The indirect-acting sympathomimetics do not directly activate adrenergic receptors but instead increase the availability of endogenous catecholamines at the synapse. Amphetamines and methylphenidate are the prototypical agents of this class, widely used in clinical medicine for attention-deficit/hyperactivity disorder (ADHD) and narcolepsy, and representing an important toxicological challenge when misused.
Mechanism of Indirect Sympathomimetic Action. Amphetamines exert their effects through multiple complementary mechanisms that collectively increase synaptic monoamine concentrations. The primary mechanism is carrier-mediated reverse transport: amphetamine enters the presynaptic terminal via the dopamine (DA) transporter (DAT) and norepinephrine (NE) transporter (NET), and once intracellular, causes the transporter to run in reverse, pumping DA and NE out of the cytosol and into the synapse rather than clearing them. Simultaneously, amphetamine disrupts vesicular storage by displacing DA and NE from synaptic vesicles into the cytosol; this is mediated through alkalinization of the vesicular lumen (disrupting the proton gradient that drives vesicular monoamine transporter (VMAT2) activity) and, for methamphetamine, by redistribution of VMAT2 itself away from vesicle membranes. A third mechanism is inhibition of monoamine oxidase (MAO), the primary intraneuronal degradative enzyme, which further increases cytosolic monoamine levels available for reverse transport. The net effect is a large, non-exocytotic (action potential-independent) efflux of DA, NE, and serotonin (5-HT) into the synapse.1
Methylphenidate: Reuptake Inhibition Without Vesicular Disruption. Methylphenidate acts primarily as a reuptake inhibitor at the DAT and NET, blocking transporter-mediated clearance of DA and NE from the synapse without triggering reverse transport or displacing vesicular stores. This mechanistic distinction from amphetamine has practical consequences: methylphenidate produces less of the large-amplitude monoamine surge associated with amphetamine and has a lower potential for triggering cardiovascular and psychological adverse effects at therapeutic doses. Methylphenidate does not significantly inhibit MAO and does not cause vesicular depletion. Both mechanisms ultimately increase synaptic DA in the prefrontal cortex (PFC) and striatum, improving executive function and attention through enhancement of cortical signal-to-noise ratios via DA and NE receptor activation in the PFC.12
Absorption, Distribution, Metabolism, and Excretion (ADME) of Amphetamines. Amphetamine and its salts (amphetamine mixed salts, dextroamphetamine) are well absorbed orally, with bioavailability of approximately 75 to 90%. The plasma half-life of amphetamine is approximately 10 to 12 hours and is substantially pH-dependent: urinary acidification increases renal clearance and shortens the effective half-life, while urinary alkalinization (as with bicarbonate administration) decreases tubular secretion and prolongs half-life and effect. This pH dependence is exploited in amphetamine overdose management, where urinary acidification can accelerate drug elimination. Amphetamine is metabolized by the cytochrome P450 2D6 isoform (CYP2D6) and monoamine oxidase (MAO)-mediated deamination. Extended-release formulations (amphetamine mixed salts extended-release (XR), lisdexamfetamine) extend the duration of action to 10 to 14 hours; lisdexamfetamine is a prodrug requiring cleavage by red blood cell (RBC) hydrolases to release active d-amphetamine, which provides a smoother pharmacokinetic profile and reduces abuse potential.13
Clinical Applications and Adverse Effects. Amphetamines and methylphenidate are approved for ADHD (both children and adults) and narcolepsy. In ADHD, the paradoxical calming effect reflects normalization of hypoactive DA and NE signaling in the PFC rather than sedation. Cardiovascular adverse effects are dose-dependent and include increased heart rate (HR), blood pressure (BP), and rarely arrhythmias; growth monitoring is required in pediatric patients on long-term therapy due to modest suppressive effects on height velocity. The central nervous system (CNS) adverse effects include insomnia, anorexia, anxiety, and, at high doses, psychosis and stereotyped behavior. Both amphetamines and methylphenidate are Schedule II controlled substances in the United States (US) due to their high abuse potential; tolerance develops to the euphoric effects more rapidly than to the therapeutic cognitive effects.123
Amphetamine: reverse transport (DAT/NET runs backwards) + vesicular depletion (VMAT2 disruption) + MAO inhibition → massive non-vesicular monoamine efflux. Methylphenidate: reuptake inhibition only (blocks DAT/NET) → no reverse transport, no vesicular depletion, no MAO inhibition → smaller, more physiologically regulated monoamine increase. Lisdexamfetamine: prodrug; cleavage by RBC hydrolases releases d-amphetamine; smoother PK curve; reduced abuse potential vs. immediate-release amphetamine. Both are Schedule II; both improve ADHD via DA and NE signaling enhancement in PFC.
Cocaine occupies a unique position in pharmacology: it is simultaneously the prototypical reuptake inhibitor of the indirect sympathomimetic class and a clinically used local anesthetic. Ephedrine and its stereoisomer pseudoephedrine are mixed-acting sympathomimetics with both direct receptor agonism and indirect catecholamine-releasing properties, making them important agents in both clinical medicine and toxicology.
Cocaine: Mechanism and Cardiovascular Toxicity. Cocaine blocks the reuptake transporters for all three monoamines (DAT, NET, and SERT), but its most clinically consequential actions involve the DAT (producing euphoria via mesolimbic DA pathway activation) and the NET (producing sympathomimetic cardiovascular effects). By blocking the norepinephrine transporter (NET), cocaine prevents norepinephrine (NE) clearance from adrenergic synapses, amplifying sympathetic stimulation of the heart and vasculature. The cardiovascular consequences are: tachycardia and hypertension from increased sympathetic tone; coronary vasoconstriction from α1 stimulation, which can precipitate myocardial infarction (MI) even in young patients with structurally normal coronary arteries; and ventricular arrhythmias from increased automaticity and QTc prolongation. Cocaine also blocks fast sodium (Na⁺) channels in a use-dependent manner, contributing to both its local anesthetic effect and, at toxic doses, to wide-complex arrhythmias similar to those caused by class I antiarrhythmic agents. The combination of coronary vasospasm, increased myocardial oxygen demand, and sodium channel blockade makes cocaine the most cardiovascularly dangerous sympathomimetic in clinical toxicology.45
Management of Cocaine-Induced Cardiovascular Toxicity. Hypertensive urgency and acute coronary syndrome (ACS) caused by cocaine require specific management considerations. Benzodiazepines are first-line for agitation, hypertension, and tachycardia because they reduce central sympathetic drive and reduce myocardial oxygen demand without direct cardiovascular effects. Nitroglycerin and phentolamine are useful for cocaine-induced coronary vasospasm and hypertension by reversing α-mediated vasoconstriction. Beta-blockers are historically contraindicated in cocaine toxicity due to the theoretical risk of unopposed α vasoconstriction (with non-selective agents) worsening hypertension and coronary spasm; however, current evidence suggests that cardioselective agents may be used cautiously in the post-acute setting. Sodium bicarbonate is used for wide-complex arrhythmias caused by sodium channel blockade. For cocaine-related MI, percutaneous coronary intervention (PCI) remains the treatment of choice when indicated; fibrinolytics carry higher hemorrhagic risk in cocaine users due to associated hypertension.5
Ephedrine and Pseudoephedrine: Mixed-Acting Sympathomimetics. Ephedrine exerts sympathomimetic effects through two mechanisms: direct agonism at α1, β1, and β2 receptors, and indirect release of endogenous NE from presynaptic terminals via a mechanism similar to amphetamine (non-vesicular, carrier-mediated reverse transport). The relative contribution of direct versus indirect action depends on the state of endogenous NE stores: in catecholamine-replete patients, the indirect mechanism predominates; in patients with depleted NE stores (severe autonomic neuropathy, chronic reserpine treatment), direct agonism accounts for most of the response. Clinically, ephedrine is used in anesthesia to treat spinal or epidural anesthesia-induced hypotension (where it increases both heart rate (HR) and blood pressure (BP) via β1 and β2 mechanisms), as a bronchodilator in mild asthma, and as a nasal decongestant. Tachyphylaxis occurs rapidly with repeated dosing of ephedrine because repeated use depletes NE stores faster than they can be replenished by new synthesis, progressively reducing the indirect component of its action.46
Pseudoephedrine and Regulatory Status. Pseudoephedrine, the diastereomer of ephedrine, has similar pharmacological properties but with less central stimulant activity. It is used orally as a nasal decongestant via α1-mediated mucosal vasoconstriction. In the US, pseudoephedrine was moved behind the pharmacy counter under the Combat Methamphetamine Epidemic Act of 2005 because it serves as a precursor in illicit methamphetamine synthesis; purchases are quantity-limited and require identification. Phenylephrine, a pure α1 agonist discussed in Module 03, has replaced pseudoephedrine in many over-the-counter (OTC) decongestant products, though its oral bioavailability is substantially lower and its efficacy as an oral decongestant has been questioned by the US Food and Drug Administration (FDA). The FDA advisory committee voted in 2023 that oral phenylephrine is not effective as a nasal decongestant, as reviewed in Module 03.6
First-line: benzodiazepines (reduce central sympathetic activation). Coronary vasospasm/HTN: nitroglycerin or phentolamine. Wide-complex arrhythmias (Na⁺ channel block): sodium bicarbonate. Cocaine-ACS: PCI preferred over fibrinolytics. Non-selective beta-blockers: avoid acutely (unopposed α vasoconstriction risk); cardioselective agents may be used cautiously post-acute. Do not use physostigmine for cocaine toxicity (does not address the mechanism). Cocaine local anesthetic: only cocaine retains vasoconstrictive property among local anesthetics; used in ENT surgery for this reason.
Reserpine and guanethidine represent an older pharmacological approach to sympathetic blockade that targets the presynaptic terminal directly, depleting or preventing release of catecholamine stores rather than blocking postsynaptic receptors. Although largely supplanted by newer agents, their mechanisms illuminate fundamental principles of sympathetic neurotransmission and remain important for understanding drug interactions, particularly with sympathomimetics and vesicular monoamine transporter 2 (VMAT2) physiology, and with monoamine oxidase inhibitors (MAOIs).
Reserpine: VMAT2 Blockade and Catecholamine Depletion. Reserpine is an alkaloid derived from Rauwolfia serpentina that irreversibly inhibits the vesicular monoamine transporter 2 (VMAT2), the protein responsible for packaging dopamine (DA), norepinephrine (NE), and serotonin (5-HT) from the cytosol into storage vesicles. With VMAT2 blocked, monoamines that would normally be protected from intraneuronal monoamine oxidase (MAO) by vesicular sequestration are instead exposed to MAO in the cytosol and degraded. The result is progressive depletion of vesicular DA, NE, and 5-HT stores across both peripheral sympathetic neurons and central nervous system (CNS) neurons. Peripheral depletion produces sustained reduction in sympathetic tone, lowering blood pressure (BP) through decreased vascular resistance and cardiac output (CO). Because reserpine acts on VMAT2 covalently and new VMAT2 synthesis requires days, the blood pressure-lowering effect persists for days to weeks after drug discontinuation. The CNS monoamine depletion causes the most clinically limiting adverse effects: profound depression (historically a major cause of drug-induced depression), sedation, and extrapyramidal effects from DA depletion in the basal ganglia. Reserpine has essentially no role in modern antihypertensive therapy due to its CNS adverse effects, but it remains a reference drug for understanding monoamine physiology.14
Guanethidine: Uptake and Storage Disruption in Peripheral Adrenergic Neurons. Guanethidine is taken up into peripheral adrenergic nerve terminals via the NET (the same transporter responsible for NE reuptake), competing with NE for neuronal entry. Once intraneuronal, guanethidine accumulates in vesicles and exerts two effects: an initial transient sympathomimetic phase from displacement of stored NE (causing transient hypertension and tachycardia shortly after initiation), followed by sustained sympatholysis from depletion of vesicular NE stores and blockade of vesicle-mediated NE release.8 The net effect is a reduction in sympathetic neurotransmission limited entirely to the peripheral nervous system (PNS): unlike reserpine, guanethidine does not cross the blood-brain barrier and produces no CNS monoamine depletion or depression. Its antihypertensive effect is profound, particularly in the upright position, because reflex sympathetic vasoconstriction on standing is blocked; severe orthostatic hypotension was the primary dose-limiting adverse effect. Guanethidine is now virtually obsolete as an antihypertensive but remains important for understanding drug interactions with tricyclic antidepressants (TCAs) and cocaine, both of which block NET and prevent guanethidine uptake, thus abolishing its antihypertensive effect.14
Drug Interactions with Reserpine and Guanethidine. The pharmacology of these neuron-depleting agents creates specific drug interaction profiles. Reserpine blocks the indirect sympathomimetic response to amphetamines and ephedrine: because these agents depend on displacing NE from vesicular stores, reserpine-depleted neurons have no releasable NE and the indirect sympathomimetic effect is abolished. Guanethidine is blocked by any drug that inhibits NET, because guanethidine must enter the neuron via NET to exert its effect. TCAs (imipramine, amitriptyline, desipramine), cocaine, ephedrine, and amphetamines all block NET and therefore prevent guanethidine's antihypertensive action, causing a loss of blood pressure control. Sympathomimetics given to a reserpine-pretreated patient show exaggerated responses to directly acting agonists (phenylephrine, methoxamine) due to postsynaptic supersensitivity (upregulation of adrenergic receptors in response to denervation-like depletion), while indirect agents (amphetamine, tyramine) show reduced or absent pressor responses.14
Reserpine: VMAT2 blockade (irreversible); depletes DA + NE + 5-HT; both CNS and peripheral; crosses blood-brain barrier (BBB); causes depression, sedation, extrapyramidal effects; prolonged effect after discontinuation. Guanethidine: NET uptake required; depletes peripheral NE only; does NOT cross BBB; no CNS effects; severe orthostatic hypotension; blocked by TCAs, cocaine, ephedrine (all NET inhibitors). Both: potentiate directly-acting sympathomimetics (postsynaptic supersensitivity); abolish response to indirectly-acting sympathomimetics (no releasable NE).
The tyramine-monoamine oxidase inhibitor (MAOI) interaction represents a pharmacodynamically elegant and clinically dangerous drug-food interaction that integrates the physiology of intestinal and hepatic first-pass metabolism with the pharmacology of monoamine storage and release. Understanding this interaction requires synthesizing the mechanisms of tyramine, monoamine oxidase (MAO) isoforms, and indirect sympathomimetic action.
Normal Tyramine Metabolism. Tyramine is a biogenic amine present in fermented and aged foods (aged cheeses, cured meats, fermented soy products, tap beer, and certain wines) that is formed by bacterial decarboxylation of the amino acid tyrosine. Under normal physiological conditions, orally ingested tyramine is efficiently metabolized by intestinal and hepatic MAO isoform A (MAO-A) before reaching the systemic circulation, providing a robust first-pass barrier that prevents dietary tyramine from exerting sympathomimetic effects. MAO-A in enterocytes and the hepatic portal circulation constitutes the primary defense; less than 1% of ingested tyramine normally escapes to reach systemic adrenergic nerve terminals. The gut and liver thus function as a physiological filter against dietary biogenic amines.9
MAOI Inhibition and the Tyramine Pressor Response. Non-selective monoamine oxidase inhibitors (MAOIs) (phenelzine, tranylcypromine, isocarboxazid) and the MAO-A-selective MAOI moclobemide inhibit intestinal and hepatic MAO-A, destroying the first-pass barrier to dietary tyramine. When a patient on an MAOI ingests tyramine-containing food, tyramine is absorbed intact into the systemic circulation and reaches peripheral adrenergic nerve terminals in large quantities. There, tyramine enters sympathetic neurons via the norepinephrine transporter (NET) and acts as a potent indirect sympathomimetic, displacing vesicular norepinephrine (NE) stores into the synapse. In MAOI-treated patients, the NE that is released cannot be metabolized by MAO (which is inhibited), and the NET reuptake that would normally clear synaptic NE is overwhelmed by the ongoing tyramine-driven efflux. The result is massive, sustained release of NE into adrenergic synapses, producing a hypertensive crisis: sudden, severe hypertension (systolic blood pressure (BP) often exceeding 200 mmHg), throbbing occipital headache, diaphoresis, palpitations, and, in severe cases, intracranial hemorrhage and death.910
Clinical Management of MAOI-Tyramine Hypertensive Crisis. The management of MAOI-tyramine hypertensive crisis requires rapid blood pressure reduction without aggravating the adrenergic excess. Phentolamine (5 mg IV, repeated as needed) is the classic pharmacological treatment, directly blocking the α1-mediated vasopressor response while the tyramine-NE surge is ongoing. Nicardipine (IV) is an alternative and frequently preferred in current practice as a titratable calcium channel blocker (CCB) that rapidly lowers peripheral vascular resistance. Chlorpromazine is a historical antidote with α-blocking properties that was used before specific agents were available. Nifedipine sublingual has been used in outpatient settings but carries unpredictable absorption and risk of precipitous hypotension. Non-selective beta-blockers are contraindicated for the same reason as in cocaine toxicity: blocking β2-mediated vasodilation while α1-mediated vasoconstriction remains unopposed can worsen hypertension. All patients on MAOIs must follow tyramine-restricted diets; the dietary restriction applies equally to the tranylcypromine and phenelzine generations of non-selective MAOIs.910
MAOIs interact lethally with multiple drug classes beyond dietary tyramine. Serotonin syndrome: MAOIs + SSRIs, SNRIs, meperidine, dextromethorphan, tramadol, St. John's Wort → potentially fatal serotonin excess (hyperthermia, rigidity, clonus, autonomic instability). Sympathomimetic crisis: MAOIs + indirect sympathomimetics (amphetamines, ephedrine, pseudoephedrine, phenylpropanolamine) → hypertensive crisis (same mechanism as tyramine). Opioids: avoid meperidine (severe serotonin syndrome risk) and tramadol; morphine and codeine are relatively safer. Washout required: 14 days after stopping most MAOIs before starting interacting drugs (5 weeks for fluoxetine before starting MAOI, due to fluoxetine's long half-life).
The adrenergic receptor subtypes α1, α2, β1, β2, and β3, when blocked or activated, produce predictable physiological responses that form the foundation of rational sympathomimetic and sympatholytic drug selection. Mastery of this framework allows prediction of responses to novel combinations, toxicological presentations, and physiological states not covered by specific trial data.
Receptor Subtype Profiles and Clinical Predictions. Alpha-1 (α1) receptors mediate vasoconstriction in arterioles and veins, contraction of bladder neck and prostate smooth muscle, and dilation of the pupil via the iris dilator. Activation raises peripheral vascular resistance (PVR) and blood pressure (BP); blockade lowers BP and relieves urinary obstruction in benign prostatic hyperplasia (BPH). Alpha-2 (α2) receptors at presynaptic terminals inhibit norepinephrine (NE) release (autoreceptors); postsynaptic central α2 receptors mediate sympatholysis when activated by clonidine. Alpha-2 blockade (yohimbine) disinhibits NE release, raising BP and heart rate (HR). Beta-1 (β1) receptors in the heart mediate increased HR, conduction velocity, and contractility; in the juxtaglomerular apparatus (JGA), β1 stimulation releases renin. Beta-2 (β2) receptors mediate bronchodilation, vasodilation in skeletal muscle, glycogenolysis, and uterine relaxation; β2 stimulation also drives potassium (K⁺) into cells, lowering serum K⁺. Beta-3 (β3) receptors in adipose tissue mediate lipolysis; in the detrusor, β3 agonism relaxes the bladder and increases capacity.111
The Epinephrine Dose-Response Framework. Epinephrine provides the clearest model for dose-dependent receptor activation. At low doses (less than 0.1 mcg/kg/min), β2 receptor-mediated vasodilation in skeletal muscle vasculature predominates, lowering diastolic BP while β1-mediated increases in HR and cardiac output (CO) maintain or slightly raise systolic BP; the net result is a widened pulse pressure and reduced mean arterial pressure (MAP). At high doses, α1 receptor-mediated vasoconstriction becomes dominant, overriding β2 vasodilation and raising both systolic and diastolic BP. This dose-dependent pattern explains why high-dose epinephrine in cardiac arrest primarily works through α1-mediated aortic vasoconstriction maintaining coronary perfusion pressure rather than through direct cardiac stimulation.112
Direct versus Indirect Sympathomimetic Distinction in Clinical Practice. The distinction between direct and indirect mechanisms is clinically important in three contexts. First, in patients with depleted catecholamine stores (chronic reserpine use, autonomic neuropathy, prolonged critical illness), indirect sympathomimetics (amphetamine, ephedrine, tyramine) will produce markedly attenuated pressor responses because there is no vesicular NE available for release; direct agonists remain fully effective. Second, in patients pretreated with guanethidine or reserpine, the response to directly acting sympathomimetics is supernormal due to receptor upregulation (postsynaptic supersensitivity), while indirect agents produce absent or markedly reduced responses. Third, tachyphylaxis (progressive attenuation of response with repeated doses) affects only indirect sympathomimetics because repeated release depletes the releasable NE pool; direct agonists maintain consistent responses because they do not depend on NE stores.47
Clinical Decision Rules for Adrenergic Agent Selection. Several practical decision rules distill the receptor pharmacology into actionable guidance. For vasopressor selection in shock: NE provides α1 vasoconstriction with modest β1 cardiac support and is the first-line vasopressor for septic shock (SOAP II trial); phenylephrine is a pure α1 agonist useful when tachycardia must be avoided (hypertrophic obstructive cardiomyopathy (HOCM), severe aortic stenosis); epinephrine is the drug of choice in anaphylaxis. For benign prostatic hyperplasia (BPH) with hypertension: a selective α1 blocker addresses both conditions with one agent. For asthma in a patient requiring a beta-blocker: choose a cardioselective β1 agent (bisoprolol, metoprolol) to preserve β2-mediated bronchodilation, and weigh chronic obstructive pulmonary disease (COPD) severity and reversibility with care.12
α1: vasoconstriction, pupil dilation, bladder neck contraction → phenylephrine (agonist); prazosin, tamsulosin (antagonists). α2 presynaptic: inhibits NE release → clonidine, dexmedetomidine (agonists); yohimbine (antagonist). β1: HR, contractility, AV conduction, renin → epinephrine, dobutamine (agonists); metoprolol, esmolol (antagonists). β2: bronchodilation, vasodilation, glycogenolysis → albuterol, salmeterol (agonists); propranolol blocks (risk: bronchospasm). β3: lipolysis, detrusor relaxation. Indirect agents: amphetamine (VMAT2 + reverse DAT/NET); cocaine/methylphenidate (DAT/NET reuptake block); tyramine (NET-mediated NE release); ephedrine (mixed direct + indirect). Neuron depleters: reserpine (VMAT2 block); guanethidine (NET uptake required, blocked by TCAs/cocaine).
Chapter 5 has covered the full scope of adrenergic pharmacology, from receptor subtype biology through direct agonists, selective antagonists, third-generation vasodilatory agents, and indirect-acting sympathomimetics. This final section synthesizes the chapter's clinical decision framework and highlights the highest-yield concepts for practice and examination.
Direct Agonists: Modules 02 and 03 Key Points. Epinephrine is the drug of choice for anaphylaxis due to its combined α1, β1, and β2 actions; in cardiac arrest, its benefit is primarily α1-mediated coronary perfusion pressure maintenance (PARAMEDIC2 trial). Norepinephrine (NE) is first-line for septic shock (SOAP II trial). Dopamine's dose-dependent receptor profile (low-dose dopamine type 1 receptor (DA1)-mediated renal vasodilation, moderate-dose β1 cardiac stimulation, high-dose α1 vasoconstriction) is foundational, though NE has largely supplanted dopamine for septic shock. Dobutamine's predominantly β1 positive inotropy makes it the inotrope of choice for cardiogenic shock without profound hypotension. Clonidine and dexmedetomidine act via α2A receptors in the locus coeruleus; dexmedetomidine provides opioid-sparing sedation without respiratory depression. Albuterol and salmeterol provide short-acting and long-acting (LABA) bronchodilation; LABA monotherapy without inhaled corticosteroids (ICS) in asthma is contraindicated (SMART trial).1
Alpha Antagonists: Module 04 Key Points. Phenoxybenzamine (irreversible α1/α2) is the only appropriate agent for pheochromocytoma preoperative preparation; phentolamine (reversible α1/α2 IV) treats hypertensive emergencies from catecholamine excess and reverses NE extravasation. Selective α1 blockers (prazosin, terazosin, doxazosin) are adjunctive antihypertensives post-ALLHAT; the first-dose phenomenon requires bedtime initial dosing. Tamsulosin and silodosin (α1A-uroselective) are first-line for benign prostatic hyperplasia (BPH); intraoperative floppy iris syndrome (IFIS) risk persists indefinitely. Prazosin is endorsed for post-traumatic stress disorder (PTSD) nightmares. The pheochromocytoma sequencing rule is absolute: α-blockade before β-blockade.1
Beta Antagonists: Module 05 Key Points. Only carvedilol, bisoprolol, and metoprolol succinate extended-release (XR) have proven HFrEF mortality benefit. Asthma is an absolute contraindication to all beta-blockers. Propranolol uniquely inhibits thyroxine (T4)-to-triiodothyronine (T3) conversion, making it preferred in thyroid storm. Abrupt discontinuation in coronary artery disease (CAD) causes rebound angina and myocardial infarction (MI); always taper over 1 to 2 weeks. Carvedilol inhibits P-glycoprotein (P-gp), raising digoxin levels approximately 15%. Propranolol overdose causes wide-complex arrhythmias via membrane-stabilizing activity (MSA); treat with IV lipid emulsion and sodium bicarbonate.1
Indirect Agents and Neuron Blockers: Module 06 Key Points. Amphetamine acts via reverse transport at the dopamine transporter (DAT) and norepinephrine transporter (NET) plus vesicular monoamine transporter 2 (VMAT2) disruption plus monoamine oxidase (MAO) inhibition; methylphenidate acts only by reuptake inhibition. Lisdexamfetamine is a red blood cell (RBC)-hydrolyzed prodrug with reduced abuse potential. Cocaine blocks DAT, NET, and the serotonin transporter (SERT) and blocks sodium channels; cocaine-ACS is treated with benzodiazepines, nitroglycerin, and phentolamine; avoid non-selective beta-blockers acutely. Reserpine irreversibly blocks VMAT2, depleting both central nervous system (CNS) and peripheral monoamines, causing depression and sedation. Guanethidine requires NET uptake; TCAs, cocaine, and ephedrine block NET, abolishing guanethidine's antihypertensive effect. Monoamine oxidase inhibitor (MAOI)-tyramine crisis arises from destroyed first-pass barrier allowing systemic tyramine to trigger massive NE release; treat with phentolamine or nicardipine; 14-day washout applies before adding interacting drugs.19
Anaphylaxis: epinephrine (α1 + β1 + β2). Septic shock: NE (SOAP II). Pheochromocytoma: α-block first (phenoxybenzamine), then β; plasma free metanephrines for diagnosis. HFrEF-proven beta-blockers: carvedilol, bisoprolol, metoprolol succinate XR only. MAOI crisis: phentolamine or nicardipine; 14-day washout. Propranolol unique: T4→T3 block (thyroid storm), portal HTN, essential tremor, long QT. Cocaine-ACS: benzodiazepines + nitroglycerin/phentolamine; avoid non-selective beta-blockers acutely. Guanethidine blocked by TCAs/cocaine/ephedrine (NET block prevents entry). Reserpine supersensitizes postsynaptic receptors to direct agonists while abolishing indirect agonist responses. Esmolol: ultra-short β1 agent (t½ 9 min) for acute AF rate control and perioperative HTN. Sotalol: non-selective β-block + K⁺ channel block; TdP risk; inpatient initiation.
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