Singapore Drugs Database

Indication

- Indicated for the treatment of major depressive disorder in adults - Indicated for the management of neuropathic pain in adults - Indicated for the prophylactic treatment of chronic tension type headache (CTTH) in adults - Indicated for the prophylactic treatment of migraine in adults - Indicated for the the treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This medicinal product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis. -Other off-label uses include irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia

Mechanism of Action

Amitriptyline has anticholinergic and sedative properties. It is metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons [FDA Label]. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline. There is some evidence in literature that neuronal and glial plasticity may be a critical action mediated by antidepressants via production of neurotrophic factors, such as GDNF, that promote neurogenesis, gliogenesis, development, plasticity, and survival [A31905]. In a study involving C6 glioma cells and normal human astrocytes, amitriptyline may activate the FGFR/FRS2α/ERK/CREB signaling cascade, thus resulting in GDNF production [A31905]. Amitriptyline displays affinity for muscarinic and histamine H1 receptors [FDA Label]. At both central and spinal cord level, amitriptyline exhibits ion-channel blocking effects on sodium, potassium and NMDA channel [FDA Label]. The noradrenaline, sodium and the NMDA effects are mechanisms known to be involved in the maintenance of neuropathic pain, chronic tension type headache prophylaxis and migraine prophylaxis [FDA Label]. In cultured rat cortical neurons, amitriptyline blocked sodium channel current (I(Na)) in a concentration-dependent, not voltage-dependent manner and reduced mRNA expression of sodium channels [A31906]. This may explain the actions of amitriptyline leading to migraine prophylaxis.

Pharmacokinetics

Absorption

Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations occur 2-12 hours following oral or intramuscular administration. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts can be excreted with the breast milk [FDA Label].

Distribution

The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg) [FDA Label].

Metabolism

Amitriptyline undergoes hepatic metabolism that mainly involves demethylation. Demethylation leads to the formation of its primary active metabolite, nortriptyline. This secondary amine retains a pharmacological activity. It can further undergo hydroxylation (mediated by CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved are CYP1A2 and CYP2C9. The metabolism is subject to genetic polymorphism [FDA Label]. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same profile as nortriptyline but is considerably weaker.Demethylnortriptyline and amitriptyline N oxide are only present in plasma in minute amounts; the latter is almost inactive. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. In plasma the amount of total 10-hydroxynortriptyline dominates but most of the metabolites are conjugated [FDA Label].

Elimination

Clearance

The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h, range 24.53-53.73 L/h [FDA Label].

Toxicity

LD₅₀=350 mg/kg (in mice). Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.

Active Ingredient/Synonyms

10,11-dihydro-5-(gamma-Dimethylaminopropylidene)-5H-dibenzo(a,D)cycloheptene | 10,11-dihydro-N,N-Dimethyl-5H-dibenzo(a,D)heptalene-delta(5),gamma-propylamine | 3-(10,11-dihydro-5H-Dibenzo(a,D)cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine | 3-(10,11-dihydro-5H-Dibenzo[a,D]cyclohepten-5-ylidene)-N,N-dimethylpropan-1-amine | 5-(3-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,D)cycloheptatriene | 5-(3-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,D)cycloheptene | 5-(gamma-Dimethylaminopropylidene)-5H-dibenzo[a,D][1,4]cycloheptadiene | Amitriptilina | Amitriptylin | Amitriptyline | Amitriptylinum | Amitriptyline |