Pharmacology: Amitriptyline is a tertiary amine tricyclic antidepressant. The manner in which the tricyclic antidepressants exert their clinical antidepressant effect is uncertain but they have been shown to block, in different degrees, the reuptake of various neurotransmitters including serotonin and norepinephrine at the neuronal membrane. This action potentiates the effects of these neurotransmitters.
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.
Pharmacokinetics: Amitriptyline is well absorbed from the gastrointestinal tract with peak plasma concentrations occurring between 2 and 12 hours after administration. Bioavailability of the drug is between 30 and 60% due to extensive first pass metabolism of the drug in the liver. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline.
Amitriptyline is over 90% protein bound. Its elimination half-life varies from 10 to 50 hours, with an average of 15 hours. Within 24 hours, approximately 25 to 50% of a dose of amitriptyline is excreted in the urine as inactive metabolites; small amounts are excreted in the bile.
Routine serum drug concentration monitoring is not warranted but may be useful to assess compliance or suspected toxicity. Recommended therapeutic trough levels, i.e., the sum of both amitriptyline and its metabolite nortriptyline, vary widely and range from 250 to 900 nmol/L (60 to 250 ng/mL). Ideally, the trough level should be taken 12 hours following administration of the last dose.
Indications: In the pharmacologic management of depressive illness.
Amitriptyline may be used in depressed phase of bipolar affective disorder or in melancholic or psychotic depression. The use of amitriptyline in patients with bipolar illness may precipitate a hypomanic or manic state.
Patients with transient mood disturbances or normal grief reaction are not expected to benefit from tricyclic antidepressants.
Although not a labelled indication, amitriptyline and other antidepressants are widely used in the management of chronic nonmalignant pain (e.g., post-herpetic neuralgia, fibromyalgia).
Contraindications: Amitriptyline is contraindicated in patients who have shown hypersensitivity to the drug. Cross-sensitivity between amitriptyline and related tricyclic antidepressants is possible.
Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and MAO inhibiting drugs simultaneously; however, patients with refractory depression have received combination therapy without significant adverse effects, under certain strict conditions and under the supervision of prescribers experienced with such therapy.
Amitriptyline is not recommended during the acute recovery phase following myocardial infarction or in the presence of congestive heart failure (see Precautions).
Warnings: Anticholinergic Effects: Because of its strong anticholingergic properties, amitriptyline must be used with caution in patients with urinary retention, benign prostatic hypertrophy, angle-closure glaucoma or increased intraocular pressure.
Cardiovascular: Orthostatic hypotension, arrhythmias and conduction abnormalities have occurred during therapy with amitriptyline. Caution is advised if tricyclic antidepressants are used in patients with pre-existing cardiovascular disease.
Sedation: Patients should be warned about the possible sedation and mental or motor impairment associated with amitriptyline therapy and advised of the potential danger of operating machinery or driving a motor vehicle if this occurs.
Suicide: The potential for attempted suicide must always be considered in depressed patients. It is considered prudent to provide a limited supply of amitriptyline to patients known to be suicidal.
Precautions: Bipolar Illness: The use of antidepressants during the depressed phase of bipolar illness may precipitate a hypomanic or manic state.
CNS: Sedation is the most common CNS effect of tricylic antidepressants. Other reactions have occurred such as agitation, confusion, nightmares, restlessness, hostility, exacerbation of psychosis and extrapyramidal symptoms. Elderly patients may be more susceptible to some of these effects.
Hematologic: Rarely, blood dyscrasias have occurred in patients taking tricyclic antidepressants. A leukocyte and differential count should be performed in patients who develop symptoms such as sore throat and fever while taking these drugs.
Hypersensitivity: Allergic reactions have included rash, edema, drug fever and photosensitivity. The possibility of cross-sensitivity among the tricyclic agents must be considered.
Seizures: Tricyclic antidepressants can lower the seizure threshold and should be used with caution in patients with a history of seizures or those who may be predisposed to seizures.
Thyroid: Tricyclic antidepressants should be used with caution in patients who are hyperthyroid or receiving thyroid medication, because of the possibility of cardiac arrhythmias.
Drug Interactions : Anticholinergics: Concurrent use of tricyclic antidepressants and other drugs with anticholinergic activity may necessitate dosage adjustments to minimize the additive effects. Elderly patients may be particularly susceptible to excessive anticholinergic effects.
Antihypertensives: Tricyclic antidepressants may antagonize the antihypertensive effects of clonidine or guanethidine.
Carbamazepine: Plasma concentrations of tricyclic antidepressants may be decreased because of induction of hepatic enzymes by carbamazepine.
Cimetidine: Plasma concentrations of amitriptyline may be increased because of inhibition of hepatic enzymes by cimetidine.
CNS Depressants: The concomitant use of tricylcic antidepressants and other CNS depressants may result in additive depressant effects.
Lithium: There is some evidence that concurrent use of lithium and tricyclic antidepressants may increase the risk of neurotoxicity, particularly in the elderly. It has been suggested that reducing the dose of lithium in elderly patients may reduce the risk of neurotoxicity without compromosing its clinical effect. Elderly patients should be monitored carefully for signs of neurotoxicity (e.g., tremor, ataxia, seizures) when on combined therapy.
MAO Inhibitors: Because of the additive serotonergic effects, combination therapy with tricyclic antidepressants and MAO inbibitors is not recommended, except under certain conditions (see Contraindications).
Sympathomimetics: Tricyclic antidepressants can significantly enhance the pressor response to norepinephrine and may ptoentiate the cardiovascular effects (e.g., arrhythmia) of sympathomimetics in general.
Selective Serotonin Reuptake Inhibitors (SSRIs): Amitriptyline toxicity may occur if used concurrently with fluoxetine, because of inhibition of the hepatic mirosomal enzyme responsible for the metabolism of amitriptyline. Reduction of amitriptyline dose by as much as 75% may be necessary. The potential for this interaction occurring with other SSRIs must be considered. Because of the extremely long elimination half-life of fluoxetine, the potential for interacting with other drugs remains for several weeks after its discontinuation.
Thyroid Medications: Concomitant use of amitriptyline and levothyroxine may potentiate the cardiovascular effects (e.g., arrhythmias) of both drugs.
Pregnancy: Amitriptyline has not been proven to be without risk to the developing fetus; however, it is often continued during pregnancy when the need to treat an underlying depression justifies the potential risk to the fetus.
Lactation: Amitriptyline and its metabolite are excreted into breast milk, although levels have not been detected in infants’ serum. Amitriptyline’s effect in breast-feeding is unknown.
Children: Not recommended for treatment of depression in children under 12 years of age.
Geriatrics: Elderly patients may be more susceptible to the anticholinergic, cardiovascular and CNS effects of tricyclic antidepressants. Lower initial dosages with more gradual increases are warranted.
Adverse Effects: The more common adverse reactions involve anticholinergic effects such as dry mouth, disturbances of visual accommodation, constipation and urinary retention. Also commonly seen are light headedness, drowsiness, increased perspiration and mild tremors as well as insomnia. Adverse reactions of the cardiovascular system may be much more serious; however, these occur less frequently.
Note: Included in this listing are a few adverse reactions reported with other tricyclics but not specifically with amitriptyline. Pharmacological similarities among the tricyclic antidepressant drugs require that each reaction be considered when amitriptyline is administered.
Autonomic: Frequently: dry mouth and rarely associated sublingual adenitis, blurred vision, disturbances of accommodation, constipation, perspiration, flushing. Occasionally: delayed micturition, dilation of the urinary tract. In isolated cases: mydriasis, glaucoma, paralytic ileus, urinary frequency.
Behavioral: Occasionally: confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, agitation, insomnia, restlessness, nightmares, hypomania, mania, exacerbation of psychosis, decrease in memory, feeling of unreality. In isolated cases: feeling of weakness, aggressiveness.
Cardiovascular: Frequently: hypotension, particularly orthostatic hypotension with associated vertigo, tachycardia, ECG changes (including flattening or inversion of T waves). Occasionally: arrhythmia, disturbances in cardiac conduction, palpitation, syncope. In isolated cases: hypertension, congestive heart failure, myocardial infarction, heart block, asystole, stroke, peripheral vasospastic reactions.
CNS: Frequently: drowsiness, fatigue, tremors. Occasionally: insomnia, dizziness, headache, paresthesia (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy). Rarely: seizures. In isolated cases: tinnitus, incoordination, ataxia, alterations in EEG patterns, extrapyramidal symptoms, myoclonus, speech disorders.
Endocrine: Frequently: weight gain. Occasionally: increased or decreased libido, impotence. In isolated cases: gynecomastia in the male, breast enlargement and galactorrhea in the female, testicular swelling, elevation or depression of blood sugar levels, weight loss, syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Hematologic: In isolated cases: agranulocytosis, eosinophilia, leukopenia, purpura and thrombocytopenia may occur as an idiosyncratic response.
Hypersensitivity: Occasionally: skin rash, urticaria. In isolated cases: petechiae, itching, photosensitization (avoid excessive exposure to sunlight), edema (general or of face and tongue), drug fever, obstructive jaundice, nasal congestion, alopecia, allergic alveolitis (pneumonia) with or without eosinophilia.
Gastrointestinal: Occasionally: nausea, vomiting, anorexia. Rarely: elevated transaminases. In isolated cases: diarrhea, bitter taste, stomatitis, epigastric distress, abdominal cramps, black tongue, dysphagia, increased salivation, hepatitis with or without jaundice.
Withdrawal: If treatment is terminated abruptly, withdrawal symptoms, such as gastrointestinal discomfort, nervousness, anxiety and muscle twitching may occur.
tag_OverdoseOverdose: Symptoms: Overdose of tricyclic antidepressants may be manifest with doses as small as 50 mg in a child. Of patients who are alive at initial presentation, a mortality rate of between 0 and 15% has been reported. Symptoms of overdose of tricyclic antidepressants may begin within several hours of oral ingestion. Symptoms and signs may include: blurred vision, confusion, restlessness, dizziness, hyporeflexes, dilated pupils, fever, rapid heart rate, decreased bowel sounds, dry mouth, inability to void, myoclonic jerks, seizures, respiratory depression, myoglobinuric renal failure, nystagmus, ataxia, dysarthria, choreoathetosis, coma, hypotension and cardiac arrhythmias. An effect on cardiac conduction similar to that of quinidine may be seen with slowing of conduction, prolongation of the QRS complex and QT intervals, right bundle branch and AV block, ventricular tachyarrhythmias (including torsades de pointes and fibrillation) and death. Prolongation of the QRS duration to more than 0.1 seconds is predictive of more severe toxicity. The absence of sinus tachycardia does not ensure a benign course. Hypotension may be caused by vasodilation, central and peripheral alpha adrenergic blockade, and cardiac depression. In an otherwise healthy young person, prolonged resuscitation may be effective.
Treatment: In managing overdose, consider the possibility of multiple drug overdose, interactions among drugs, and unusual drug kinetics. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain the patient’s vital signs, blood gases, serum electrolytes, and acid-base balance. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal. The usual dose in adults is 50 to 100 g and in children 1 to 2 g/kg. One dose of a saline or sorbitol cathartic may be administered with the charcoal or separately. If gastric lavage is performed, an endotracheal tube with cuff inflated should be in place to prevent aspiration of gastric contents.
Ventricular arrhythmias, especially when accompanied by lengthened QRS intervals, may respond to alkalinization by hyperventilation or administration of sodium bicarbonate. It is important to monitor and manage serum electrolyte levels. Refractory arrhythmias may respond to propranolol, bretylium or lidocaine. Propranolol should be used with caution. Its negative inotropic effect may cause hypotension. Quinidine and procainamide usually should not be used because they may exacerbate arrhythmias and conduction already slowed by the overdosage.
Seizures may respond to diazepam. Phenytoin has pharmacologic properties that may be helpful in dealing with both the seizures and cardiac rhythm disturbances of tricyclic antidepressant overdose. Although the prophylactic use of phenytoin has been suggested, it is not of proven value.
In some patients, physostigmine may be used to antagonize some of the effects of tricyclic antidepressant overdose, such as atrial tachycardia, gut immotility, myoclonic jerks and somnolence. It is less effective for seizures and ventricular arrhythmias. When giving physostigmine, the patient’s condition should be carefully monitored and ventilation and cardiac rhythm should be supported. Cholinergic toxicity from physostigmine may include bronchospasm, bronchorrhea, bradycardia, asystole, diaphoresis, incontinence and seizures. Most clinicians caution against the routine use of physostigmine in tricyclic antidepressant overdose and many feel it should be reserved only for life-threatening anticholinergic symptoms not responding to other measures. If physostigmine is used, give it slowly because rapid injection may cause seizures. The effects of physostigmine may be short-lived; repeated doses may lead to continued improvement.
Diuresis and dialysis remove little of the tricyclic antidepressant present in the body of a patient who has taken an overdose. Hemoperfusion is of unproven benefit. The patient who has taken a tricyclic overdose should be monitored closely, at least until the QRS duration is normal.
Dosage: Depression: Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of adverse effects.
Initial dose for adults: 25 mg 3 times daily. The dose may be gradually increased, if necessary, to the level providing maximal clinical benefit with minimal toxicity, to a maximum of 300 mg daily.
Hospitalized patients may require higher initial or overall dosage.
Adolescents: An initial dose of 10 mg 3 times daily with 20 mg at bedtime is recommended. The dose may be increased to a maximum of 100 mg daily, either in divided doses or as a single bedtime dose.
Geriatrics: Recommended initial dose is 10 to 25 mg at bedtime. May be increased by 10 to 25 mg daily, at weekly intervals, up to 150 mg daily.
Maintenance: When satisfactory improvement has been achieved, dosage should be reduced to the lowest amount that will maintain relief of symptoms. The usual maintenance dose is 50 to 100 mg/day in divided doses; however, in suitable patients, the total daily dosage may be given in a single dose, preferably at bedtime. It is appropriate to continue maintenance therapy throughout the active phase of the depression and for the expected duration of the depressive episode, in order to lessen the possibility of relapse.
Chronic Nonmalignant Pain (see Indications): 10 to 25 mg at bedtime or 2 to 3 hours before bedtime.
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