Amitrip
Amitriptyline hydrochloride
Presentation
Tablets 10mg: Blue film coated biconvex tablet, 9/32" diameter, imprinted "AM10" one side.
Tablets 25mg: Yellow film coated biconvex tablet, 9/32" diameter.
Tablets 50mg: Orange film coated biconvex tablet, 11/32" diameter.
Uses
Actions
Amitriptyline hydrochloride is a potent antidrepressant with sedative properties. The mechanism of action in humans is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system. In broad clinical use Amitriptyline has been found to be well tolerated.
Amitriptyline has also been found effective in the treatment of enuresis in some cases where organic pathology has been excluded. The mode of action of Amitriptyline in enuresis is not known. However, Amitriptyline does have anticholinergic properties and medicines of this group, such as belladonna, have been used in the treatment of enuresis.
Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmcologically 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.
Pharmacokinetics
Absorption
Appears in plasma within 30 to 60 minutes after oral ingestion and 5 to 10 minutes after intramuscular injection. Approximately 62% of the radioactive doses of 14C was recovered in human urine after oral or intravenous administration. Plasma levels are very low with broad peaks ranging from 2-12 hours after administration.
Metabolism
In one study, 12 normal subjects received 25 mg of Amitriptyline t.i.d.; plasma Amitriptyline levels were maximal (62 ± 20 ng/ml) at 4 hours post therapy. In another study in which 12 normal subjects received 25 mg Amitriptyline hydrochloride t.i.d. for 2 weeks, the plasma half-life averaged 30 hours.
Studies in humans following oral administration of 14C-labeled medicine indicated that Amitriptyline is rapidly absorbed and metabolised. Radioactivity of the plasma was practically negligible, although significant amounts of radioactivity appeared in the urine by 4 to 6 hours and one-half to one-third of the medicine was excreted within 24 hours.
Amitriptyline is metabolised by N-demethylation and bridge hydroxylation in humans, rabbit, and rat. Virtually the entire dose is excreted as glucuronide or sulphate conjugate of metabolites, with little unchanged medicine appearing in the urine. Other metabolic pathways may be involved.
Excretion
Urine
Following an intravenous dose, an average total of 62.9% of radioactivity was excreted in 7 days, with 25.1% being excreted in the first 24 hours. Following oral administration, an average total of 63.0% of radioactivity was excreted in 7 days, with 27.0% excreted in the first 24 hours.
Faeces
Following oral administration 14C-labeled tablets, excretion of radioactivity was calculated to be 10.5% (average) over 7 days; after intravenous administration, an average of 12.7% was recovered in the faeces in 7 days.
Bile:
Animal studies show that Amitriptyline and its metabolites are excreted in the bile.
Milk
In one report, following 100 mg/day of oral Amitriptyline, levels of 135-151 ng/ml were found in the breast milk of a lactating patient.
Indications
Amitrip is recommended in:
- The treatment of depression
- Nocturnal enuresis where organic pathology has been excluded.
Dosage and Administration
Depression
Dosage Considerations
Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.
Oral Dosage
Initial Dosage for Outpatient Adults - 75 mg of Amitriptyline a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg a day. Increases are made preferably in the late afternoon and/or bedtime doses. The sedative effect is usually rapidly apparent. The antidepressant activity may be evident within 3 or 4 days or may take up to 30 days to develop adequately.
Alternate methods of initiating therapy in outpatients are: Begin therapy with 50 to 100 mg Amitriptyline preferably in the evening or at bedtime; this may be increased by 25 to 50 mg as necessary to a total of 150 mg per day. Initiate therapy with one 75 mg capsule or tablet preferably in the evening or at bedtime and increase, if necessary, to two, or one in the morning and one in the evening.
Dosage for Hospitalised Patients - 100 mg a day may be required initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalised patients may need as much as 300 mg a day.
Dosage for Adolescent and Elderly Patients - In general, lower dosages are recommended for these patients. In those adolescent and elderly patients who may not tolerate higher doses, 50 mg daily may be satisfactory. The required daily dose may be administered either as divided doses or as a single dose preferably in the evening or at bedtime.
Maintenance Dosage
The usual maintenance dose is 50 to 100 mg Amitriptyline per day. For maintenance therapy, the total daily dosage may be given in a single dose preferably in the evening or at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.
Enuresis
A dose of 10 mg at bedtime has been found effective in children under six years of age. In older children, the dosage should be increased as necessary according to weight and age.
Children 6 to 10 years of age may receive 10 to 20 mg of Amitriptyline per day. In the age group from 11 to 16 a dose of 25 to 50 mg may be required.
Most patients respond in the first few days of therapy. In those who do respond, the tendency is for increasing, continued improvement as the period of treatment is extended. Continued treatment is usually required to maintain the response until control is established.
The doses of Amitriptyline recommended in the treatment of enuresis are low compared with those used in the treatment of depression, even allowing for differences in age and weight. This recommended dose must not be exceeded. This medication should be kept out of reach of children.
Plasma Levels
Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected. Adjustments in dosage should be made according to the patient's clinical response and not on the basis of plasma levels.
Contraindications
Amitriptyline is contraindicated in patients who have shown prior hypersensitivity to it. It should not be given concomitantly with a monoamine oxidase inhibiting compound. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting medicines simultaneously. When it is desired to substitute Amitriptyline for a monoamine oxidase inhibitor, a minimum of 14 days should be allowed to elapse after the latter is discontinued. Amitriptyline should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.
This medicine is not recommended for use during the acute recovery phase following myocardial infarction.
See Use in Pregnancy under Warnings and Precautions.
Warnings and Precautions
General
Amitriptyline should be used with caution in patients with a history of seizures, in patients with impaired liver function and, because of its atropione-like action, in patients with a history of urinary retention, or with narrow angle glaucoma or increased intraocular pressure. In patients with narrow-angle glaucoma, even average doses may precipitate an attack.
There has been a report of fatal dysrhythmia occurring as late as 56 hours after Amitriptyline overdose.
Discontinue the medicine several days before elective surgery if possible.
Hyperpyrexia has been reported when tricyclic antidepressants are administered with anticholinergic agents or with neuroleptic medicines, particularly during hot weather.
The medicine may impair alertness in some patients; operation of automobiles and other activities made hazardous by diminished alertness should be avoided.
Cardiovascular Disorders
Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant medicines, including Amitriptyline, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial Infarction and stroke have been reported with medicines of this class.
Endocrine Disorders
Close supervision is required when Amitriptyline is given to hyperthyroid patients or those receiving thyroid medication.
Central Nervous System Disorders
The possibility of suicide in depressed patients remains during treatment. Patients should not have access to large quantities of this medicine during treatment.
When Amitriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be aggravated. Likewise, in manic-depressive psychosis, depressed patients may experience a shift toward the manic phase.
Paranoid delusions, with or without associated hostility, may be exaggerated. In any of these circumstances, it may be advisable to reduce the dose of Amitriptyline or to use a major tranquillising medicine, such as perphenazine, concurrently.
Use in Children
In view of the lack of experience with the use of this medicine in treating depression in children, it is not recommended for depressed patients under 12 years of age.
Use in Pregnancy
There are no well controlled studies in pregnant women; therefore, in administering the medicine to pregnant patients or women who may become pregnant, the potential benefits must be weighed against the possible hazards to mother and child.
Nursing Mothers
Amitriptyline is detectable in breast milk. Because of the potential for serious adverse reactions in infants from Amitriptyline, a decision should be made whether to discontinue nursing or discontinue the medicine.
Adverse Effects
Note: Included in the listing which follows are a few adverse reactions which have not been reported with this specific medicine. However, pharmacological similarities among the tricyclic antidepressant medicines require that each of the reactions be considered when Amitriptyline is administered.
Cardiovascular
Hypotension, syncope, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke, non-specific ECG changes and changes in AV conduction.
CNS and Neuromuscular
Confusional states; disturbed concentration; disorientation; delusions; hallucinations; excitement; anxiety; restlessness; drowsiness; insomnia; nightmares; numbness; tingling, and paresthesias of the extremities; peripheral neuropathy; incoordination; ataxia; tremors; coma; seizures; alteration in EEG patterns; extrapyramidal symptoms, including abnormal involuntary movements and tardive dyskinesia; dysarthria; tinnitus.
Anticholinergic
Dry mouth, blurred vision, mydriasis, disturbance of accommodation, increased intraocular pressure, constipation, paralytic ileus, hyperpyrexia, urinary retention, dilatation of urinary tract.
Allergic
Skin rash, urticaria, photosensitization, oedema of face and tongue.
Haematologic
Bone marrow depression including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.
Gastrointestinal
Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhoea, parotid swelling, black tongue, rarely hepatitis (including altered liver function and jaundice).
Endocrine
Testicular swelling and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, elevation or lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Other
Dizziness, weakness, fatigue, headache, weight gain or loss, oedema, increased perspiration, urinary frequency, mydriasis, drowsiness, alopecia.
Withdrawal Symptoms
Abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2-7 days following cessation of chronic therapy with tricyclic antidepressants.
In Enuresis
The doses of Amitriptyline recommended in the treatment of enuresis are low compared with those used in the treatment of depression, even allowing for differences in age and weight. Side effects consequently are even less frequent than when the medicine is used in treating depression. The most common side effects are:
- Drowsiness
This is unlikely to be a disadvantage since the medicine is being taken at bedtime, and in fact may be an asset.
- Anticholinergic effects
These also may be an asset, as anticholinergic medicines have long been used in the treatment of enuresis.
- The only other side effects which have been encountered with the doses of Amitriptyline recommended for enuresis have been mild sweating and itching, but these have been infrequent.
Adverse Effects - Casual Relationship Unknown
The following additional adverse effects have been reported; however, a casual relationship to therapy with Amitriptyline has not been established.
Body as a Whole
Lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor).
Interactions
Other Antidepressant Medicines
The potency of Amitriptyline is such that addition of other antidepressant medicines generally does not result in any additional therapeutic benefit. Untoward reactions have been reported after the combined use of antidepressant agents having varying modes of activity. Accordingly, combined use of Amitriptyline hydrochloride and other antidepressant medicines should be undertaken only with due recognition of the possibility of potentiation and with a thorough knowledge of the pharmacology of both medicines. There have been no reports of untoward events when patients receiving Amitriptyline were changed immediately to protriptyline or vice versa.
Guanethidine
Amitriptyline may block the antihypertensive action of guanethidine or similarly acting compounds.
Anticholinergic Agents/Sympathomimetic Medicines
When Amitriptyline is given with anticholinergic agents or sympathomimetic medicines, including epinephrine combined with local anaesthetics, close supervision and careful adjustment of dosage are required. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type medicines.
Cimetidine
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.
Central Nervous System Depressants
Amitriptyline may enchance the response to alcohol and the effects of barbiturates and other CNS depressants. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with 1 g of ethchlorvynol and 75-150 mg of Amitriptyline.
Disulfiram
Delirium has been reported with concurrent administration of Amitriptyline and disulfiram.
Electroshock Therapy
Concurrent administration of Amitriptyline and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to patients for whom it is essential.
Overdosage
Manifestations
High doses may cause temporary confusion, disturbed concentration, or transient visual hallucinations. Over-dosage may cause drowsiness; hypothermia; tachycardia and other arrhythmic abnormalities, such as bundle branch block; ECG evidence of impaired conduction; congestive heart failure; dilated pupils; disorders of ocular motility; convulsions; severe hypotension; stupor; coma and polyradiculoneuropathy; constipation.
Other symptoms may be agitation, hyperactive reflexes, muscle rigidity, vomiting, hyperpyrexia, or any of those listed under Adverse Effects.
All patients suspected of having taken an overdose should be admitted to a hospital as soon as possible. Treatment is symptomatic and supportive. Empty the stomach as quickly as possible by emesis followed by gastric lavage upon arrival at the hospital. Following gastric lavage, activated charcoal may be administered. Twenty to 30 g of activated charcoal may be given every four to six hours during the first 24 to 48 hours after ingestion. An ECG should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality. Maintain an open airway and adequate fluid intake; regulate body temperature.
The intravenous administration of 1-3 mg of physostigmine salicylate has been reported to reverse the symptoms of tricyclic antidepressant poisoning. Because physostigmine is rapidly metabolised, the dosage of physostigmine should be repeated as required particularly if life-threatening signs such as arrhythmias, convulsions and deep coma recur or persist after the initial dose of physostigmine. Because physostigmine itself may be toxic, it is not recommended for routine use.
Standard measures should be used to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine, or propranolol. Should cardiac failure occur, the use of digitalis should be considered. Close monitoring of cardiac function of not less than five days is advisable.
Anticonvulsants may be given to control convulsions. Amitriptyline increases the CNS depressant action but not the anticonvulsant action of barbiturates; therefore, an inhalation anaesthetic, diazepam, or paraldehyde is recommended for control of convulsions.
Dialysis is of no value because of low plasma concentrations of the medicine.
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental overdosage have occurred with this class of medicine.
Pharmaceutical Precautions
Store below 25°C.
Package Quantities
Tablet: 10mg; Blister strip packs of 100's and 500's
Tablet: 25mg; Blister strip packs of 100's and 500's
Tablet: 50mg; Blister strip packs of 100's
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