Amitriptyline

Mechanism

Chemical and Commercial Profile

Common trade names: Tryptizol, Deprelio, Laroxyl.
Group: Tricyclic Antidepressant (Tertiary Amine).

Mechanism of Action

It exerts a potent and non-selective inhibition on the presynaptic reuptake transporters of serotonin (SERT) and norepinephrine (NET). Its demethylated secondary metabolite (nortriptyline) is a preferred NET inhibitor.

Its secondary profile explains the high rate of systemic effects:

• M₁ receptor blockade (Muscarinic): Powerful anticholinergic effect.
• H₁ receptor blockade (Histaminergic): Deep sedation and weight gain.
• Blockade of α₁-adrenergic receptors: Reflex orthostatic hypotension.
• Blockade of voltage-dependent Sodium channels (Na_v 1.5): Myocardial membrane stabilization (class Ia antiarrhythmic effect in therapeutic doses, but lethal proarrhythmic effect in overdose).

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid but incomplete due to variable first hepatic passage. Bioavailability of 40-50%. C_max in 2-4 hours.
• Distribution: Highly lipophilic. High binding to plasma proteins (>95%). Volume of distribution (V_d) extreme: 15-20 L/kg.
• Metabolism: Hepatic through demethylation via CYP2C19 (generating the active metabolite nortriptyline) and hydroxylation via CYP2D6.
• Excretion: Renal (70%) mainly as inactive conjugated metabolites.
• Half-life (t_1/2): 15 to 30 hours.

Indicators and dose

Indications

• Severe major depression (melancholic or refractory to SSRIs).
• First-line treatment in Central and Peripheral Neuropathic Pain (postherpetic neuropathy, diabetic polyneuropathy).
• Prophylaxis of chronic tension headache and migraine.
• Fibromyalgia and chronic fatigue syndrome.
• Off-label: Infantile idiopathic nocturnal enuresis.

Dosage and Settings

• Major depression: Start with 25-50 mg at night; gradually increase up to 100-150 mg/day.
• Neuropathic Pain and Headache: Low doses: 10-25 mg/day, usual therapeutic range: 25-75 mg/day taken at night.
• Geriatric Population: Avoid its prescription due to high vulnerability to falls, arrhythmias and delirium. If mandatory, limit to a dose of 10 mg/day.
• Renal Failure: Does not require complex dose adjustments, but requires strict clinical monitoring of urinary retention.
• Liver Failure: Contraindicated in severe decompensated liver disease. In mild forms, reduce the dose by half.

Security

Contraindications

Absolute cardiac contraindication

The initiation of amitriptyline is strictly prohibited during the acute phase of recovery after acute myocardial infarction (AMI), in the presence of pre-existing bundle branch blocks, congenital long QT syndrome or previous cardiac arrhythmias due to the risk of inducing torsade de pointes or other fatal ventricular arrhythmias.

Adverse Effects (ADR)

• Central and peripheral anticholinergics: Xerostomia, blurred vision (due to cycloplegia), mydriasis, persistent constipation, acute urinary retention (extremely dangerous in benign prostatic hyperplasia), delirium and mental confusion in the elderly.
• CNS: Refractory daytime sedation, fine hand tremor, myoclonus, marked decrease in seizure threshold.
• Cardiovascular: Reflex sinus tachycardia, prolongation of the PR, QRS and QTc interval.

Clinical Interactions

• Drugs that alter clearance: CYP2D6 inhibitors increase myocardial toxicity.
• Direct sympathomimetics: Multiplies the risk of hypertensive crises due to synaptic accumulation of norepinephrine.
• Anticholinergics: Extremely serious additive effect (risk of paralytic ileus or intestinal obstruction).

Pregnancy and Breastfeeding

FDA Category: C. It can induce neonatal withdrawal symptoms (tachycardia, irritability, urinary retention) if maintained until delivery. Breastfeeding: Compatible with strict caution. Its passage into breast milk is reduced due to its high protein binding, but its active metabolite accumulates in the infant due to immaturity of conjugation.