓ insulin release↓ lipolysis↑ platelet aggregation↓ aqueous humor production
- β1 Gs ↑ heart rate↑ contractility↑ renin release↑ lipolysis
- β2 G2 Vasodilation, bronchodilation↑ lipolysis↑ insulin release↑ glycogenolysis↓ uterine tone (tocolysis)↑ aqueous humor production↑ cellular K+ uptake
- β3 Gs ↑ lipolysis↑ thermogenesis in skeletal muscle↑ bladder relaxation
- M1 Gq - Mediates higher cognitive functions- Stimulates enteric nervous system
- M2 Gi ↓ heart rate and contractility of atria
- M3 Gq ↑ exocrine gland secretions (eg, lacrimal, sweat, salivary, gastric acid)↑ gut peristalsis↑ bladder contractionBronchoconstriction↑ pupillary sphincter muscle contration (miosis)Ciliary muscle ...
- D1 Gs Relaxes renal vascular smooth muscleActivates direct pathway of striatum
- D2 Gi Modulates transmitter release, especially in brainInhibits indirect pathway of striatum
- H1 Gq ↑ nasal and bronchial mucus production↑ vascular permeabilityBronchoconstrictionPruritusPain
- H2 Gs ↑ gastric acid secretion
- V1 Gq ↑ vascular smooth muscle contraction
- V2 Gs ↑ H2O permeability and reabsorption via upregulating aquaporin-2 in collecting tubules of kidney
- G-protein-linked second messengers H1, α1, V1, M1, M3 receptor → Gq → Phospholipase C → DAG → Protein kinase C→ IP3 → ↑ [Ca2+]i → Smooth muscle contraction β1, β2, β3, D1, H2, V2 receptor → Gs → cAMP → ...
- Autonomic drugs Release of NE from a sympathetic nerve ended is modulated by NE itself, acting on presynaptic α2-autoreceptors → negative feedback. Amphetamines use the NE transporter (NET) to enter the presynaptic ...
- Bethanechol Direct cholinomimetic agonist - Activates bowel and bladder smooth muscle- Resistant to AChE- No nicotinic activity Applications:- Postoperative ileus- Neurogenic ileus- Urinary retention
- Carbachol Direct cholinomimetic agonist - Carbon copy of acetylcholine (but resistant to AChE) Application:- Constricts pupil and relieves intraocular pressure in open-angle glaucoma
- Methacholine Direct cholinomimetic agonist - Stimulates muscarinic receptors in airway when inhaled Application:- Challenge test for diagnosis of asthma
- Pilocarpine Direct cholinomimetic agonist - Contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma)- Resistant to AChE- Can cross blood-brain barrier (tertiary amine) Application:- ...
- Donepezil, rivastigmine, galantamine Indirect cholinomimetic agonist (anticholinesterases) ↑ ACh Application:- Alzheimer disease
- Edrophonium Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh Application:- Historically used to diagnose myasthenia gravis; replaced by anti-AChR Ab (anti-acetylcholine receptor antibody) test.
- Neostigmine Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh- No CNS penetration (quaternary amine) Application:- Postoperative and neurogenic ileus- Urinary retention- Myasthenia gravis- Reversal of ...
- Physostigmine Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh- Freely crosses blood-brain barrier → CNS (tertiary amine) Application:- Antidote for anticholinergic toxicity- physostigmine "phyxes" atropin ...
- Pyridostigmine Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh↑ muscle strength Application:- Myasthenia gravis (long acting)- Does not penetrate CNS (quaternary amine)
- Cholinesterase inhibitor poisoning Often due to organophosphages, such as parathion, that irreversible inhibit AChE. - Diarrhea- Urination- Miosis- Bradycardia- Emesis- Lacrimation, salivation- Sweating- BronchospasmMay lead to respiratory ...
- Atopine Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications. Eye: ↑ pupil dilation, cycloplegiaAirway: Bronchodilation, ↓ secretionsStomach: ↓ acid secretionGut: ↓ motilityBladder: ↓ ...
- Benztropine, trihexyphenidyl Muscarinic antagonist CNS Application:- Parkinson disease- Acute dystonia
- Glycopyrrolate Muscarinic antagonist GI, respiratory Application:- Parenteral: preoperative use to reduce airway secretions- Oral: drooling, peptic ulcer
- Hyoscyamine, dicyclomine Muscarinic antagonist GI Application: Antispasmodics for irritable bowel syndrome
- Ipratropium, tiotropium Muscarinic antagonist Respiratory Appliation: COPD, asthma
- Oxybutynin, solifenacin, tolterodine Muscarinic antagonist Genitourinary Application: Reduce bladder spasms and urge urinary incontinence (overactive bladder)
- Scopolamine Muscarinic antagonist CNS Application: Motion sickness