Amitriptyline

 

Elavil®, Endep®, Amitriptyline by Mylan, Amitriptyline by Sidmak

  CAUTION: Federal law prohibits dispensing without prescription.

For migraine prophylaxis-

Oral dosage-

Adults: Titrate to response. Doses of 10-300 mg PO per day have been used.

BACKGROUND

     Schulman EA, Silberstein SD. Symptomatic and prophylactic treatment of migraine and tension-type headache. Neurology 1992;42(suppl 2):16—21. [amitriptyline dosage, atenolol dosage, chlorpromazine dosage, cyproheptadine dosage, dexamethasone dosage, diflunisal dosage, diltiazem dosage, doxepin dosage, fluoxetine dosage, haloperidol dosage, ibuprofen dosage, indomethacin dosage, ketoprofen dosage, meclofenamate, mefenamic acid dosage, meperidine dosage, morphine dosage, nadolol dosage, naproxen dosage, nifedipine dosage, nimodipine dosage, nortriptyline dosage, phenelzine dosage, phenytoin dosage, piroxicam dosage, prednisone dosage, propranolol dosage, sulindac dosage, timolol dosage, verapamil dosage, £-blockers overview]

 

DESCRIPTION

     Amitriptyline is an oral and parenteral tertiary amine tricyclic antidepressant. It is structurally related to the thioxanthene antipsychotics such as thiothixene. Amitriptyline is also related to the skeletal muscle relaxant cyclobenzaprine, although amitriptyline is not believed to possess muscle-relaxant properties. Amitriptyline is metabolized to nortriptyline, an active metabolite that is also marketed separately. Clinically, amitriptyline is used to treat depression, pain of neuropathic origin, attention-deficit hyperactivity disorder, functional enuresis in children, panic disorder, and phobic disorder, and to manage some eating disorders. Amitriptyline was approved by the FDA in 1961.

 

CLINICAL PHARMACOLOGY

     Mechanism of Action: The precise action of tricyclic antidepressants is not fully understood, but it is believed that the most important effect is the decreased reuptake of norepinephrine and serotonin. Amitriptyline appears to exert effects on both norepinephrine and serotonin (5-HT), although the selective-acting desipramine is a more potent inhibitor of norepinephrine transport. Amitriptyline is metabolized to nortriptyline, which accounts for most of the norepinephrine-reuptake inhibition after amitriptyline administration. Nortriptyline itself also possesses antidepressant activity. Additional hydroxy metabolites apparently are active as well. The down-regulation of limbic beta-receptors that results from this synaptic neurotransmitter increase occurs ~5—7 days after therapeutic concentrations are reached.

     Monoamine oxidase is not inhibited by either amitriptyline or nortriptyline. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, and the seizure threshold can be lowered. Amitriptyline possesses strong anticholinergic activity. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose can result from amitriptyline's effect on the endocrine system.

     Pharmacokinetics: Amitriptyline is well absorbed from the GI tract, but individual response can vary considerably. The full antidepressant effects can take several weeks to produce, although adverse effects can occur after the first dose. Peak plasma concentrations are obtained within 2—12 hours following oral or IM administration. Tricyclic antidepressants are highly protein-bound (predominantly to alpha1-acid glycoprotein) in plasma and tissues. Because tricyclic antidepressants are long-acting, a single daily dose may be given to improve patient compliance. Half-life values range from 10—50 hours for amitriptyline and 20—100 hours for nortriptyline.

     Amitriptyline is metabolized in the liver to nortriptyline, which is lipophilic and crosses the blood-brain barrier. Amitriptyline and nortriptyline are distributed into the lungs, heart, brain, and liver. Nortriptyline is known to cross the placenta and is also distributed into breast milk. Both undergo enterohepatic circulation. Lipophilic metabolites, such as nortriptyline, are most likely to be reabsorbed and further metabolized. Between 25—50% of a single dose is excreted in urine as active metabolites within 24 hours. A small amount of excretion occurs in feces.

 

CONTRADICTIONS

  • abrupt discontinuation
  • agranulocytosis
  • alcoholism
  • asthma
  • bipolar disorder
  • breast-feeding
  • cardiac disease
  • children
  • contact lenses
  • diabetes mellitus
  • elderly
  • gastroesophageal reflux disease (GERD)
  • GI disease
  • glaucoma
  • hematological disease
  • hepatic disease
  • hyperthyroidism
  • ileus ointramuscular injections
  • myocardial infarction
  • Parkinson's disease
  • pregnancy
  • prostatic hypertrophy
  • respiratory depression
  • schizophrenia
  • seizure disorder
  • suicidal ideation
  • surgery
  • thrombocytopenia
  • urinary retention

     The anticholinergic effects of tricyclic antidepressants contraindicate their use in patients with decreased GI motility. Tricyclic antidepressants can induce or exacerbate hiatal hernia, and can cause paralytic ileus or constipation. Patients who have increased intraocular pressure or angle-closure glaucoma, benign prostatic hypertrophy, GI disease, gastroesophageal reflux disease (GERD), or urinary retention should be treated with caution because of the anticholinergic activity of tricyclic antidepressants. Anticholinergic effects appear most frequently and cause the greatest morbidity in geriatric patients.

     The anticholinergic effects of amitriptyline may increase lens discomfort for wearers of contact lenses. Mydriasis, disturbance of accommodation, and dry eyes may contribute to blurred vision and lens intolerance. The use of lubricating drops may be necessary, or in severe cases discontinued use of contact lenses while taking amitriptyline.

     Following prolonged therapy with high doses, abrupt discontinuation of the tricyclic antidepressant should be avoided because it could precipitate symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea. This is particularly true for the tertiary amine tricyclic antidepressants: amitriptyline, imipramine, clomipramine, trimipramine, and doxepin.

     Tricyclic antidepressants should be used with caution in patients with a history of alcoholism or who may use alcohol or other sedative medications because the depressant effects on the CNS can be potentiated. Decreased mental alertness can occur.

     Tricyclic antidepressants can exacerbate schizophrenia or manic symptoms of bipolar disorder because of the drugs' effects on the CNS. Bipolar disorder patients who are not concomitantly treated with an anticyclic medication are likely to switch from depression to mania, and some schizophrenic patients can experience exacerbation of psychosis.

     Tricyclic antidepressants should be used with extreme caution in patients with a preexisting seizure disorder because these drugs can lower the seizure threshold.

     Tricyclic antidepressants should be used with caution in patients with Parkinson's disease. Tricyclic antidepressants rarely can induce or worsen extrapyramidal symptoms. In addition, involuntary movements, which appear to be tardive dyskinesia, can occur.

     Patients with respiratory depression should be treated cautiously with tricyclic antidepressants because of additive CNS-depressant effects.

     Tricyclic antidepressants should be used with caution in patients (especially children and elderly) with cardiac disease because of the alterations in ECG patterns. Many adverse cardiovascular effects are associated with the use of tricyclic antidepressant drugs, and they can lead to complete cardiac collapse and sudden death. Although the risk of these events occurring is higher after acute overdose, patients with cardiovascular disease should be closely monitored and regular ECG tracings made. Tricyclic antidepressants should not be given to patients who are in the acute recovery phase following myocardial infarction; this could cause sudden death.

     Asthma can be aggravated by administering tricyclic antidepressants to patients with the disease.

     Tricyclic antidepressants are known to produce an allergic response in some patients. There appears to be cross-sensitivity, and caution should be used when changing from one tricyclic antidepressant to another. Alternative therapy should be considered. Tricyclic antidepressants can also display cross-sensitivity to carbamazepine, maprotiline, or trazodone.

     Tricyclic antidepressant therapy should be discontinued several days before elective surgery because of the risk of hypertensive episodes.

     On rare occasions, agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, or purpura have been reported with tricyclic antidepressants. Any patient with symptoms of blood dyscrasia (sore throat, fever, bruising, etc.) should have immediate laboratory studies performed and suitable therapy initiated. Use tricyclic antidepressants cautiously in patients with preexisting hematological disease.

     Intramuscular injections should be administered cautiously to patients receiving amitriptyline. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to amitriptyline therapy.

     Tricyclic antidepressants should be used with caution in patients with hepatic disease. These agents have caused hepatitis and jaundice, which are reversible on discontinuation of the drug. Hepatic failure and death have occurred when tricyclic antidepressants were continued. Liver-function tests should be performed and the drug discontinued if there is persistent elevation of enzymes. Metabolism of tricyclic antidepressants may be altered in patients with hepatic impairment.

     Patients may be more prone to sunburn during therapy with a tricyclic antidepressant. Suitable precautions should be taken such as wearing long-sleeved clothing and a hat, and routinely applying a sunblock with an SPF >=15.

     Tricyclic antidepressants should be used with caution in patients who have hyperthyroidism or are receiving thyroid drugs. Concomitant use with thyroid drugs can produce cardiac arrhythmias. Hypothyroidism that is untreated will prevent adequate response to antidepressant therapy. Thyroid agents also can accelerate the onset of the response to tricyclic antidepressants.

     Tricyclic antidepressants affect blood glucose concentrations because of their effect on the endocrine system, so they should be used with caution in patients with diabetes mellitus. Tricyclic antidepressants are not recommended for use during pregnancy, unless the possible benefits outweigh the risks. Amitriptyline is classified as FDA category C. Patients should be told about the risks to the neonate: possible fetal abnormality, delayed development, or withdrawal symptoms. Because these drugs are excreted into breast milk, the benefits and risks of breast-feeding should be carefully weighed if tricyclic antidepressants are needed in the mother.

     All antidepressants should be used with caution in depressed patients because of the possibility of suicidal ideation. Close monitoring of the patient is essential during the initial stages of therapy and amitriptyline prescribed in the smallest quantity consistent with good management.

     Intrathecal administration of metrizamide to a patient taking amitriptyline can increase the risk of developing seizures. Tricyclic antidepressant therapy should be discontinued 48 hours before, and not restarted until 24 hours after, myelography.

 

PATIENT INFORMATION

(Amitriptyline tablets)

What do amitriptyline tablets do?
AMITRIPTYLINE (Elavil®, Endep®) is an antidepressant. Amitriptyline can lift your spirits by treating your depression, especially if it is associated with sleep disturbance. Improvement of sleep patterns can be the first benefit of treatment. Your doctor may prescribe amitriptyline for other conditions, such as relief from nerve pain. Generic amitriptyline tablets are available.

What should my health care professional know before I take amitriptyline? They need to know if you have any of these conditions:

  • an alcohol problem
  • asthma, difficulty breathing
  • blood disorders or disease
  • diabetes
  • difficulty passing urine, prostate trouble
  • glaucoma
  • having intramuscular injections
  • heart disease or previous heart attack
  • liver disease
  • over active thyroid
  • Parkinson's disease oschizophrenia
  • seizures (convulsions)
  • stomach disease
  • an unusual or allergic reaction to amitriptyline, other medicines, foods, dyes, or preservatives
  • pregnant or trying to get pregnant
  • breast-feeding

How should I take this medicine?
Take amitriptyline tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. You can take the tablets with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.

Special precautions for use in children: This medicine is not for general use in children under 12 years old, but may be prescribed in special circumstances by the doctor.

Adolescents, 12 to 18 years old, and elderly patients over 65 years old may have a stronger reaction to this medicine and need smaller doses.

What if I miss a dose?
If you miss a dose normally taken at bedtime to avoid daytime drowsiness, it may be better to miss that dose. If you take more than one dose a day and miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Follow your doctor's advice on missed doses. Do not take double or extra doses.

What other medicines can interact with amitriptyline?
Amitriptyline can interact with many other medicines. An interaction can be very important or fairly insignificant. Make sure your doctor knows about all other medicines you are taking. The most important medicines are listed below:

  • alcohol
  • barbiturate medicines for inducing sleep or treating seizures (convulsions)
  • blood thinners
  • cimetidine and ranitidine
  • clonidine
  • diltiazem
  • female hormones, including contraceptive or birth control pills
  • lithium
  • medicines for anxiety or sleeping problems, such as diazepam or temazepam
  • medicines for colds and breathing difficulties
  • medicines for hay fever and other allergies
  • medicines for mental problems and psychotic disturbances
  • medicines for movement abnormalities as in Parkinson's disease, or for gastrointestinal problems
  • other medicines for mental depression oseizure (convulsion) or epilepsy medicine
  • thyroid hormones

Tell your doctor or pharmacist-
About all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking amitriptyline?
Serious side effects with amitriptyline include:

  • abnormal production of milk in females
  • blurred vision or eye pain
  • breast enlargement in both males and females
  • confusion, hallucinations (seeing or hearing things that are not really there)
  • difficulty breathing
  • fainting spells
  • fever with increased sweating
  • irregular or fast, pounding heartbeat, palpitations
  • muscle stiffness, or spasms
  • pain or difficulty passing urine, loss of bladder control oseizures (convulsions)
  • sexual difficulties (decreased sexual ability or desire, difficulty ejaculating)
  • stomach pain
  • swelling of the testicles
  • tingling, pain, or numbness in the feet or hands
  • unusual weakness or tiredness
  • yellowing of the eyes or skin

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with amitriptyline include:

  • oanxiety
  • oconstipation, or diarrhea
  • odrowsiness or dizziness
  • odry mouth
  • oincreased sensitivity of the skin to sun or ultraviolet light
  • oloss of appetite
  • onausea, vomiting
  • oskin rash or itching
  • oweight gain or loss

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take amitriptyline?
Visit your doctor for regular checks on your progress. It can take several days before you feel the full effect of amitriptyline.

If you have been taking amitriptyline regularly for some time, do not suddenly stop taking it. You must gradually reduce the dose or you may get severe side effects. Ask your doctor for advice. Even after you stop taking amitriptyline it can still affect your body for several days.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how amitriptyline affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol may increase dizziness and drowsiness. Avoid alcoholic drinks.

Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects.

Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help.

Amitripyline may cause dry eyes and blurred vision. If you wear contact lenses you may feel some discomfort. Lubricating drops may help. See your ophthalmologist if the problem does not go away or is severe.

Amitriptyline may make your skin more sensitive to the sun. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.

If you are diabetic, check your blood sugar more often than usual, especially during the first few weeks of treatment with amitriptyline. Amitriptyline can affect blood glucose (sugar) levels. Call your doctor for advice if you notice a change in the results of blood or urine glucose tests.

If you are going to have surgery, tell your doctor or dentist that you are taking amitriptyline.

Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30°C (59 and 86°F). Throw away any unused medicine after the expiration date.

Interactions-

  • amantadine
  • anticonvulsants
  • antimuscarinics
  • bupropion
  • carbinoxamine
  • chlorpromazine
  • cimetidine
  • cisapride
  • clemastine
  • clonidine
  • clozapine
  • cocaine
  • cyclobenzaprine
  • diphenhydramine
  • disopyramide
  • disulfiram
  • erythromycin
  • ethanol
  • furazolidone
  • guanabenz
  • guanadrel
  • guanethidine
  • guanfacine
  • levodopa
  • MAOIs
  • maprotiline
  • mesoridazine
  • methdilazine
  • methyldopa
  • metoclopramide
  • naphazoline
  • opiate agonists
  • oxymetazoline
  • parasympathomimetics
  • procainamide
  • promazine
  • promethazine
  • reserpine
  • selegiline
  • SSRIs
  • sympathomimetics
  • thioridazine
  • thyroid hormones
  • triflupromazine
  • trimeprazine
  • trimipramine
  • xylometazoline

Barbiturates and carbamazepine induce hepatic microsomal enzymes and increase the metabolism of tricyclic antidepressants. Plasma concentrations of the tricyclic antidepressant are reduced and may require an increased dosage to achieve equivalent therapeutic effects. In addition, tricyclic antidepressants can lower the seizure threshold, however, this is a concern mainly after acute overdoses. Nevertheless, concomitant use with anticonvulsants may require increased concentrations of the anticonvulsant to achieve equivalent effects.

Cimetidine can inhibit the systemic clearance of tricyclic antidepressants, resulting in increased plasma levels of the antidepressant. In some cases, clinical symptoms of toxicity were observed. Patients should be monitored for tricyclic antidepressant toxicity if cimetidine is added. It does not appear that the other H2-receptor antagonists affect the pharmacokinetics of the tricyclics.

A potentially serious interaction can occur between clonidine and tricyclic antidepressants (reported with desipramine and imipramine). Administration of tricyclic antidepressants to hypertensive patients stabilized on clonidine can lead to hypertension, especially during the second week of tricyclic antidepressant therapy. Occasionally, the hypertension will occur within the first few days of tricyclic antidepressant therapy. Guanabenz and guanfacine possess a mechanism of action similar to clonidine, although the alpha2/alpha1 affinity ratio is much higher for guanfacine than the other two (agonism at alpha2-receptors reduces blood pressure, while agonism at alpha1-receptors increases blood pressure.) Despite an absence of reports, clinicians should assume that there is the possibility for a similar hypertensive response if a tricyclic antidepressant is added to patients stabilized on either guanabenz or guanfacine.

The risk of developing cardiac arrhythmias is increased when cocaine is used in patients receiving tricyclic antidepressants. If local anesthesia with cocaine is essential in a patient receiving a tricyclic antidepressant, lower doses of cocaine and/or electrocardiographic monitoring may be necessary.

Limited data suggest that tricyclic antidepressants used concomitantly with disulfiram can produce transient delirium. This has been reported with amitriptyline. Pharmacokinetic interactions have been noted between disulfiram and imipramine, and disulfiram and desipramine (imipramine's metabolite) but the clinical significance of these data are uncertain. Disulfiram is known to inhibit cytochrome isozyme CYP2C9, the enzyme responsible for metabolism of amitriptyline and imipramine.

Ethanol or other CNS depressants should be combined cautiously with tricyclic antidepressants because this could cause additive depressant effects and possible respiratory depression or hypotension.

Tricyclic antidepressants (with the exception of doxepin <150 mg/day) block the uptake of guanadrel, guanethidine, and methyldopa into norepinephrine neurons, preventing the expected antihypertensive effects. The antihypertensive effects of reserpine and other rauwolfia alkaloids may also be decreased in the presence of tricyclic antidepressants.

The antimuscarinic activity of tricyclic antidepressants can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.

The pressor response to norepinephrine infusions is greatly exaggerated in patients currently receiving tricyclic antidepressants. One drug information reference suggests that tricyclics potentiate the pharmacologic effects of direct-acting sympathomimetics (e.g., epinephrine and norepinephrine) but decrease the pressor response to indirect-acting sympathomimetics (e.g., amphetamines), however, the data are not consistent. Concomitant use of tricyclic antidepressants with other sympathomimetics (e.g., isoproterenol, or phenylephrine), therefore, should be avoided whenever possible. Clinicians should presume that the pressor effects of ophthalmic or nasal vasoconstrictors (e.g., naphazoline, oxymetazoline, phenylephrine, or xylometazoline) may be potentiated by tricyclic antidepressants. Methylphenidate has been reported to inhibit the metabolism of imipramine in vitro, however, the clinical significance of this is lacking.

Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties are used concomitantly with other antimuscarinics. The following drugs are known to possess antimuscarinic properties and should be used together cautiously: atropine and other similar antimuscarinics; some H1-blockers (e.g., carbinoxamine, clemastine, diphenhydramine, methdilazine, promethazine, trimeprazine); some phenothiazines (e.g., mesoridazine, promazine, thioridazine, triflupromazine); some tricyclic antidepressants (e.g., amitriptyline, amoxapine, clomipramine, protriptyline); and other drugs with substantial antimuscarinic properties such as clozapine, cyclobenzaprine, and disopyramide. Drugs with minor degrees of anticholinergic effects include amantadine, bupropion, chlorpromazine, doxepin, imipramine, maprotiline, nortriptyline, procainamide, and trimipramine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.

In addition to additive drowsiness, combining tricyclic antidepressants with opiate agonists may lead to additive effects on intestinal motility or bladder function.

The anticholinergic (i.e., antimuscarinic) effects of tricyclic antidepressants vary; amitriptyline exhibits the strongest and desipramine exhibits the weakest. Depending on the specific agent, this antimuscarinic action may interfere with the therapeutic effects of prokinetic agents such as cisapride, erythromycin (when used to improve GI motility), or metoclopramide. Amitriptyline may also antagonize some of the effects of parasympathomimetics such as bethanechol or cholinesterase inhibitors such as neostigmine, however, bethanechol has been used therapeutically to offset some of the adverse antimuscarinic effects of tricyclic antidepressants.

Concurrent use of monoamine oxidase inhibitors (MAOIs), such as furazolidone, phenelzine, procarbazine, selegiline, or tranylcypromine, with tricyclic antidepressants can cause hyperpyrexia, hypertension, or seizures. In the rare patient for whom this combination therapy is necessary, the interaction can be minimized by initiating therapy with a tricyclic antidepressant and then beginning MAOI therapy at low doses, followed by a very gradual increase. The tricyclic antidepressant should inhibit the uptake of tyramine from food in the GI tract; subsequent addition of a MAOI should not lead to high levels of tyramine. Conversely, tricyclic antidepressants should not be added to an exisiting MAOI regimen because the reuptake blockade will be unopposed due to the existing inhibition of the main elimination pathway. An interval of 14 days is recommended between cessation of an irreversible MAOI agent and initiation of tricyclic antidepressant therapy.

Clinicians should be alert for pharmacokinetic interactions between tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit isozymes of the cytochrome P-450 mixed-function oxidase system including CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the tricyclic antidepressants. Cytochrome CYP2D6 is impaired most by fluoxetine and least by sertraline and is the isozyme most responsible for metabolism of tricyclic antidepressants. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. The CYP2D6 isozyme is a common pathway for both of these drugs and norfluoxetine also inhibits this enzyme. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7—9 days).

Older literature describes a variety of responses when tricyclic antidepressants are used concomitantly with thyroid hormones. One limited study states that small doses of thyroid hormone accelerated the onset of action of tricyclic antidepressants while several case reports have described cardiovascular toxicity as a result of this drug combination while still other reports describe no interaction. Although this drug combination appears to be safe, clinicians should be aware of the remote possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.

Animal data indicate that some tricyclic antidepressants (amitriptyline, nortriptyline) can inhibit the metabolism of warfarin, however, clinical data are extremely limited. A major review of warfarin drug interactions published in 1994 did not include tricyclic antidepressants as an offending agent. It appears that warfarin can be used safely in patients taking tricyclic antidepressants.

Adverse Reactions-

  • abdominal pain
  • anorexia
  • anxiety
  • blurred vision
  • breast enlargement
  • confusion
  • constipation
  • cycloplegia
  • diarrhea
  • dizziness
  • drowsiness
  • EEG changes
  • ejaculation dysfunction
  • erythema
  • fever
  • galactorrhea
  • gynecomastia
  • heart failure
  • hypertension
  • ileus
  • impotence
  • jaundice
  • libido decrease
  • mydriasis
  • myocardial infarction
  • nausea/vomiting
  • ocular hypertension
  • orthostatic hypotension
  • palpitations
  • parkinsonism
  • photosensitivity
  • PR prolongation opruritus
  • QT prolongation
  • sedation
  • seizures
  • SIADH
  • stroke
  • testicular swelling
  • torsade de pointes
  • tremor
  • urinary retention
  • urticaria
  • vasculitis
  • ventricular tachycardia
  • withdrawal
  • xerostomia

A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants due to their direct quinidine-like action, their potent anticholinergic properties, and their ability to potentiate norepinephrine. Ventricular tachycardia, palpitations, hypertension, and orthostatic hypotension all can be precipitated, with the possibility of more severe reactions occurring such as myocardial infarction, congestive heart failure, or stroke. Imipramine, and possibly other tricyclic antidepressants, can cause both PR prolongation and QT prolongation. Imipramine and nortriptyline are known to prolong the QRS interval. Other tricyclics would be expected to produce similar ECG changes. The cardiovascular response to tricyclic antidepressants depends on the specific agent and the dose. Although all tricyclic antidepressants are thought to be proarrhythmic after acute overdoses, at therapeutic doses, their actions on the conducting system of the heart may vary. Imipramine has been utilized therapeutically for its antiarrhythmic effect. The cardiovascular response to tricyclic antidepressants is varied, and patients most at risk have preexisting cardiovascular disease. While amitriptyline is included on lists of drugs associated with either QT prolongation or torsade de pointes, this reaction is rare at therapeutic doses.

Drowsiness is the most frequent adverse CNS effect during therapy with tricyclic antidepressants. Sedation can be made into a desirable effect by administration of the tricyclic antidepressant at bedtime, which minimizes undesirable drowsiness and sedation during the day. Dizziness is usually due to orthostatic hypotension and can be reduced by having the patient change positions more slowly. Some patients exhibit excitation and anxiety. Confusion is most apparent in the elderly.

Peripheral nervous system adverse reactions can occur during therapy with tricyclic antidepressants. Tremor may result from norepinephrine reuptake blockade. Rarely, extrapyramidal symptoms can occur in both young and elderly patients. Parkinsonism is more likely to occur in the elderly, especially if they are receiving high doses.

Seizures and EEG changes have been observed more commonly in children than in adults during therapy with tricyclic antidepressants. Patients who have a preexisting seizure disorder may require increased concentrations of their anticonvulsant to maintain seizure control.

Ocular manifestations of the anticholinergic actions of tricyclic antidepressants can result in blurred vision due to cycloplegia, mydriasis, and increased intraocular pressure. Ocular hypertension can precipitate a crisis in patients with angle-closure glaucoma. Ophthalmological examination is recommended when there are visual changes.

Gastrointestinal manifestations of tricyclic antidepressants' anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, adynamic ileus, abdominal pain or cramps, nausea/vomiting, anorexia, diarrhea, and jaundice. Constipation is more commonly observed in elderly patients. If these symptoms become severe, discontinuation of the drug may be required.

Allergic reactions to tricyclic antidepressants can include photosensitivity, vasculitis, erythema, urticaria, fever, and/or pruritus. Fever also may indicate a blood dyscrasia.

The effects of tricyclic antidepressants on the endocrine system can result in sexual dysfunction including libido decrease, impotence, testicular swelling, ejaculation dysfunction (no or painful ejaculation), breast enlargement, and galactorrhea in females or gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.

Patients receiving prolonged therapy with high doses of tricyclic antidepressants can experience withdrawal symptoms following abrupt discontinuation of the tricyclic antidepressant. Symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea can occur. This particularly occurs with the tertiary amine tricyclic antidepressants: amitriptyline, imipramine, clomipramine, trimipramine, and doxepin.

Product Identification-

Elavil® Tablets

  • Zeneca Pharmaceuticals
    Available as 10, 25, 50, 75, 100 or 150 mg of amitriptyline hydrochloride.
    10 mg
  • tablet
  • blue
  • round
  • "ELAVIL"
  • "STUART 40"
    25 mg
  • tablet
  • yellow
  • round
  • "ELAVIL"
  • "STUART 45"
    50 mg
  • tablet
  • beige
  • round
  • "ELAVIL"
  • "STUART 41"
    75 mg
  • tablet
  • round
  • oorange
  • "ELAVIL"
  • "STUART 42"
    100 mg
  • tablet
  • pink
  • round
  • "ELAVIL"
  • "STUART 43"
    150 mg
  • tablet
  • oblong
  • blue
  • "ELAVIL"
  • "STUART 47"

Elavil® Injection

  • Zeneca Pharmaceuticals
    Available as 10 mg of amitriptyline hydrochloride per ml, in 10 ml vials.

Endep® Tablets

  • Roche Products
    Available as 10, 25, 50, 75, 100 or 150 mg amitrityline hydrochloride.

Amitriptyline Tablets

  • Mylan
    Available as 10, 25, 50, 75, 100, or 150 mg of amitriptyline hydrochloride.
    75 mg
  • tablet
  • round
  • blue
  • "M 37"

Amitriptyline Tablets

  • Sidmak
    Available as 10, 25 or 50 mg of amitriptyline hydrochloride.
    10 mg
  • tablet
  • round
  • pink
  • "SL"
  • "66"
    25 mg
  • tablet
  • round
  • green
  • "SL"
  • "67"
    50 mg
  • tablet
  • round
  • brown
  • "SL"
  • "368"