What are the clinical manifestations of anticholinergic (antimuscarinic) toxicity, and what mnemonic describes them?

Mnemonic: 'Blind as a bat' (mydriasis, cycloplegia, loss of accommodation); 'Mad as a hatter' (delirium, agitation, hallucinations); 'Red as a beet' (cutaneous vasodilation, flushing); 'Hot as a hare' (hyperthermia due to anhidrosis / inability to sweat); 'Dry as a bone' (dry mouth, dry skin, urinary retention, absent bowel sounds); 'Fast as a fiddle' (tachycardia). Antidote is Physostigmine (crosses BBB).

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 potent Beta-2 receptors (at low doses beta-2 vasodilation/bronchodilation predominates; at high doses alpha-1 vasoconstriction predominates); drug of choice for Anaphylaxis and cardiac arrest. Norepinephrine activates Alpha-1, Alpha-2, and Beta-1, with negligible Beta-2 activity; produces profound vasoconstriction and moderate inotropy; first-line vasopressor for Septic Shock.

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.

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 (percentage) of drug is eliminated per unit time; the rate of elimination is proportional to plasma concentration; half-life (t1/2) is CONSTANT regardless of dose (most drugs). Zero-order kinetics: a constant AMOUNT of drug is eliminated per unit time because metabolic enzymes/transporters are saturated; half-life INCREASES with dose (e.g., Phenytoin, Ethanol, high-dose Aspirin).

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.

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 Gs-cAMP in bronchial smooth muscle, activating PKA, inactivating myosin light-chain kinase (MLCK), and opening K+ channels, causing rapid bronchodilation. Adverse effects: skeletal muscle tremor (beta-2 in skeletal muscle), tachycardia/palpitations (peripheral vasodilation + mild beta-1 stimulation), and transient hypokalemia (stimulates Na+/K+-ATPase shifting potassium into cells).

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.

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.

What genetic mutation predisposes patients to Malignant Hyperthermia during general anesthesia, what triggers it, and what is the specific antidote?

Autosomal dominant mutation in the Ryanodine Receptor (RYR1) gene (or CACNA1S) in skeletal muscle. Triggered by Succinylcholine or volatile halogenated inhalation anesthetics (Halothane, Isoflurane, Sevoflurane). Leads to uncontrolled massive release of sarcoplasmic calcium, hypermetabolism, sustained muscle rigidity, extreme hyperthermia, rhabdomyolysis, and acidosis. Antidote: Dantrolene (blocks RYR1 channels).

What is the mechanism of action of Sugammadex, and which neuromuscular blockers does it reverse?

Sugammadex is a modified gamma-cyclodextrin with a hydrophobic cavity that selectively chelates, encapsulates, and inactivates aminosteroid non-depolarizing neuromuscular blocking agents in plasma in a 1:1 ratio (affinity: Rocuronium >> Vecuronium > Pancuronium). It terminates neuromuscular blockade within 2-3 minutes independent of AChE inhibition.

What is the formula for Volume of Distribution (Vd), and what does a very high Vd (>40 L in a 70 kg human) indicate?

Vd = Amount of drug in the body / Plasma drug concentration (C0). A high Vd (>40 L, exceeding total body water) indicates extensive lipophilicity and extensive distribution into peripheral tissues, intracellular compartments, or adipose tissue, leaving very low concentrations in plasma (e.g., chloroquine, amiodarone, digoxin).

What is the formula for the Therapeutic Index (TI), and what is the clinical distinction between narrow and wide TI drugs?

TI = TD50 / ED50 (Median Toxic Dose / Median Effective Dose) or LD50 / ED50. A narrow TI (e.g., Warfarin, Digoxin, Lithium, Theophylline, Gentamicin) means the therapeutic and toxic blood levels are very close, requiring routine therapeutic drug monitoring (TDM). A wide TI (e.g., Penicillin) means large differences exist between therapeutic and lethal doses, providing high safety margins.

What is steady-state plasma concentration (Css), and how many elimination half-lives are required to reach >= 95% steady-state?

Css is the equilibrium state where the rate of drug administration equals the rate of drug elimination (Css = Infusion rate / CL). It takes approximately 4 to 5 half-lives to reach ~95% of steady-state (1 half-life = 50%, 2 = 75%, 3 = 87.5%, 4 = 93.75%, 5 = 96.88%).

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.

What are the major contraindications and physiological risks of non-selective beta-blocker therapy?

Severe bradycardia, second- or third-degree heart block, cardiogenic shock, and severe decompensated acute heart failure. Beta-2 blockade can trigger life-threatening bronchospasm in patients with asthma. In insulin-dependent diabetics, beta-blockers mask early sympathetic warning signs of hypoglycemia (tremor, palpitations, tachycardia) except diaphoresis, and inhibit glycogenolysis.

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 * CL * Dosing Interval) / Bioavailability (F). (Loading dose depends on Vd to fill the volume; maintenance dose depends on CL to replace drug eliminated over time).

How do Succinylcholine and Rocuronium differ in their mechanisms of neuromuscular junction blockade?

Succinylcholine is a DEPOLARIZING neuromuscular blocker: acts as an acetylcholine analog that binds nicotinic receptors, causing persistent channel opening, continuous depolarization, transient muscle fasciculations, and flaccid paralysis (Phase I block; unreversed by AChE inhibitors). Rocuronium / Vecuronium are NON-DEPOLARIZING competitive antagonists: competitively block nicotinic ACh receptors without depolarizing the motor end-plate (reversed by neostigmine or sugammadex).

What are the primary G-protein couplings for the adrenergic and muscarinic receptors (QISS and QIQ mnemonics)?

Alpha-1: Gq Alpha-2: Gi Beta-1: Gs Beta-2: Gs Beta-3: Gs (Mnemonic: 'QISS') M1: Gq M2: Gi M3: Gq (Mnemonic: 'QIQ').

How do competitive and noncompetitive antagonists alter the agonist dose-response curve in terms of potency (EC50) and efficacy (Emax)?

Competitive antagonist: binds reversibly to the active site; shifts the agonist log concentration-effect curve to the RIGHT (increases EC50, decreases potency) with NO change in maximal efficacy (Emax can still be reached with higher agonist concentrations). Noncompetitive (allosteric or irreversible) antagonist: reduces maximal efficacy (DECREASES Emax) with NO shift in EC50.

What mathematical relationship links elimination half-life (t1/2), Volume of Distribution (Vd), and systemic Clearance (CL)?

t1/2 = (0.693 * Vd) / CL. Half-life is directly proportional to volume of distribution and inversely proportional to clearance. If clearance decreases (e.g., renal or hepatic failure), half-life increases.

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 (safer in patients with mild-to-moderate reactive airway disease). Non-selective Beta-1/Beta-2 antagonists: Propranolol, Timolol, Nadolol. Combined Alpha-1 and non-selective Beta antagonists: Carvedilol, Labetalol (produce peripheral vasodilation without reflex tachycardia; used in HFrEF, aortic dissection, hypertensive emergencies).

What is the mechanism of action of Clonidine and Methyldopa, and why is Methyldopa preferred in gestational hypertension?

Centrally acting selective Alpha-2 adrenergic agonists (Gi-coupled in medulla/nucleus tractus solitarii). Stimulation of presynaptic alpha-2 autoreceptors decreases central sympathetic outflow, reducing norepinephrine release, SVR, and heart rate. Methyldopa is a first-line agent in pregnancy because of extensive long-term safety data demonstrating no teratogenicity or adverse fetal hemodynamics.

What defines bioavailability (F), and what is the mathematical formula for calculating it from oral versus intravenous administration?

Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. Formula: F = (AUC_oral / Dose_oral) / (AUC_iv / Dose_iv) * 100. For intravenous administration, F = 100% (F = 1.0) by definition because first-pass hepatic metabolism and gastrointestinal absorption barriers are bypassed.

What are the mechanisms and clinical indications of the reversible acetylcholinesterase inhibitors Neostigmine, Pyridostigmine, and Donepezil?

They inhibit acetylcholinesterase, preventing ACh degradation and prolonging cholinergic transmission at nicotinic and muscarinic synapses. Neostigmine: quaternary amine (does not cross blood-brain barrier); used to reverse non-depolarizing neuromuscular blockade. Pyridostigmine: long-acting; first-line symptomatic maintenance for Myasthenia Gravis. Donepezil / Rivastigmine: lipophilic tertiary amines crossing BBB; used for Alzheimer's disease.

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 blocker; used preoperatively to control hypertension in pheochromocytoma. Phentolamine is a REVERSIBLE, competitive, short-acting non-selective alpha blocker; used for diagnosis of pheochromocytoma, acute hypertensive crises from MAOI tyramine interactions, and local extravasation of alpha-agonists (norepinephrine).

What intracellular downstream signaling cascades are triggered by Gs, Gi, and Gq protein-coupled receptors?

Gs: activates Adenylyl Cyclase -> increases cAMP -> activates Protein Kinase A (PKA). Gi: inhibits Adenylyl Cyclase -> decreases cAMP -> decreases PKA activity. Gq: activates Phospholipase C (PLC) -> cleaves PIP2 into Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG) -> IP3 mobilizes intracellular Ca2+ from sarcoplasmic reticulum; DAG activates Protein Kinase C (PKC).

What is the pharmacological selectivity of Tamsulosin compared to Doxazosin/Prazosin, and why does it have fewer cardiovascular side effects?

Tamsulosin is a subtype-selective Alpha-1A antagonist primarily found on smooth muscle of the prostate stroma and bladder neck. In contrast to non-subtype selective alpha-1 blockers (Doxazosin, Terazosin, Prazosin) which block vascular alpha-1B receptors causing systemic vasodilation and orthostatic hypotension, Tamsulosin relieves BPH urinary outflow obstruction with minimal effect on systemic blood pressure.

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.

What biochemical reactions characterize Phase I versus Phase II hepatic drug metabolism?

Phase I: functionalization reactions (Oxidation, Reduction, Hydrolysis) primarily catalyzed by Cytochrome P450 monooxygenases, introducing or unmasking polar groups (-OH, -NH2, -SH) to produce slightly polar active/inactive metabolites. Phase II: conjugation reactions (Glucuronidation, Sulfation, Acetylation, Glutathione conjugation), transferring large endogenous hydrophilic moieties to yield water-soluble inactive conjugates excreted by kidneys or bile.

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.

What are the dose-dependent receptor affinities and cardiovascular effects of intravenous Dopamine infusions?

Low dose (1-3 mcg/kg/min): D1 dopaminergic receptors in renal, mesenteric, and coronary beds -> vasodilation and increased renal blood flow. Intermediate dose (3-10 mcg/kg/min): Beta-1 adrenergic receptors -> positive inotropy and chronotropy, increasing cardiac output. High dose (>10 mcg/kg/min): Alpha-1 adrenergic receptors predominate -> widespread systemic vasoconstriction and elevated SVR.

What is the pharmacological mechanism by which Atropine treats symptomatic sinus bradycardia and atrioventricular (AV) nodal block?

Atropine is a competitive reversible antagonist of M2 muscarinic receptors on nodal tissue in the heart. By blocking parasympathetic (vagal) cholinergic tone at the sinoatrial (SA) node and AV node, it increases SA node firing rate and speeds conduction velocity through the AV node, increasing heart rate.

Farmacologia — Bàsic (A1/A2) 1: Pharmacokinetics, Pharmacodynamics & Autonomic Nervous System Drugs

[Català] Farmacologia: Core principles of ADME (absorption, distribution, metabolism, elimination), receptor kinetics, dose-response curves, and autonomic nervous system (sympathetic and parasympathetic) pharmacology.

Level: basic
Languages: ca → ca
Cards: 32
Markdown: Farmacologia — Bàsic (A1/A2) 1: Pharmacokinetics, Pharmacodynamics & Autonomic Nervous System Drugs (.md)

Flashcards (32)

#	Front (Term / Question)	Back (Definition / Answer)
1	What are the clinical manifestations of anticholinergic (antimuscarinic) toxicity, and what mnemonic describes them?	Mnemonic: 'Blind as a bat' (mydriasis, cycloplegia, loss of accommodation); 'Mad as a hatter' (delirium, agitation, hallucinations); 'Red as a beet' (cutaneous vasodilation, flushing); 'Hot as a hare' (hyperthermia due to anhidrosis / inability to sweat); 'Dry as a bone' (dry mouth, dry skin, urinary retention, absent bowel sounds); 'Fast as a fiddle' (tachycardia). Antidote is Physostigmine (crosses BBB).
2	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 potent Beta-2 receptors (at low doses beta-2 vasodilation/bronchodilation predominates; at high doses alpha-1 vasoconstriction predominates); drug of choice for Anaphylaxis and cardiac arrest. Norepinephrine activates Alpha-1, Alpha-2, and Beta-1, with negligible Beta-2 activity; produces profound vasoconstriction and moderate inotropy; first-line vasopressor for Septic Shock.
3	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.
4	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 (percentage) of drug is eliminated per unit time; the rate of elimination is proportional to plasma concentration; half-life (t1/2) is CONSTANT regardless of dose (most drugs). Zero-order kinetics: a constant AMOUNT of drug is eliminated per unit time because metabolic enzymes/transporters are saturated; half-life INCREASES with dose (e.g., Phenytoin, Ethanol, high-dose Aspirin).
5	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.
6	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 Gs-cAMP in bronchial smooth muscle, activating PKA, inactivating myosin light-chain kinase (MLCK), and opening K+ channels, causing rapid bronchodilation. Adverse effects: skeletal muscle tremor (beta-2 in skeletal muscle), tachycardia/palpitations (peripheral vasodilation + mild beta-1 stimulation), and transient hypokalemia (stimulates Na+/K+-ATPase shifting potassium into cells).
7	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.
8	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.
9	What genetic mutation predisposes patients to Malignant Hyperthermia during general anesthesia, what triggers it, and what is the specific antidote?	Autosomal dominant mutation in the Ryanodine Receptor (RYR1) gene (or CACNA1S) in skeletal muscle. Triggered by Succinylcholine or volatile halogenated inhalation anesthetics (Halothane, Isoflurane, Sevoflurane). Leads to uncontrolled massive release of sarcoplasmic calcium, hypermetabolism, sustained muscle rigidity, extreme hyperthermia, rhabdomyolysis, and acidosis. Antidote: Dantrolene (blocks RYR1 channels).
10	What is the mechanism of action of Sugammadex, and which neuromuscular blockers does it reverse?	Sugammadex is a modified gamma-cyclodextrin with a hydrophobic cavity that selectively chelates, encapsulates, and inactivates aminosteroid non-depolarizing neuromuscular blocking agents in plasma in a 1:1 ratio (affinity: Rocuronium >> Vecuronium > Pancuronium). It terminates neuromuscular blockade within 2-3 minutes independent of AChE inhibition.
11	What is the formula for Volume of Distribution (Vd), and what does a very high Vd (>40 L in a 70 kg human) indicate?	Vd = Amount of drug in the body / Plasma drug concentration (C0). A high Vd (>40 L, exceeding total body water) indicates extensive lipophilicity and extensive distribution into peripheral tissues, intracellular compartments, or adipose tissue, leaving very low concentrations in plasma (e.g., chloroquine, amiodarone, digoxin).
12	What is the formula for the Therapeutic Index (TI), and what is the clinical distinction between narrow and wide TI drugs?	TI = TD50 / ED50 (Median Toxic Dose / Median Effective Dose) or LD50 / ED50. A narrow TI (e.g., Warfarin, Digoxin, Lithium, Theophylline, Gentamicin) means the therapeutic and toxic blood levels are very close, requiring routine therapeutic drug monitoring (TDM). A wide TI (e.g., Penicillin) means large differences exist between therapeutic and lethal doses, providing high safety margins.
13	What is steady-state plasma concentration (Css), and how many elimination half-lives are required to reach >= 95% steady-state?	Css is the equilibrium state where the rate of drug administration equals the rate of drug elimination (Css = Infusion rate / CL). It takes approximately 4 to 5 half-lives to reach ~95% of steady-state (1 half-life = 50%, 2 = 75%, 3 = 87.5%, 4 = 93.75%, 5 = 96.88%).
14	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.
15	What are the major contraindications and physiological risks of non-selective beta-blocker therapy?	Severe bradycardia, second- or third-degree heart block, cardiogenic shock, and severe decompensated acute heart failure. Beta-2 blockade can trigger life-threatening bronchospasm in patients with asthma. In insulin-dependent diabetics, beta-blockers mask early sympathetic warning signs of hypoglycemia (tremor, palpitations, tachycardia) except diaphoresis, and inhibit glycogenolysis.
16	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 * CL * Dosing Interval) / Bioavailability (F). (Loading dose depends on Vd to fill the volume; maintenance dose depends on CL to replace drug eliminated over time).
17	How do Succinylcholine and Rocuronium differ in their mechanisms of neuromuscular junction blockade?	Succinylcholine is a DEPOLARIZING neuromuscular blocker: acts as an acetylcholine analog that binds nicotinic receptors, causing persistent channel opening, continuous depolarization, transient muscle fasciculations, and flaccid paralysis (Phase I block; unreversed by AChE inhibitors). Rocuronium / Vecuronium are NON-DEPOLARIZING competitive antagonists: competitively block nicotinic ACh receptors without depolarizing the motor end-plate (reversed by neostigmine or sugammadex).
18	What are the primary G-protein couplings for the adrenergic and muscarinic receptors (QISS and QIQ mnemonics)?	Alpha-1: Gq Alpha-2: Gi Beta-1: Gs Beta-2: Gs Beta-3: Gs (Mnemonic: 'QISS') M1: Gq M2: Gi M3: Gq (Mnemonic: 'QIQ').
19	How do competitive and noncompetitive antagonists alter the agonist dose-response curve in terms of potency (EC50) and efficacy (Emax)?	Competitive antagonist: binds reversibly to the active site; shifts the agonist log concentration-effect curve to the RIGHT (increases EC50, decreases potency) with NO change in maximal efficacy (Emax can still be reached with higher agonist concentrations). Noncompetitive (allosteric or irreversible) antagonist: reduces maximal efficacy (DECREASES Emax) with NO shift in EC50.
20	What mathematical relationship links elimination half-life (t1/2), Volume of Distribution (Vd), and systemic Clearance (CL)?	t1/2 = (0.693 * Vd) / CL. Half-life is directly proportional to volume of distribution and inversely proportional to clearance. If clearance decreases (e.g., renal or hepatic failure), half-life increases.
21	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 (safer in patients with mild-to-moderate reactive airway disease). Non-selective Beta-1/Beta-2 antagonists: Propranolol, Timolol, Nadolol. Combined Alpha-1 and non-selective Beta antagonists: Carvedilol, Labetalol (produce peripheral vasodilation without reflex tachycardia; used in HFrEF, aortic dissection, hypertensive emergencies).
22	What is the mechanism of action of Clonidine and Methyldopa, and why is Methyldopa preferred in gestational hypertension?	Centrally acting selective Alpha-2 adrenergic agonists (Gi-coupled in medulla/nucleus tractus solitarii). Stimulation of presynaptic alpha-2 autoreceptors decreases central sympathetic outflow, reducing norepinephrine release, SVR, and heart rate. Methyldopa is a first-line agent in pregnancy because of extensive long-term safety data demonstrating no teratogenicity or adverse fetal hemodynamics.
23	What defines bioavailability (F), and what is the mathematical formula for calculating it from oral versus intravenous administration?	Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. Formula: F = (AUC_oral / Dose_oral) / (AUC_iv / Dose_iv) * 100. For intravenous administration, F = 100% (F = 1.0) by definition because first-pass hepatic metabolism and gastrointestinal absorption barriers are bypassed.
24	What are the mechanisms and clinical indications of the reversible acetylcholinesterase inhibitors Neostigmine, Pyridostigmine, and Donepezil?	They inhibit acetylcholinesterase, preventing ACh degradation and prolonging cholinergic transmission at nicotinic and muscarinic synapses. Neostigmine: quaternary amine (does not cross blood-brain barrier); used to reverse non-depolarizing neuromuscular blockade. Pyridostigmine: long-acting; first-line symptomatic maintenance for Myasthenia Gravis. Donepezil / Rivastigmine: lipophilic tertiary amines crossing BBB; used for Alzheimer's disease.
25	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 blocker; used preoperatively to control hypertension in pheochromocytoma. Phentolamine is a REVERSIBLE, competitive, short-acting non-selective alpha blocker; used for diagnosis of pheochromocytoma, acute hypertensive crises from MAOI tyramine interactions, and local extravasation of alpha-agonists (norepinephrine).
26	What intracellular downstream signaling cascades are triggered by Gs, Gi, and Gq protein-coupled receptors?	Gs: activates Adenylyl Cyclase -> increases cAMP -> activates Protein Kinase A (PKA). Gi: inhibits Adenylyl Cyclase -> decreases cAMP -> decreases PKA activity. Gq: activates Phospholipase C (PLC) -> cleaves PIP2 into Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG) -> IP3 mobilizes intracellular Ca2+ from sarcoplasmic reticulum; DAG activates Protein Kinase C (PKC).
27	What is the pharmacological selectivity of Tamsulosin compared to Doxazosin/Prazosin, and why does it have fewer cardiovascular side effects?	Tamsulosin is a subtype-selective Alpha-1A antagonist primarily found on smooth muscle of the prostate stroma and bladder neck. In contrast to non-subtype selective alpha-1 blockers (Doxazosin, Terazosin, Prazosin) which block vascular alpha-1B receptors causing systemic vasodilation and orthostatic hypotension, Tamsulosin relieves BPH urinary outflow obstruction with minimal effect on systemic blood pressure.
28	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.
29	What biochemical reactions characterize Phase I versus Phase II hepatic drug metabolism?	Phase I: functionalization reactions (Oxidation, Reduction, Hydrolysis) primarily catalyzed by Cytochrome P450 monooxygenases, introducing or unmasking polar groups (-OH, -NH2, -SH) to produce slightly polar active/inactive metabolites. Phase II: conjugation reactions (Glucuronidation, Sulfation, Acetylation, Glutathione conjugation), transferring large endogenous hydrophilic moieties to yield water-soluble inactive conjugates excreted by kidneys or bile.
30	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.
31	What are the dose-dependent receptor affinities and cardiovascular effects of intravenous Dopamine infusions?	Low dose (1-3 mcg/kg/min): D1 dopaminergic receptors in renal, mesenteric, and coronary beds -> vasodilation and increased renal blood flow. Intermediate dose (3-10 mcg/kg/min): Beta-1 adrenergic receptors -> positive inotropy and chronotropy, increasing cardiac output. High dose (>10 mcg/kg/min): Alpha-1 adrenergic receptors predominate -> widespread systemic vasoconstriction and elevated SVR.
32	What is the pharmacological mechanism by which Atropine treats symptomatic sinus bradycardia and atrioventricular (AV) nodal block?	Atropine is a competitive reversible antagonist of M2 muscarinic receptors on nodal tissue in the heart. By blocking parasympathetic (vagal) cholinergic tone at the sinoatrial (SA) node and AV node, it increases SA node firing rate and speeds conduction velocity through the AV node, increasing heart rate.