Chapter 5  ·  Module 6  ·  Visual Summary

Indirect-Acting Agents & Integrated Pharmacology

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

Indirect-Acting and Neuron-Blocking Agents

Amphetamine

Triple Mechanism

Mechanism(1) Reverse transport via dopamine transporter/norepinephrine transporter; (2) Vesicular monoamine transporter-2 disruption; (3) Monoamine oxidase inhibition
ResultMassive non-vesicular monoamine efflux
UsesAttention deficit hyperactivity disorder, narcolepsy (Schedule II)
Tachyphy.Yes — depletes norepinephrine stores with repeated dosing

Methylphenidate

Reuptake Block Only

MechanismBlocks dopamine transporter and norepinephrine transporter only — no reverse transport, no vesicular depletion, no monoamine oxidase inhibition
ResultSmaller, regulated monoamine increase vs. amphetamine
UsesAttention deficit hyperactivity disorder (Schedule II); lower abuse potential than amphetamine

Cocaine

Reuptake Block + Na&sup+; Channel

MechanismBlocks dopamine transporter + norepinephrine transporter + serotonin transporter; 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. Avoid non-selective beta-blockers.

Reserpine / Guanethidine

Neuron-Depleting Agents

ReserpineIrreversible vesicular monoamine transporter-2 block; depletes dopamine + norepinephrine + serotonin centrally AND peripherally; causes depression
Guaneth.Requires norepinephrine transporter uptake; peripheral norepinephrine depletion only; no central nervous system effects
Key ruleGuanethidine blocked by tricyclic antidepressants, cocaine, ephedrine (all block norepinephrine transporter) → loss of antihypertensive effect

Monoamine Oxidase Inhibitor Hypertensive Crisis

Tyramine + Monoamine Oxidase Inhibitor → Massive Norepinephrine Release

Mechanism

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

On Monoamine Oxidase Inhibitor: First-pass barrier destroyed → tyramine reaches nerve terminals

Tyramine enters terminal via norepinephrine transporter → displaces vesicular norepinephrine

Norepinephrine cannot be degraded (monoamine oxidase inhibited) → hypertensive crisis

Management and Rules

Treatment: Phentolamine (intravenous) or nicardipine

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

Serotonin syndrome risk: Monoamine oxidase inhibitors + selective serotonin reuptake inhibitors, meperidine, dextromethorphan, tramadol

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

14-day washout after stopping monoamine oxidase inhibitor before starting interacting drugs or resuming normal diet

Chapter 5 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 (Sepsis Occurrence in Acutely Ill Patients 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
Monoamine oxidase inhibitor crisis Alpha-1 blockade to reverse norepinephrine surge Phentolamine or nicardipine
Thyroid storm Beta blockade + inhibits T4→T3 conversion Propranolol — only beta-blocker with deiodinase inhibition