indication

For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.

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.

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.

biotransformation

Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline.

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.

half life

10 to 50 hours, with an average of 15 hours

route of elimination

Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with little unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination.

drug interactions

Altretamine: Risk of severe hypotension

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if atazanavir if initiated, discontinued or dose changed.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like amitriptyline. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Butalbital: Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants such as amitriptyline. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Carbamazepine: Carbamazepine may decrease the serum concentration of the tricyclic antidepressant, amitriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if carbamazepine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine may increase the effect of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if cimetidine is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonidine: The tricyclic antidepressant, amitriptyline, decreases the effect of clonidine.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroquinidine barbiturate: Dihydroquinidine barbiturate increases the effect of the tricyclic antidepressant, amitriptyline.

Dobutamine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect, dobutamine.

Donepezil: Possible antagonism of action

Dopamine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect, dopamine.

Duloxetine: Possible increase in the levels of this agent when used with duloxetine

Ephedra: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of ephedra.

Ephedrine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of ephedrine.

Epinephrine: The tricyclic antidepressant, amitriptyline, may increase the sympathomimetic effect of epinephrine.

Fenoterol: The tricyclic antidepressant, amitriptyline, may increase the sympathomimetic effect of fenoterol.

Fluconazole: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of amitriptyline if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Fluoxetine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amitriptyline if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amitriptyline if fluvoxamine is initiated, discontinued or dose changed.

Galantamine: Possible antagonism of action

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: The tricyclic antidepressant, amitriptyline, decreases the effect of guanethidine.

Isocarboxazid: Possibility of severe adverse effects

Isoproterenol: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of isoproterenol.

Ketoconazole: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of amitriptyline by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if ketoconazole is initiated, discontinued or dose changed.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephentermine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of mephentermine.

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Metaraminol: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of metaraminol.

Methoxamine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of methoxamine.

Moclobemide: Possible severe adverse reaction with this combination

Norepinephrine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of norepinephrine.

Orciprenaline: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of orciprenaline.

Phenelzine: Possibility of severe adverse effects

Phenylephrine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of phenylephrine.

Phenylpropanolamine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of phenylpropanolamine.

Pirbuterol: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of pirbuterol.

Procaterol: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of procaterol.

Pseudoephedrine: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of pseudoephedrine.

Quinidine: Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Quinidine barbiturate: Quinidine barbiturate increases the effect of tricyclic antidepressant, amitriptyline.

Rasagiline: Possibility of severe adverse effects

Rifabutin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, amitriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if rifabutin is initiated, discontinued or dose changed.

Rifampin: The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, amitriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if ritonavir if initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Salbutamol: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of salbutamol.

Sibutramine: Increased risk of CNS adverse effects

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Amitriptyline, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Amitryptyline. Consider alternate therapy or monitor for therapeutic/adverse effects of Amytriptyline if Terbinafine is initiated, discontinued or dose changed.

Terbutaline: The tricyclic antidepressant, amitriptyline, increases the sympathomimetic effect of terbutaline.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimethobenzamide: Trimethobenzamide and Amitriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Amitriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Amitriptyline, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Vilazodone: Monitor for toxic effects of tricyclic antidepressants if a selective serotonin reuptake inhibitor (SSRI) is initiated or the dose is increased. The influence of the SSRI may take several days or weeks to be fully realized or resolved.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and amitriptyline, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).