Brands, Medical Use, Clinical Data
Drug Category
- Analgesics, Non-Narcotic
- Antidepressive Agents, Tricyclic
- Adrenergic Uptake Inhibitors
Dosage Forms
- Syrup
- Tablet (10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg)
Brands / Synonyms
Adepress; Adepril; Amitid; Amitril; Amitriprolidine; Amitriptylin; Amitriptyline HCL; Amitriptyline Hydrochloride; Amitryptiline; Amitryptyline; Amytriptiline; Chlordiazepoxide and Amitriptyline; Damilan; Damilen; Damitriptyline; Elanil; Elavil; Endep; Flavyl; Hexathane; Horizon; Lantron; Laroxil; Laroxyl; Lentizol; Perphenazine and Amitriptyline; Proheptadiene; Redomex; Saroten; Sarotex; Seroten; Sylvemid; Triptanol; Triptilin; Triptisol; Tryptanol; Tryptizol
Indications
For the treatment of anxiety, bipolar disorders, and depression.
Pharmacology
Amitriptyline, a tertiary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is extremely sedating, and thus improvement of sleep patterns can be the first benefit of treatment. Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction, and a lowering of the seizure threshold. As with other antidepressants, several weeks of therapy may be required in order to realize the full clinical benefit of amitriptyline. Although not a labelled indication, amitriptyline is widely used in the management of chronic nonmalignant pain (e.g., post-herpetic neuralgia, fibromyalgia).
Mechanism of Action
Amitriptyline 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. 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.
Absorption
Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism).
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.
Biotrnasformation / Drug Metabolism
Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline.
Contraindications
Amitriptyline HCl is contraindicated in patients who have shown prior hypersensitivity to it.
It should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions,
and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs
simultaneously. When it is desired to replace a monoamine oxidase inhibitor with amitriptyline HCl, a minimum of 14
days should be allowed to elapse after the former is discontinued. Amitriptyline HCl should then be initiated
cautiously with gradual increase in dosage until optimum response is achieved.
This drug is not recommended for use during the acute recovery phase following myocardial infarction.
Drug Interactions
Drugs Metabolized by P450 2D6 ¾ The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10%
of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than
expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction
of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase
in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor
metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these
inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not
metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other
antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective
serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they
may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will
depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated
in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of
particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from
fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower
doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of
these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is
desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an
inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors: Guanethidine or similarly acting compounds; thyroid medication;
alcohol, barbiturates and other CNS depressants; and disulfiram
When amitriptyline HCl is given with anticholinergic agents or sympathomimetic drugs, including epinephrine
combined with local anesthetics, close supervision and careful adjustment of dosages are required.
Hyperpyrexia has been reported when amitriptyline HCl is administered with anticholinergic agents or with
neuroleptic drugs, particularly during hot weather.
Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type
drugs.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying
elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been
reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of
tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been
reported when cimetidine was added to the drug regimen. Discontinuation of cimetidine in well-controlled patients
receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the
antidepressants.
Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been
reported in patients who were treated with one gram of ethchlorvynol and 75 - 150 mg of amitriptyline HCl.
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