Drug Interactions between amitriptyline / perphenazine and Mudrane GG

GENERALLY AVOID: Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents and vasoconstrictor-containing local anesthetics. Several-fold increases in the effects of norepinephrine and, to a lesser extent, epinephrine and phenylephrine were reported in healthy subjects pretreated with desipramine, imipramine, or nortriptyline. The mechanism is TCA inhibition of norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, hypertension, throbbing headache, tremor, palpitation, chest pain, and cardiac dysrhythmia have been reported in association with this interaction. Various TCAs have been implicated including amitriptyline, desipramine, imipramine, nortriptyline, and protriptyline. It is not known whether the interaction also occurs with mixed-acting sympathomimetic agents (e.g., dopamine, ephedrine, metaraminol).

MANAGEMENT: Parenteral administration of direct-acting sympathomimetic agents should preferably be avoided during therapy with tricyclic antidepressants except in cases of emergency (e.g., treatment of anaphylaxis). If concomitant use is necessary, initial dose and rate of administration of the sympathomimetic should be reduced, and cardiovascular status including blood pressure should be monitored closely. Although clinical data are lacking, it may be prudent to follow the same precaution with mixed-acting sympathomimetic agents.

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MONITOR: Tricyclic antidepressants may counteract the anticonvulsive effects of barbiturates by lowering the seizure threshold. Barbiturates may decrease the serum levels and effects of tricyclic antidepressants by induction of hepatic metabolism. In addition, the respiratory-depressant effects of both agents may be increased due to additive pharmacologic effects.

MANAGEMENT: If the barbiturate is being taken for a seizure disorder, patients should be closely monitored for loss of seizure control. Dose adjustments may be required. Monitoring for clinical evidence of additive toxicity and for clinical and/or laboratory evidence of reduced antidepressant effect is also advisable.

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MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

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MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

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MONITOR: Concomitant use of phenothiazines with barbiturates may reduce the plasma concentrations and therapeutic effects of both agents. The mechanism is unclear but may relate to metabolic induction of CYP450 hepatic enzymes. In addition, coadministration of phenothiazines and barbiturates may lead to a reduction in seizure threshold and additive central nervous system (CNS) and respiratory depressant effects.

MANAGEMENT: Administration of phenothiazines in patients receiving large doses of barbiturates is considered contraindicated by some authorities (US). If coadministration is required, caution as well as clinical and laboratory monitoring should be considered whenever either of these agents is added to or withdrawn from therapy. If chlorpromazine is coadministered with a barbiturate, the manufacturer of chlorpromazine recommends using 1/4 to 1/2 of the usual barbiturate dosage. Patients should be monitored for hypotension, loss of seizure control and the development of adverse effects including CNS and respiratory depression.

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GENERALLY AVOID: Phenothiazines may antagonize the pharmacologic effects of amphetamine, amphetamine derivatives, and other centrally-acting sympathomimetic agents (i.e., CNS stimulants). Conversely, these agents may diminish the neuroleptic efficacy of phenothiazines. The exact mechanism of interaction is unknown but may involve opposing effects on dopaminergic activity. Several clinical studies have demonstrated the reduction or lack of effect of amphetamines on weight loss in obese psychiatric patients treated with chlorpromazine and other neuroleptic agents. In one of these studies, dextroamphetamine also had no effect on sleep patterns. As for the reverse interaction, it is uncertain whether CNS stimulants actually antagonize the neuroleptic effect of phenothiazines, since CNS stimulants alone have been reported to cause or aggravate preexisting psychotic symptoms. Finally, it is conceivable that, because of their sympathomimetic effects, CNS stimulants may also potentiate the arrhythmogenicity of phenothiazines. A case of fatal ventricular arrhythmia was reported in a patient treated chronically with thioridazine who ingested a single capsule containing phenylpropanolamine 50 mg and chlorpheniramine 4 mg. However, a causal relationship was not established.

MANAGEMENT: Amphetamine, amphetamine derivatives, and other CNS stimulants should generally not be used, particularly for weight reduction, in patients treated with phenothiazines.

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Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

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