Indirect Acting Sympathomimetics

Indirect acting sympathomimetics raise noradrenaline at the synapse without directly stimulating the receptor, either by displacing it from vesicles or blocking its reuptake. They include decongestants, stimulants for attention deficit hyperactivity disorder, a pressor used in anaesthesia, and common drugs of misuse.

Classification. Releasing agents: ephedrine, pseudoephedrine, amphetamine, dexamfetamine, methamphetamine, lisdexamfetamine, cathinones (khat), mephentermine, and tyramine in food. Reuptake inhibitors: cocaine, methylphenidate, atomoxetine, reboxetine, and some antidepressants.

Mechanism. Releasing agents enter the nerve terminal through the noradrenaline transporter, displace noradrenaline from vesicles through VMAT2, and reverse the transporter to expel noradrenaline. Reuptake inhibitors block the transporter and prolong synaptic noradrenaline and dopamine. Ephedrine also has direct alpha and beta activity.

Tachyphylaxis. Repeated dosing depletes vesicular noradrenaline, so the response falls rapidly. Patients depleted by reserpine or guanethidine respond poorly. Tricyclic antidepressants block uptake and so reduce the effect of indirect agents but potentiate direct ones.

Central effects. Dopamine and noradrenaline release produces alertness, reduced appetite, euphoria and insomnia. Dependence is an important risk with amphetamines, methamphetamine and cocaine.

Region-specific point. Khat (Catha edulis), chewed widely in East Africa and the Horn, contains cathinone and cathine and produces sympathomimetic effects including hypertension, tachycardia, insomnia and psychosis.

Pharmacokinetics. Ephedrine and pseudoephedrine are well absorbed orally and excreted largely unchanged by the kidney, with urinary acidification shortening duration. Amphetamines are metabolised by CYP2D6 and also excreted renally.

• Ephedrine: vasopressor in anaesthesia, mixed direct and indirect, longer acting than phenylephrine.
• Pseudoephedrine: oral nasal decongestant.
• Dexamfetamine, lisdexamfetamine, methylphenidate: ADHD and narcolepsy.
• Atomoxetine: non-stimulant ADHD reuptake inhibitor.
• Metaraminol and mephentermine: mixed agents used for hypotension.
• Methamphetamine, cocaine, cathinones: substances of misuse.
• Tyramine: in aged cheese, cured meats and fermented foods; causes hypertensive crisis with monoamine oxidase inhibitors.

• Hypotension under anaesthesia: ephedrine 3 to 6 mg intravenously, repeated every 3 to 4 minutes to effect, with a usual total under 30 mg because tachyphylaxis develops.
• Nasal congestion: pseudoephedrine 60 mg orally every 4 to 6 hours to a maximum of 240 mg daily. Avoid in uncontrolled hypertension. Rare cases of posterior reversible encephalopathy and reversible cerebral vasoconstriction have been reported.
• ADHD: methylphenidate immediate release 5 mg twice daily, increased weekly to a usual range of 20 to 60 mg daily in divided doses; lisdexamfetamine 30 mg each morning, increased by 10 to 20 mg weekly to a maximum of 70 mg daily; dexamfetamine 5 mg once or twice daily, titrated.
• Narcolepsy: dexamfetamine or methylphenidate, or newer wake-promoting agents.
• Selection: non-stimulants are preferred if there is cardiac disease, tics or substance misuse risk.
• Sympathomimetic toxicity: benzodiazepines first, external cooling, and fluids. Severe hypertension is treated with phentolamine, glyceryl trinitrate or sodium nitroprusside. Beta blockers are avoided in isolation because of unopposed alpha stimulation.

Contraindications. Monoamine oxidase inhibitor use within 14 days, uncontrolled hypertension, significant structural cardiac disease, arrhythmia, hyperthyroidism, narrow-angle glaucoma, and, for ADHD stimulants, active substance misuse (relative).

Adverse effects. Tachycardia, hypertension, palpitations, insomnia, anxiety, tremor, reduced appetite and growth effects, tics, psychosis, hyperthermia, rhabdomyolysis, cardiomyopathy with chronic misuse, and stroke.

Hypertensive crisis with monoamine oxidase inhibitors. Severe headache, hypertension and arrhythmia after tyramine or an indirect agent. Use phentolamine 5 to 10 mg intravenously for severe cases.

Toxidrome. Agitation, mydriasis, tachycardia, hypertension, hyperthermia and sweating. Moist skin separates it from the dry skin of the anticholinergic toxidrome. Serotonin syndrome and anticholinergic toxicity are the main differentials.

Interactions. Monoamine oxidase inhibitors, linezolid, selegiline and moclobemide are dangerous. Tricyclic antidepressants, other sympathomimetics and general anaesthetics raise arrhythmia risk. Antihypertensives are antagonised.

Monitoring. Blood pressure, heart rate, weight and growth in children on ADHD therapy, sleep, and psychiatric symptoms.

Special groups. Pregnancy: pseudoephedrine in the first trimester is associated with gastroschisis. Children: height and weight monitoring on stimulants. Older adults: higher cardiovascular risk. Breastfeeding: amphetamines and pseudoephedrine enter milk, and pseudoephedrine can reduce supply.