The P-I-E-N-O Parkinsn's List Drug Database
nortriptyline / PamelorTM
ANTIDEPRESSANt:
Tricyclic
Description: Nortriptyline is a tricyclic antidepressant of the dibenzocycloheptene type and is the active metabolite of amitriptyline. Nortriptyline is similar to protriptyline. Nortriptyline is used to treat depression and for the management of chronic, severe neurogenic pain. Some efficacy has been reported with nortriptyline in phobic disorderư and panic disorderư. Nortriptyline was approved as an antidepressant by the FDA in 1964.
Mechanism of Action: The concise action of tricyclic antidepressants is not fully understood, but it is believed that the most important effect is the enhancement of the actions of norepinephrine and serotonin caused by blocking the reuptake of various neurotransmitters at the neuronal membrane. Nortriptyline is more likely to inhibit the reuptake of serotonin than norepinephrine. There is more likelihood of orthostatic hypotension occurring with nortriptyline than with other tricyclics. Recent evidence suggests that the upset of monoamine output seen in depressed patients may be regulated by antidepressants following long-term treatment due to their action on œ-adrenergic receptors. This action on œ-receptors may be a better explanation than the reuptake theory for their antidepressant effects.
Monoamine oxidase is not inhibited by nortriptyline. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced and is low to moderate for nortriptyline, and the seizure threshold can be lowered. Anticholinergic activity is strong and may be responsible for the inhibition of urination in the treatment of enuresis. Cardiac dysrhythmias may result from the direct quinidine-like effect on cardiac function in combination with anticholinergic activity and the potentiation of norepinephrine. Changes in sex hormone concentrations and blood glucose may result from the effect of nortriptyline on the endocrine system.
Pharmacokinetics: Nortriptyline is well absorbed from the GI tract, but there may be considerable variation in individual response. Lower doses are usually sufficient in adolescent or geriatric patients. The full antidepressant effects can take several weeks to stabilize, but adverse effects can be seen within a few hours. Peak plasma concentrations are obtained within 7-8.5 hours following oral administration. Tricyclic antidepressants are highly protein-bound in plasma and tissues. Because the tricyclic antidepressants are long-acting, a single daily dose may be given to improve patient compliance.
Nortriptyline is distributed into the lungs, heart, brain, and liver. Nortriptyline is known to cross the placenta and is also distributed into breast milk. Plasma half-life of nortriptyline is between 16 and 90 hours. Metabolism takes place in the liver. Nortriptyline is lipophilic, facilitating crossing of the bloodbrain barrier. There may be enterohepatic circulation and secretion of both unchanged drug and metabolites into gastric juice. Like nortriptyline, lipophilic metabolites are most likely to be reabsorbed and further metabolized. About one-third of a single dose is excreted in urine as metabolites within 24 hours. A small amount is excreted in 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, 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 with a history of alcoholism or who may use alcohol or other sedative medications because the depressant effects on the CNS can be potentiated. There may be decreased mental alertness.
Tricyclic antidepressants can exacerbate schizophrenia or manic symptoms of bipolar disorder because of the effects of the drug on the CNS. Bipolar disorder patients 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, which 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 is possible.
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 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 for several days before elective surgery because of the risk of hypertensive episodes.
On rare occasions, agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, or purpura has 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 nortriptyline. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to nortriptyline therapy.
Tricyclic antidepressants should be used with caution in patients with hepatic disease. Hepatitis and jaundice have resulted from use of tricyclic antidepressants, 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 can 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.
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. The benefits and risks of breast-feeding should be carefully weighed if tricyclic antidepressants are needed in the mother because the drugs are excreted into breast milk.
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 nortriptyline prescribed in the smallest quantity consistent with good management.
DRUG INTERACTIONS: Monoamine oxidase inhibitors (MAOIs), including furazolidone, isocarboxazid, phenelzine, procarbazine, selegiline, or tranylcypromine, concurrently used with tricyclic antidepressants can cause hyperpyrexia, hypertension, or seizures. In the rare cases in 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 an MAOI should not lead to high levels of tyramine. Conversely, tricyclic antidepressants should not be added to an existing 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 can lead to increased 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 in combination with tricyclic antidepressants should be used with caution because of the 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 increased 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 the patient is monitored for excessive adverse effects from either agent. Benzodiazepines and tricyclic antidepressants will produce additive CNS depression.
Selective serotonin 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. 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.
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 result in 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 that could lead to 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.
Amitriptyline can increase the risk of developing cardiac arrhythmias when used in conjunction with cocaine. Since amitriptyline is metabolized to nortriptyline, similar reactions may occur with nortriptyline. If local anesthesia with cocaine is essential in a patient receiving amitriptyline, lower doses of cocaine and/or electrocardiographic monitoring may be necessary.
Intrathecal administration of metrizamide to a patient taking amitriptyline can increase the risk of seizures. Since amitriptyline is metabolized to nortriptyline, similar reactions may occur with nortriptyline. Tricyclic antidepressant therapy should be discontinued 48 hours before, and not restarted until 24 hours after, myelography.
Tricyclic antidepressants used concomitantly with thyroid hormones can increase therapeutic and toxic effects (such as arrhythmias and CNS stimulation) of both medicines.
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 use of 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 may be due to anticholinergic effects decreasing gastrointestinal motility, leading to increased bioavailability of the oral anticoagulant.
ADVERSE REACTIONS:
PATIENT INFORMATION:
What do nortriptyline capsules do?
Nortriptyline (PamelorTM ) is an antidepressant. Nortriptyline can help to lift your spirits by treating your depression. Generic nortriptyline capsules are not yet available.
What should my doctor, dentist, or pharmacist know before I take nortriptyline?
They need to know if you have any of these conditions:
How should I take this medicine?
Take nortriptyline capsules by mouth. Follow the directions on the prescription label. Swallow the capsules 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 use in children under 12 years old. Safe and effective use has not been established.
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.
What other medicines can interact with nortriptyline?
Nortriptyline 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 nortriptyline?
Serious side effects with nortriptyline include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with nortriptyline 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 nortriptyline?
Visit your doctor for regular checks on your progress. It can take several days or weeks before you feel the full effect of nortriptyline. If you have been taking nortriptyline 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 nortriptyline 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 nortriptyline 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.
Nortriptyline 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.
Nortriptyline 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 nortriptyline 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 nortriptyline.
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 below 30C (86F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
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