# Pharmacokinetics, Pharmacodynamics & Autonomic Nervous System Drugs

> Core principles of pharmacokinetics (ADME, bioavailability, volume of distribution, clearance, half-life, steady state), pharmacodynamics (dose-response, antagonism, therapeutic index), and autonomic nervous system pharmacology.

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- **Level:** basic
- **Languages:** en → en
- **Total Cards:** 32

## Flashcards (32 Cards)

| # | Front (Term / Prompt) | Back (Definition / Answer) | Example | Multiple-Choice Options |
| :--- | :--- | :--- | :--- | :--- |
| 1 | How do Succinylcholine and Rocuronium differ in their mechanisms of neuromuscular junction blockade? | Succinylcholine is a DEPOLARIZING neuromuscular blocker: acts as a nicotinic ACh receptor agonist causing persistent motor end-plate depolarization, transient fasciculations, and flaccid paralysis (Phase I block, which is potentiated rather than reversed by AChE inhibitors; contraindicated in burns, crush injury, or denervation due to life-threatening hyperkalemia). Rocuronium and Vecuronium are NON-DEPOLARIZING competitive nicotinic antagonists: prevent ACh binding without depolarizing the motor end-plate and are reversed by neostigmine (with glycopyrrolate) or sugammadex. |  |  |
| 2 | What are the formulas for calculating a drug's Loading Dose and Maintenance Dose? | Loading Dose = (Target Css * Vd) / Bioavailability (F). Maintenance Dose = (Target Css,avg * CL * Dosing Interval) / Bioavailability (F). Loading dose depends primarily on Vd to rapidly achieve target plasma concentration, whereas maintenance dose depends on systemic clearance (CL) to replace drug eliminated during each dosing interval (and must be reduced in renal or hepatic insufficiency). |  |  |
| 3 | How do Epinephrine and Norepinephrine differ in their affinities for alpha and beta adrenergic receptors, and what are their primary clinical indications? | Epinephrine activates Alpha-1, Alpha-2, Beta-1, and Beta-2 receptors (low doses favor beta-2 vasodilation and bronchodilation; high doses favor alpha-1 vasoconstriction); it is the first-line drug of choice for anaphylaxis (given IM into the anterolateral thigh) and cardiac arrest (given IV/IO). Norepinephrine potently activates Alpha-1, Alpha-2, and Beta-1 receptors with minimal Beta-2 activity, increasing systemic vascular resistance and mean arterial pressure (often with baroreceptor reflex vagal slowing that offsets direct beta-1 chronotropy); it is the first-line vasopressor for septic shock. |  |  |
| 4 | What are the clinical manifestations of anticholinergic (antimuscarinic) toxicity, and what mnemonic describes them? | Mnemonic: 'Blind as a bat' (mydriasis, cycloplegia); 'Mad as a hatter' (central antimuscarinic delirium, agitation, hallucinations); 'Red as a beet' (cutaneous flushing); 'Hot as a hare' (anhidrotic hyperthermia); 'Dry as a bone' (xerostomia, dry skin, urinary retention, decreased bowel sounds); 'Fast as a fiddle' (sinus tachycardia). For confirmed isolated antimuscarinic delirium, the specific antidote is Physostigmine (a tertiary amine AChE inhibitor that crosses the BBB), which is contraindicated if tricyclic antidepressant (TCA) co-ingestion or QRS prolongation is present. |  |  |
| 5 | What defines bioavailability (F), and what is the mathematical formula for calculating it from oral versus intravenous administration? | Bioavailability F is the fraction of a dose reaching systemic circulation unchanged: F = (AUC_oral / Dose_oral) / (AUC_IV / Dose_IV). IV administration has F = 1. To report a percentage, multiply F by 100; use the fraction, not the percentage, in loading- and maintenance-dose formulas. |  |  |
| 6 | What is the formula for the Therapeutic Index (TI), and what is the clinical distinction between narrow and wide TI drugs? | In clinical studies, TI = TD50 / ED50 (Median Toxic Dose / Median Effective Dose); in preclinical animal studies, TI = LD50 / ED50. A narrow TI (e.g., warfarin, digoxin, lithium, theophylline, aminoglycosides) indicates a small margin between effective and toxic concentrations, requiring therapeutic drug monitoring (TDM). A wide TI (e.g., penicillin in non-allergic patients) indicates a broad safety margin. |  |  |
| 7 | What clinical constellation of symptoms characterizes acute Organophosphate poisoning (cholinergic toxidrome)? | Irreversible inhibition of AChE leads to massive acetylcholine accumulation. Muscarinic symptoms (SLUDGEM / DUMBBELLS): Salivation, Lacrimation, Urination, Defecation, GI cramping, Emesis, Miosis, Bradycardia, Bronchospasm, and Bronchorrhea ('killer Bs'). Nicotinic symptoms: muscle fasciculations, weakness, diaphragmatic paralysis, and respiratory arrest. |  |  |
| 8 | How do competitive and noncompetitive antagonists alter the agonist dose-response curve in terms of potency (EC50) and efficacy (Emax)? | Reversible competitive antagonist: binds orthosterically and surmountably; produces a parallel RIGHTWARD shift of the log agonist concentration-effect curve (increases apparent EC50, reducing apparent potency) with NO change in maximal efficacy (Emax). Noncompetitive (allosteric) or irreversible orthosteric antagonist: prevents receptor activation insurmountably once receptor reserve (spare receptors) is depleted, DECREASING maximal efficacy (Emax) without shifting EC50 (though if spare receptors are present, low antagonist concentrations may initially shift the curve right before depressing Emax). |  |  |
| 9 | What are the clinical indications and mechanisms of the direct muscarinic agonists Bethanechol and Pilocarpine? | Bethanechol: activates M3 receptors on the detrusor muscle of the urinary bladder and GI smooth muscle, promoting bladder contraction and bowel motility; used for non-obstructive urinary retention (postoperative/neurogenic ileus). Pilocarpine: activates M3 receptors on the pupillary sphincter muscle (causing miosis) and ciliary muscle (opening trabecular meshwork to drain aqueous humor); used for open-angle and angle-closure glaucoma and Sjögren xerostomia. |  |  |
| 10 | What is the mechanism of action of Albuterol, and what are its common adrenergic adverse effects? | Selective short-acting Beta-2 adrenergic agonist (SABA). Activates the Gs-cAMP-PKA pathway in bronchial smooth muscle, reducing intracellular Ca2+ and myosin light-chain kinase (MLCK) activity and opening large-conductance Ca2+-activated K+ channels to produce rapid bronchodilation. Adverse effects: skeletal muscle tremor (beta-2), reflex and direct beta-1 tachycardia/palpitations, and transient hypokalemia (Na+/K+-ATPase activation shifting K+ into cells). In chronic asthma, SABA monotherapy without an inhaled corticosteroid is avoided due to beta-2 downregulation and exacerbation risk. |  |  |
| 11 | What are the primary G-protein couplings for the adrenergic and muscarinic receptors (QISS and QIQ mnemonics)? | Adrenergic receptors: Alpha-1 -> Gq; Alpha-2 -> Gi; Beta-1 -> Gs; Beta-2 -> Gs; Beta-3 -> Gs (mnemonic: 'QISS'). Muscarinic receptors: M1 -> Gq; M2 -> Gi; M3 -> Gq (mnemonic: 'QIQ'; additionally, M4 couples to Gi and M5 couples to Gq, so odd-numbered muscarinic subtypes couple to Gq and even-numbered subtypes couple to Gi). |  |  |
| 12 | How do first-order elimination kinetics and zero-order elimination kinetics differ regarding rate of elimination and half-life? | First-order kinetics: a constant FRACTION of drug is eliminated per unit time, the elimination rate is directly proportional to plasma concentration, and elimination half-life (t1/2) is constant across therapeutic doses (most drugs). Zero-order (capacity-limited / Michaelis-Menten saturation) kinetics: a constant AMOUNT of drug is eliminated per unit time because metabolic enzymes are saturated; plasma concentration decays linearly and the time required to eliminate 50% of present drug increases with concentration (e.g., ethanol, high-dose salicylates, and phenytoin at high therapeutic levels). |  |  |
| 13 | What are the major contraindications and physiological risks of non-selective beta-blocker therapy? | Severe sinus bradycardia, high-grade (second- or third-degree) AV block without a pacemaker, cardiogenic shock, and acute decompensated heart failure with hypoperfusion. Non-selective beta-2 blockade can precipitate life-threatening bronchospasm in asthma. In patients on insulin or sulfonylureas, beta-blockade blunts sympathetic warning signs of hypoglycemia (tremor, palpitations, tachycardia) and impairs hepatic glycogenolysis, while sparing cholinergic muscarinic (M3)-mediated diaphoresis. |  |  |
| 14 | What are the dose-dependent receptor affinities and cardiovascular effects of intravenous Dopamine infusions? | In the classical dose-dependent receptor model: • Low infusion rates (~1–3 mcg/kg/min): predominantly stimulate D1 dopaminergic receptors in renal, mesenteric, and coronary beds, promoting local vasodilation and natriuresis. • Intermediate rates (~3–10 mcg/kg/min): stimulate cardiac Beta-1 adrenergic receptors, increasing contractility (inotropy) and heart rate. • High rates (>10 mcg/kg/min): predominantly stimulate vascular Alpha-1 adrenergic receptors, producing systemic vasoconstriction and increased SVR. Clinical caveat: randomized trials show low-dose ('renal-dose') dopamine does not prevent acute kidney injury or improve survival, and norepinephrine is preferred over dopamine in septic and cardiogenic shock due to lower arrhythmia risk. |  |  |
| 15 | What two pharmacologic antidotes are administered for acute organophosphate poisoning, and what does each target? | 1. Atropine: competitive muscarinic receptor antagonist; immediately reverses life-threatening muscarinic symptoms (bronchorrhea, bronchospasm, severe bradycardia). Titrated until pulmonary secretions dry. 2. Pralidoxime (2-PAM): nucleophilic oxime that regenerates active acetylcholinesterase by cleaving the organophosphate-enzyme bond at the esteric site; must be given EARLY before irreversible covalent bond conformational change ('aging') occurs. |  |  |
| 16 | What genetic mutation predisposes patients to Malignant Hyperthermia during general anesthesia, what triggers it, and what is the specific antidote? | Autosomal dominant pharmacogenetic disorder most commonly caused by mutations in the skeletal muscle ryanodine receptor gene (RYR1, or less commonly CACNA1S). Triggered by volatile halogenated inhalational anesthetics (sevoflurane, isoflurane, desflurane, halothane) or succinylcholine. Uncontrolled sarcoplasmic reticulum Ca2+ release causes an early rapid rise in end-tidal CO2 (hypercapnia), generalized muscle rigidity/masseter spasm, tachycardia, hyperthermia, rhabdomyolysis, and metabolic acidosis. Specific antidote: IV Dantrolene (blocks RYR1 Ca2+ release) plus immediate discontinuation of triggering agents and active cooling. |  |  |
| 17 | What biochemical reactions characterize Phase I versus Phase II hepatic drug metabolism? | Phase I: functionalization reactions (oxidation, reduction, hydrolysis), frequently catalyzed by hepatic cytochrome P450 (CYP) monooxygenases, that introduce or unmask polar functional groups (-OH, -NH2, -SH, -COOH) to yield active, toxic, or inactive metabolites. Phase II: conjugation reactions (glucuronidation, sulfation, acetylation, methylation, glutathione or glycine conjugation) that attach hydrophilic endogenous groups to form water-soluble conjugates for renal or biliary excretion. Phase II can precede Phase I if a polar group is already present, and while most conjugates are inactive, exceptions exist (e.g., morphine-6-glucuronide is pharmacologically active). |  |  |
| 18 | What is the mechanism of action, hemodynamic effect, and clinical utility of Phenylephrine? | Pure selective Alpha-1 adrenergic agonist (Gq-coupled). Promotes vascular smooth muscle contraction, dramatically increasing Systemic Vascular Resistance (SVR) and arterial blood pressure. The acute rise in blood pressure triggers a vagally mediated baroreceptor Reflex Bradycardia. Used as a vasopressor in distributive shock and as a topical nasal decongestant. |  |  |
| 19 | How do Phenoxybenzamine and Phentolamine differ in their molecular inhibition of alpha-adrenergic receptors, and what is their clinical use? | Phenoxybenzamine is an IRREVERSIBLE, noncompetitive, long-acting non-selective alpha-1 and alpha-2 antagonist used preoperatively to control catecholamine-induced hypertension in pheochromocytoma. Phentolamine is a REVERSIBLE, competitive, short-acting non-selective alpha-1 and alpha-2 antagonist used for acute catecholamine hypertensive crises (e.g., intraoperative pheochromocytoma management or MAOI-tyramine reactions) and local dermal extravasation of alpha-1 vasopressors (e.g., norepinephrine). In pheochromocytoma, alpha-blockade must always be established before beta-blockade to prevent unopposed alpha-1 vasoconstriction. |  |  |
| 20 | What intracellular downstream signaling cascades are triggered by Gs, Gi, and Gq protein-coupled receptors? | Gs: activates adenylyl cyclase -> increases intracellular cAMP -> activates Protein Kinase A (PKA). Gi: inhibits adenylyl cyclase -> decreases cAMP and PKA activity (and in cardiac nodal cells, released Gβγ subunits directly open GIRK K+ channels to cause hyperpolarization). Gq: activates phospholipase C-beta (PLCβ) -> cleaves membrane PIP2 into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) -> IP3 triggers Ca2+ release from the endoplasmic/sarcoplasmic reticulum, while DAG and Ca2+ activate Protein Kinase C (PKC). |  |  |
| 21 | How is apparent volume of distribution (Vd) calculated, and what does a large value imply? | Vd = amount of drug in the body / plasma drug concentration. A large apparent Vd means relatively little drug remains in plasma compared with the amount in the body, often because of tissue binding or partitioning. It is a proportionality constant, not a measured anatomical volume, and does not by itself prove lipophilicity. |  |  |
| 22 | How are beta-blockers classified into cardioselective, non-selective, and combined alpha/beta antagonists, with clinical examples? | Cardioselective Beta-1 antagonists: Metoprolol, Atenolol, Bisoprolol, Esmolol, Nebivolol (nebivolol also promotes endothelial nitric oxide-mediated vasodilation; beta-1 selectivity is relative and diminishes at higher doses). Non-selective Beta-1/Beta-2 antagonists: Propranolol, Timolol, Nadolol. Combined Alpha-1 and non-selective Beta antagonists: Carvedilol and Labetalol (cause peripheral alpha-1 vasodilation without reflex tachycardia). Specifically, carvedilol, metoprolol succinate, and bisoprolol are proven to reduce mortality in chronic HFrEF, whereas labetalol and esmolol are used in acute hypertensive emergencies and aortic dissection. |  |  |
| 23 | What is the pharmacological mechanism by which Atropine treats symptomatic sinus bradycardia and atrioventricular (AV) nodal block? | Atropine is a competitive reversible antagonist at cardiac M2 muscarinic receptors. By blocking parasympathetic vagal tone at the sinoatrial (SA) and atrioventricular (AV) nodes, it increases SA nodal firing rate and speeds AV nodal conduction. Clinically, atropine is first-line for symptomatic sinus bradycardia and AV nodal block (first-degree or Mobitz Type I Wenckebach), but is generally ineffective in infranodal (His-Purkinje) blocks—such as Mobitz Type II second-degree or third-degree AV block with wide-QRS escape—and in denervated transplanted hearts. |  |  |
| 24 | What is the pharmacological selectivity of Tamsulosin compared to Doxazosin/Prazosin, and why does it have fewer cardiovascular side effects? | Tamsulosin (and silodosin) selectively antagonizes Alpha-1A (and Alpha-1D) adrenoceptors concentrated in prostatic stromal and bladder-neck smooth muscle. Unlike non-subtype-selective alpha-1 antagonists (prazosin, terazosin, doxazosin) that also block vascular Alpha-1B receptors causing systemic vasodilation and first-dose orthostatic hypotension, tamsulosin relieves BPH urinary outflow obstruction with minimal blood pressure reduction (though it can cause abnormal/retrograde ejaculation and intraoperative floppy iris syndrome). |  |  |
| 25 | What mathematical relationship links elimination half-life (t1/2), Volume of Distribution (Vd), and systemic Clearance (CL)? | In a one-compartment first-order elimination model, t1/2 = (ln 2 * Vd) / CL ≈ (0.693 * Vd) / CL, where Vd and CL are independent primary pharmacokinetic parameters. Half-life increases directly with apparent volume of distribution and inversely with systemic clearance (for example, in renal or hepatic impairment). |  |  |
| 26 | How do drug potency and efficacy differ conceptually, and which parameter is more clinically important for therapeutic success? | Potency is the concentration or dose required to produce 50% of the drug's maximal effect (measured by EC50 or ED50; lower EC50 = higher potency). Efficacy is the maximal therapeutic response an agonist can produce (Emax). Efficacy is clinically much more important than potency because a more potent drug simply requires a smaller milligram dose, whereas an efficacious drug achieves a greater clinical response. |  |  |
| 27 | What is steady-state plasma concentration (Css), and how many elimination half-lives are required to reach >= 95% steady-state? | With constant input and first-order elimination, the fraction of steady state reached after n half-lives is 1 - 2^(-n). Reaching 95% takes log2(20), about 4.32 half-lives; five complete half-lives reach 96.875%. Four reach only 93.75%. For a constant IV infusion, Css = infusion rate / clearance. |  |  |
| 28 | What is the mechanism of action of Sugammadex, and which neuromuscular blockers does it reverse? | Sugammadex is a modified gamma-cyclodextrin that encapsulates rocuronium and vecuronium, reducing the free drug available at the neuromuscular junction. Its labeled reversal indication is for blockade caused by those two drugs, not every neuromuscular blocker. Dose, reversal time, and monitoring depend on blockade depth and the clinical setting. |  |  |
| 29 | What are the mechanisms and clinical indications of the reversible acetylcholinesterase inhibitors Neostigmine, Pyridostigmine, and Donepezil? | They reversibly inhibit acetylcholinesterase (AChE), slowing acetylcholine hydrolysis and enhancing cholinergic neurotransmission at muscarinic and nicotinic synapses. Neostigmine: polar quaternary ammonium carbamate (does not cross the blood-brain barrier); used for postoperative/neurogenic ileus and reversal of non-depolarizing neuromuscular blockade. Pyridostigmine: quaternary ammonium carbamate (poor BBB penetration, longer duration); first-line symptomatic therapy for Myasthenia Gravis. Donepezil, Rivastigmine, Galantamine: lipid-soluble CNS-penetrant AChE inhibitors used for symptomatic treatment of Alzheimer's disease. |  |  |
| 30 | Why must Neostigmine always be co-administered with Glycopyrrolate or Atropine when reversing neuromuscular blockade? | Neostigmine inhibits acetylcholinesterase throughout the entire body, increasing ACh at both nicotinic receptors (the desired therapeutic target to overcome rocuronium at the neuromuscular junction) AND muscarinic receptors. Co-administering a muscarinic antagonist (Glycopyrrolate or Atropine) prevents severe muscarinic adverse effects, particularly profound bradycardia, bronchospasm, and copious airway secretions. |  |  |
| 31 | What is the receptor target, intracellular mediator, and primary cardiac effect of Dobutamine? | Predominant Beta-1 adrenergic agonist (with mild beta-2 and alpha-1 activity). Stimulates Gs protein -> increases intracellular cAMP and PKA in cardiomyocytes -> increases intracellular calcium influx during systole. Produces potent positive INOTROPY (contractility) with modest positive chronotropy and mild vasodilation, making it ideal for cardiogenic shock and severe acute decompensated heart failure. |  |  |
| 32 | How do clonidine and methyldopa lower blood pressure, and how is methyldopa used in pregnancy? | They reduce central sympathetic outflow through alpha-2 adrenergic signaling; methyldopa acts through its active metabolite alpha-methylnorepinephrine. Methyldopa has longstanding pregnancy experience but is not universally preferred. NICE recommends considering labetalol for gestational hypertension, nifedipine if unsuitable, and methyldopa if both are unsuitable. |  |  |

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