Pharmacology · Adrenergic Pharmacology

Indirect-Acting Agents, Neuron Blockers, and Integrated Adrenergic Pharmacology

Amphetamines · Cocaine · Neuron Blockers · MAOI Crisis · Chapter Integration

Amphetamine works by three simultaneous mechanisms — reverse transport via DAT and NET pushing monoamines out, VMAT-2 disruption releasing vesicular stores into the cytoplasm, and weak MAO inhibition — producing massive non-vesicular monoamine efflux; methylphenidate only blocks DAT and NET (no reverse transport, no vesicular depletion), producing a smaller and more regulated monoamine increase with lower abuse potential than amphetamine.
Cocaine's toxicity has two mechanistic components: DAT + NET + SERT blockade producing sympathomimetic excess (tachycardia, hypertension, coronary vasospasm), and sodium channel blockade producing local anesthetic effect and wide-complex arrhythmias; management is benzodiazepines first, nitroglycerin or phentolamine for vasospasm, and sodium bicarbonate for arrhythmia — non-selective beta-blockers are absolutely contraindicated because they leave alpha-1 vasoconstriction unopposed.
Reserpine irreversibly blocks VMAT-2 centrally and peripherally, depleting dopamine, norepinephrine, and serotonin — this causes depression, parkinsonism, and profound sympatholysis; guanethidine requires NET uptake to enter the terminal and depletes only peripheral norepinephrine (no CNS effects), but is blocked by anything that blocks NET (tricyclics, cocaine, amphetamine, ephedrine), losing its antihypertensive effect.
The MAOI-tyramine interaction is one of pharmacology's most important food-drug interactions: MAO-A in the gut and liver normally destroys dietary tyramine before it reaches systemic circulation; when MAO-A is irreversibly inhibited, tyramine enters nerve terminals via NET and displaces vesicular norepinephrine, triggering a hypertensive crisis that cannot be degraded; treatment is phentolamine intravenously, and a 14-day washout is required after stopping any MAOI before resuming a normal diet or starting interacting drugs.
The MAOI washout also applies to serotonergic drug combinations — MAOI plus SSRI, meperidine, dextromethorphan, or tramadol causes serotonin syndrome (agitation, hyperthermia, clonus, diaphoresis); this is distinct from the tyramine-norepinephrine crisis and requires 14 days clearance (or 5 weeks for fluoxetine, given its long half-life) before starting an MAOI.

Abbreviations: DAT = dopamine transporter · NET = norepinephrine transporter · SERT = serotonin transporter · VMAT-2 = vesicular monoamine transporter 2 · MAOI = monoamine oxidase inhibitor · SSRI = selective serotonin reuptake inhibitor · HFrEF = heart failure with reduced ejection fraction

Indirect-Acting and Neuron-Blocking Agents

Amphetamine

Triple Mechanism

Mechanism(1) Reverse transport via DAT/NET; (2) VMAT-2 disruption; (3) MAO inhibition

ResultMassive non-vesicular monoamine efflux

UsesADHD, narcolepsy (Schedule II)

Tachyphy.Yes — depletes NE stores with repeated dosing

Methylphenidate

Reuptake Block Only

MechanismBlocks DAT and NET only — no reverse transport, no vesicular depletion, no MAO inhibition

ResultSmaller, regulated monoamine increase vs. amphetamine

UsesADHD (Schedule II); lower abuse potential than amphetamine

Cocaine

Reuptake Block + Na&sup+; Channel

MechanismBlocks DAT + NET + SERT; sodium channel blockade (local anesthetic + arrhythmia)

ToxicityTachycardia, hypertension, coronary vasospasm, myocardial infarction, wide-complex arrhythmias

MgmtBenzodiazepines first; nitroglycerin/phentolamine for vasospasm; sodium bicarbonate for arrhythmia. No non-selective beta-blockers.

Reserpine / Guanethidine

Neuron-Depleting Agents

ReserpineIrreversible VMAT-2 block; depletes dopamine + NE + serotonin centrally AND peripherally; causes depression

Guaneth.Requires NET uptake; peripheral NE depletion only; no CNS effects

Key ruleGuanethidine blocked by tricyclics, cocaine, ephedrine (all block NET) → loss of antihypertensive effect

MAOI Hypertensive Crisis

Tyramine + MAOI → Massive Norepinephrine Release

Mechanism

Normally: MAO-A in gut and liver destroys dietary tyramine (first-pass barrier)

On MAOI: First-pass barrier destroyed → tyramine reaches nerve terminals

Tyramine enters terminal via NET → displaces vesicular norepinephrine

Norepinephrine cannot be degraded (MAO inhibited) → hypertensive crisis

Management and Rules

Treatment: Phentolamine (intravenous) or nicardipine

Avoid: Non-selective beta-blockers (unopposed alpha-1 vasoconstriction)

Serotonin syndrome risk: MAOI + SSRI, meperidine, dextromethorphan, tramadol

Tyramine-rich foods: aged cheese, cured meats, fermented soy, tap beer

14-day washout after stopping MAOI before starting interacting drugs or resuming normal diet

Chapter High-Yield Clinical Integration

Scenario	Receptor Mechanism	Drug of Choice
Anaphylaxis	Alpha-1 + beta-1 + beta-2 — all three simultaneously	Epinephrine intramuscular
Septic shock	Alpha-1 vasoconstriction; modest beta-1 support	Norepinephrine (SOAP II trial)
Pheochromocytoma prep	Irreversible alpha-1/alpha-2 blockade	Phenoxybenzamine — alpha before beta rule
HFrEF	Beta-1 blockade → receptor resensitization	Carvedilol, bisoprolol, or metoprolol succinate extended-release only
MAOI crisis	Alpha-1 blockade to reverse NE surge	Phentolamine or nicardipine
Thyroid storm	Beta blockade + inhibits T4→T3 conversion	Propranolol — only beta-blocker with deiodinase inhibition

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