Also known as: Amitriptyline hydrochloride
Mechanism of Action
It prevents the re-uptake, and hence the inactivation of noradrenaline and serotonin at nerve terminals. Reuptake prevention of these monoamine neurotransmitters potentiate their action in the brain. This appears to be associated with the antidepressant activity.
The mechanism of action also includes ion-channel blocking effects on sodium, potassium and NMDA channel at both central and spinal cord level. 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. The pain-reducing effect of amitriptyline is not linked to its anti-depressive properties.
Tricyclic antidepressants possess affinity for muscarinic and histamine H1 receptors to varying degrees.
Amitriptyline is a tricyclic antidepressant and an analgesic. It has marked anticholinergic and sedative properties.
Clinical efficacy and safety
The efficacy and safety of amitriptyline has been demonstrated in treatments of the following indications in adults:
- Major Depressive Disorder
- Neuropathic pain
- Chronic tension type headache prophylaxis
- Migraine prophylaxis
The efficacy and safety of amitriptyline has been demonstrated for treatments of nocturnal enuresis in children aged 6 years and above.
For treatment of depression, doses of up to 200 mg daily and, occasionally, up to 300 mg daily have been used in severely depressed patients in hospital only.
The antidepressant and analgesic effects usually set in after 2-4 weeks; the sedative action is not delayed.
Oral administration of tablets results in maximum serum levels in about 4 hours. (tmax = 3.89±1.87 hours; range 1.93-7.98 hours). After peroral administration of 50 mg the mean Cmax = 30.95±9.61 ng/ml; range 10.85-45.70 ng/ml (111.57±34.64 nmol/l; range 39.06-164.52 nmol/l). The mean absolute oral bioavailability is 53% (Fabs = 0.527±0.123; range 0.219-0.756).
The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg).
The plasma protein binding is about 95%.
Amitriptyline and the main metabolite nortriptyline pass across the placental barrier.
In nursing mothers amitriptyline and nortriptyline are excreted in small amounts with the breast milk. The ratio milk concentration/plasma concentration in women is around 1:1. The estimated daily infant exposure (amitriptyline + nortriptyline) averages 2% of the corresponding maternal weight related doses of amitriptyline (in mg/kg).
In vitro the metabolism of amitriptyline proceeds mainly by demethylation (CYP2C19, CYP3A4) and hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved are CYP1A2 and CYP2C9. The metabolism is subject to genetic polymorphism. The main active metabolite is the secondary amine, nortriptyline.
Nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin equally well. 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.
The elimination half-life (t½ β) amitriptyline after peroral administration is about 25 hours (24.65±6.31 hours; range 16.49-40.36 hours). The mean systemic clearance (Cls) is 39.24±10.18 L/h, range 24.53-53.73 L/h.
The excretion proceeds mainly with urine. The renal elimination of unchanged amitriptyline is insignificant (about 2%).
Steady state plasma levels of amitriptyline + nortriptyline are reached within a week for most patients, and in steady state the plasma level comprises approximately equal parts of amitriptyline and nortriptyline around the clock following treatment with conventional tablets 3 times a day.
Longer half-lives and decreased oral (Clo) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.
Reduced hepatic function
Hepatic impairment may reduce hepatic extraction resulting in higher plasma levels and caution should be exercised when dosing these patients.
Reduced renal function
Renal failure has no influence on the kinetics.
The metabolism is subject to genetic polymorphism (CYP2D6 and CYP2C19).
Plasma concentrations of amitriptyline and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been establishe.
Preclinical Safety Data
Amitriptyline inhibited ion channels, which are responsible for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia.
The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations revealed partially contradictory results, particularly a potential to induce chromosome aberrations cannot be excluded. Long-term carcinogenicity studies have not been performed.
In reproductive studies, teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2-40 mg/kg/day (up to 13 times the maximum recommended human amitriptyline dose of 150 mg/day or 3 mg/kg/day for a 50-kg patient). However, literature data suggested a risk for malformations and delays in ossification of mice, hamsters, rats and rabbits at 9 33 times the maximum recommended dose. There was a possible association with an effect on fertility in rats, namely a lower pregnancy rate. The reason for the effect on fertility is unknown.