The P-I-E-N-O Parkinsn's List Drug Database
imipramine / TofranilTM
ANTIDEPRESSANT:
TRICYCLIC
Description: Imipramine is an antidepressant drug of the dibenzazepine type, referred to as a tricyclic because of its chemical structure. Imipramine was first synthesized in the late 1940s. It is used to treat depression and childhood enuresis. Imipramine also has been used in the management of neurogenic painư, attention-deficit hyperactivity disorder (ADHD) in children over age 6, eating disorders, and panic or phobic disorder, although these are not FDA-approved uses. Imipramine was approved by the FDA for use for depression in 1959 and for enuresis in 1973. It is considered the prototype tricyclic antidepressant.
Mechanism of Action: The precise mechanism of action of tricyclic antidepressants is not fully understood. It is believed that imipramine and other tricyclic antidepressants interfere with the reuptake of various neurotransmitters at the neuronal membrane. This interference potentiates the neurotransmitter at the postsynaptic receptor. Imipramine, a tertiary amine, inhibits the reuptake of serotonin more than do secondary amines, which inhibit norepinephrine. Because imipramine is metabolized to a secondary amine (desipramine), however, classification according to neurotransmitter type does not further elucidate imipramine's action.
Mood elevation occurs only in depressed individuals and may require 2-3 weeks of therapy. Adverse effects, however, can be seen within a few hours. The delayed antidepressant effect has caused researchers to reconsider the reuptake theory because blockade of neurotransmitter reuptake occurs rapidly. Improvement in the depressive state may result from the correction of an abnormal neurotransmitter-receptor relationship. Monoamine oxidase is not inhibited by tricyclic drugs. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, being moderate with imipramine, due to strong binding affinity for histamine HA-receptors, and the seizure threshold may be lowered. Imipramine also blocks acetylcholine receptors, and this may be responsible for its efficacy in the treatment of enuresis. Arrhythmias associated with imipramine usually occur after toxic doses, and they may result from the combination of the direct quinidine-like effect on cardiac function along with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose may result from imipramine's effect on the endocrine system.
Pharmacokinetics: Imipramine appears to be completely absorbed from the gut following oral administration, and peak plasma concentration is achieved within 1-2 hours. The bioavailability of imipramine, however, ranges from 22-77% due to significant presystemic elimination, consistent with other tricyclic antidepressants. Due to poor correlation between tricyclic blood levels and clinical response, and the fact that imipramine is metabolized to an active metabolite, information relating to plasma concentrations is difficult to interpret. Distribution throughout the body is extensive. Imipramine is 85-95% proteinbound, and its plasma half-life ranges from 8-16 hours. Metabolism of imipramine to desipramine occurs in the liver. Enterohepatic circulation may occur, as well as secretion of both unchanged drug and metabolites into gastric juice. Due to extensive metabolism, less than 5% of unchanged imipramine is eliminated in the urine. A small amount of excretion takes place via the bile and feces.
CONTRAINDICATIONS/PRECAUTIONS:
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.
Following prolonged therapy in 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 who have 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 of the seizure threshold could be lowered.
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 CNSdepressant 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 could lead to complete cardiac collapse and sudden death. Although these events are more likely to occur 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; sudden death could occur.
Asthma can be aggravated by administering tricyclic antidepressants to patients with the disease. Special care should be taken in administering parenteral imipramine to patients with a known sulfite hypersensitivity. Sulfites can precipitate an asthmatic attack.
Tricyclic antidepressants are known to produce an allergic response in some patients. There appears to be crosssensitivity, so caution should be used when changing from one tricyclic antidepressant to another. Alternative therapy should be considered. 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 a 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 imipramine. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to imipramine therapy.
Tricyclic antidepressants should be used with caution in patients with hepatic disease. Use of tricyclic antidepressants has caused hepatitis and jaundice, which are reversible on discontinuation of the drug. Hepatic failure and death have occurred when tricyclic antidepressants were continued. Liverfunction 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 with hyperthyroidism or in patients 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 and should be used with caution in patients with diabetes mellitus.
Imipramine is classified as a pregnancy category D drug. Tricyclic antidepressants are not recommended for use during pregnancy unless the possible benefits outweigh the risks. Patients should be made aware of the risks to the neonate: possible fetal abnormality, delayed development, or withdrawal symptoms. In addition, maternal nortriptyline (chemically similar to imipramine) use has been associated with neonatal urinary retention. Because the 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 imipramine prescribed in the smallest quantity consistent with good management.
DRUG INTERACTIONS: Concurrent use of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs), such as furazolidone, isocarboxazid, phenelzine, procarbazine, selegiline, or tranylcypromine, can cause hyperpyrexia, hypertension, or seizures. In the rare patients who need this combination therapy, 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; the subsequent addition of an 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.
Tricyclic antidepressants (with the exception of doxepin in doses <150 mg/day) block the uptake of guanadrel, guanethidine, and methyldopa into norepinephrine neurons, preventing the expected antihypertensive effects. Reserpine and other rauwolfia alkaloids can have decreased antihypertensive effects in the presence of tricyclic antidepressants.
Guanabenz use can increase the circulation of catecholamines. Concomitant use of tricyclic antidepressants 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.
Labetalol, when used with tricyclic antidepressants, has been reported to cause an increased incidence of tremor.
Clonidine's antihypertensive effect can be reduced by tricyclic antidepressants (reported with imipramine and desipramine). Concomitant use of tricyclic antidepressants 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. In addition, concurrent administration of a tricyclic antidepressant (amitriptyline) and clonidine in rats has produced corneal lesions within 5 days.
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. Barbiturates and carbamazepine induce hepatic microsomal enzymes and increase the metabolism of tricyclic antidepressants. The tricyclic antidepressants' plasma concentrations are reduced and may require an increase in dosage to achieve equivalent therapeutic effects.
Benzodiazepines (alprazolam and diazepam) have been reported to increase the concentrations of tricyclic antidepressants (imipramine and amitriptyline) or metabolites (desipramine and nortriptyline) when coadministered. This is a commonly used drug combination and is considered to be safe, as long as patients are monitored for excessive adverse effects from either agent. Benzodiazepines and tricyclic antidepressants will produce additive CNS depression.
Serotonin specific reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine, and fluvoxamine, are another class of antidepressants that have been reported to cause symptoms of tricyclic antidepressant toxicity when used with a tricyclic antidepressant. The mechanism of this interaction is poorly understood but is believed to involve specific isoenzymes of the cytochrome P-450 mixed-function oxidase system. The most critical and well-studied pathway is 2D6. Cytochrome P-450 2D6 is impaired most by fluoxetine and least by sertraline. Fluvoxamine appears to inhibit the 1A2 pathway. Patients receiving an SSRI and tricyclic antidepressant should be monitored closely for excessive adverse effects from either agent.
Tricyclic antidepressants can lower the seizure threshold. Concomitant use with anticonvulsants may require increased concentrations of the anticonvulsant to achieve equivalent effects.
Tricyclic antidepressants used concomitantly with disulfiram or ethchlorvynol can produce transient delirium.
Cholestyramine can decrease the serum concentrations of imipramine. While it is logical to conclude that staggering the times of administration may avoid this interaction, doing so did not prevent a similar interaction between cholestyramine and doxepin even when the doses were separated by 6 hours. Until more data are available, clinicians should avoid using cholestyramine in patients stabilized on doxepin or imipramine.
Tricyclic antidepressants used concomitantly with strong anticholinergic agents, such as anticholinergics; HA-blockers; cyclobenzaprine; antipsychotics (haloperidol, loxapine, molindone, phenothiazines, or thioxanthenes); amoxapine; or metoclopramide, will increase the anticholinergic and sedative effects. Concomitant therapy should be avoided whenever possible. If necessary, doses of both drugs should be started lower and increased cautiously with careful monitoring. Tricyclic antidepressants can potentiate cardiac arrhythmias if used concurrently with pimozide.
Pressor effects of ophthalmic or nasal vasoconstrictors (naphazoline, oxymetazoline, phenylephrine, or xylometazoline) can be potentiated by tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics (isoproterenol, phenylephrine, norepinephrine, epinephrine, or amphetamines) can cause adverse cardiovascular effects such as arrhythmias, tachycardia, or severe hypertension or hyperpyrexia.
Tricyclic antidepressant metabolism can be inhibited by cimetidine or ranitidine, resulting in increased plasma levels of the tricyclic antidepressant and, possibly, toxicity. Patients should be closely observed for toxic effects such as orthostatic hypotension or sedation.
Oral contraceptives, fluoxetine, erythromycin, or methylphenidate can inhibit the hepatic metabolism of tricyclic antidepressants and can increase the risk of tricyclic antidepressant toxicity if used concurrently.
The risk of developing agranulocytosis is increased if tricyclic antidepressant drugs are used concurrently with antithyroid agents.
Tricyclic antidepressants used concomitantly with thyroid hormones can increase the therapeutic and toxic effects (such as arrhythmias and CNS stimulation) of both medicines.
Diltiazem has been shown to increase imipramine area-under-thecurve in healthy volunteers. Although the clinical impact of this pharmacokinetic interaction is unclear, diltiazem should be used cautiously in patients stabilized on imipramine.
The anticholinergic 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 prothrombin time (and presumably INR) of patients stabilized on warfarin has been reported to increase from tricyclic antidepressants (amitriptyline). Similarly, dicumarol plasma concentrations have been observed to increase when tricyclic antidepressants (amitriptyline and nortriptyline) were added. The mechanism is not understood, but it may be due to anticholinergic effects decreasing gastrointestinal motility, leading to increased bioavailability of the oral anticoagulant.
ADVERSE REACTIONS: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants due to their direct quinidinelike 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.
Drowsiness is the most frequent adverse CNS effect during therapy with tricyclic antidepressants. Sedation can be a made into a desirable effect by administering the tricyclic antidepressant at bedtime, which minimizes any 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 can 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 include blurred vision due to cycloplegia, mydriasis, and increased intraocular pressure. Increased intraocular pressure 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 symptons become severe, withdrawal of the drug may be necessary.
Allergic reactions to tricyclic antidepressants can include photosensitivity, vasculitis, erythema, urticaria, fever, and/or pruritus. Fever also can 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 (painful or delayed ejaculation), orgasm dysfunction (delayed orgasm),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.
Imipramine may cause hematologic adverse reactions. These effects inclue agranulocytosis, eosinophilia, purpura, thrombocytopenia, and leukopenia.
PATIENT INFORMATION:
What do imipramine tablets do?
Imipramine (TofranilTM ) is an antidepressant. Imipramine can help to lift your spirits by treating your depression. Imipramine can help children who have a nighttime bed-wetting problem. Generic imipramine tablets are available.
What should my doctor, dentist, or pharmacist know before I take imipramine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take imipramine tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. 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 children under 6 years old for the treatment of bed-wetting.
Elderly patients over 65 years old and adolescents may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. If children take a single dose of imipramine for bed-wetting problems and miss a dose, skip that dose and resume normal dosing schedule the following day.
What other medicines can interact with imipramine?
Imipramine 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:
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 imipramine?
Serious side effects with imipramine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with imipramine include:
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 imipramine?
Visit your doctor for regular checks on your progress. It can take several days or weeks before you feel the full effect of imipramine. If you have been taking imipramine 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 imipramine 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 imipramine 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 can 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.
Imipramine 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.
Imipramine can affect blood glucose (sugar) levels. If you are a diabetic, check your blood sugar more often than usual, especially during the first few weeks of imipramine treatment. 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 imipramine.
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 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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