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Maprotiline

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Maprotiline chemical structure
Maprotiline

N-Methyl-9,10-ethanoanthracene-9(10H)-propanamine
IUPAC name
CAS number
10262-69-8
ATC code

N06AA21

PubChem
4011
DrugBank
APRD00747
Chemical formula {{{chemical_formula}}}
Molecular weight 277.403 g/mol
Bioavailability 66 to 70%
Metabolism hepatic
Elimination half-life 27-58 hours
Excretion biliar (30%) and urine (57%) as gluconurides, 3 to 4% as unchanged drug
Pregnancy category Sufficient data does not exist. Exert caution.
Legal status Rx-only (not a controlled substance)
Routes of administration oral, intramuscular, intravenous (infusion)

Maprotiline (sold as Deprilept®, Ludiomil®, Psymion®) is a tetracyclic antidepressant. It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake.

It exerts blocking effects at the following postsynaptic receptors:

  • Strong : alpha1
  • Moderate : 5-HT2, muscarinic, H1, D2
  • Weak : alpha2
  • Extremely weak : 5-HT1

The pharmacologic profile of Maprotiline explains its antidepressant, sedative, anxiolytic, sympatholytic, and anticholinergic activities. Additionally, it shows a strong antagonism against Reserpine-induced effects in animal studies, as do the other 'classical' antidepressants. Although Maprotiline behaves in most regards as a 'first generation antidepressant' it is commonly referred to as 'second generation antidepressant'.

Sedation has a fast onset (the same day), while remission of the depression itself is noted usually after a latent period of one to four weeks.

Maprotiline does not brighten up the mood in nondepressed persons.

History

Maprotiline was developed and has been marketed by the Swiss manufacturer Geigy (now Novartis) since the early 1980s under the brand name Ludiomil®. Generics are widely available.

Indications

  • Treatment of depressions of all forms and severities (endogenous, psychotic, involutional, and neurotic)
  • Treatment of the depressive phase in bipolar depression
  • For the symptomatic relief of anxiety, tension or insomnia

N.B. The use of maprotiline in the treatment of enuresis in pediatric patients has so far not been systemetically explored and its use can therefore not be recommended.

Contraindications

Absolute

  • Hypersensitivity to Maprotiline or to other tri-/tetracyclic antidepressants
  • Hypertrophy of the prostate gland with urine hesitancy
  • Closed Angle Glaucoma

Special caution needed

  • Concomitant treatment with a MAO-Inhibitor
  • Serious impairment of liver and kidney function
  • Epilepsy and other conditions that lower the seizure threshold (active brain tumors, alcohol withdrawal, other medications)
  • Serious cardiovascular conditions (arrhythmias, heart insufficience, state after myocardial infarction etc.)
  • Treatment of patients under age 18

Pregnancy and nursing

If you are pregnant or thinking of becoming pregnant, before taking this medicine talk to your doctor about the benefits versus the risks to your pregnancy. Animal studies showed delayed bone development. Use this medicine only if it is clearly needed.

Maprotiline should not be given to nursing mothers. If you have any questions, ask your doctor or pharmacist.

Side effects

The side-effect profile is comparable to other tri-/tetracyclic antidepressants. Most often seen are:

  • Dizziness, drowsiness, fatigue
  • Dry mouth, obstipation
  • Increased appetite and weight gain
  • Hypotension, tachycardia, other arrhythmias
  • Impaired sexual functions in men (impotence, ejaculation difficulties, decreased libido)
  • Allergic skin reactions (more often than with other antidepressants), photosensitivity, rarely severe skin reactions (Erythema multiforme)
  • Agitation, confusion
  • Mood swing to hypomania, worsening of psychotic disease
  • Seizures (more often seen with high doses)
  • Prolonged and painful erections (call your doctor immediately)
  • Leukopenia and agranulocytosis (dangerous fall in white blood cells)
  • Liver damage, hepatitis (rarely)
  • Polyneuritis (very rarely)

Other uncommon side effects may be seen. Consult your doctor, if these are more than mild.

Maprotiline causes a strong initial sedation (first 2 to 3 weeks of therapy) and is therefore indicated to treat agitated patients ot those with suicidal risks. It causes anticholiergic side effects with a lower incidence than Amitritypline. Originally, the manufacturer claimed that Maprotiline is better tolerated than other tri-/tetrcyclic drugs. This is not the case because seizures, leukopenia and skin reactions occur more often with Maprotiline than with comparable drugs like Amitriptyline.

Necessary examinations during therapy

All patients should have frequent blood pressure checks and periodic white bloodcell counts. Risk patients need also regular EKG and EEG monitoring as well.

Suicidal patients

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Maprotiline. Perhaps, the decision is made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or Chlorprothixene for 2-4 weeks of initial treatment with Maprotiline (until significant remission). At least, the smallest amount of Maprotiline should be prescribed at one time to minimize the risk of deliberate overdose.

Generally, many antidepressants (SSRIs, other tricyclic drugs) have been shown to cause a significant higher rate of suicidal thoughts and suicidal attempts in patients under 18 yrs. of age compared to placebo. It is not known if Maprotiline shares this risk. If Maprotiline treatment is considered essentially in these patient group, all persons so-treated should be monitored closely for signs of suicidal risk.

Drug abuse and dependence

Maprotiline has no known potential for abuse and psychological dependence.

Withdrawal symptoms frequently seen when treatment with Maprotiline is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of Maprotiline gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Other remarks

Maprotiline may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

Bipolar patients during acute manic phase should not be treated.

Interactions

Maprotiline has a wide range of possible interactions. Some are typical for tri-/tetracyclic antidepressants, others are caused by specific metabolic effects (e.g. high plasma-protein-binding) of Maprotiline:

  • Irreversible MAO-Inhibitors: agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. N.B. Treatment-resistant and hospitalized patients may be treated concomitantly with an MAO-Inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.

Increased drug actions:

  • Other antidepressants, barbiturates, narcotics, sedating antihistaminics, anticonvulsive drugs, alcohol - resulting in increased central depression
  • Anticholinergics (antiparkinsonian agents, tri- and tetracyclic antidepressants) - resulting in increased anticholinergic action (dry mouth, obstipation etc.)
  • Sympathomimetics (also those used in local anesthetics like Noradrenaline) : sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc)
  • Nitrates and Antihypertensives (e.g. Beta-Blockers) - increased antihypertensive action with pronounced fall in blood pressure

Decreased drug actions:

  • Guanethidin, Reserpin, Guanfacin : antihypertensive effects decreased
  • Clonidin : antihypertensive effects decreased and risk of (massive) rebound hypertension.

Other types of interaction:

  • Drugs, which induce certain enzymes in the liver, e.g. Barbiturates, Phenytoin, Carbamazepin and oral anticonceptive drugs, enhance the elimination of Maprotiline and decrease its antidepressant effects. If necessary, increase the Maprotiline dose. Additionally the blood-concentrations of Phenytoin or Carbamazepin can be increased, leading to a higher incidents of side effects of the latter drugs. Adjust the dose of these drugs, if necessary, too.
  • The concomitant use of Maprotiline and neuroleptics can lead to increased Maprotiline blood-levels and to seizures. Combining Maprotiline and Thioridazine could induce severe arrhythmias.
  • Additionally, increased blood-levels of Maprotiline are possible, if certain beta-blocking agents (e.g. Propranolol) are given concomitantly. Adjust the dose of Maprotiline if necessary.
  • Maprotiline may amplify the actions of coumarin-type anticogulants (e.g. Warfarin, Phenprocoumon). The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings. Reduce the anticoagulant dose, if necessary.
  • Maprotiline can increase the actions of oral antidiabetic drugs (sulfonylureas) and Insulin. Diabetic patients should have regular assessments of their blood-glucose-levels. Adjust antidiabetic therapy as needed.
  • The concomitant application with Fluoxetin or Fluvoxamin may lead to significantly increased plasma-levels of Maprotiline with a high incidence of Maprotiline side effects. Due to the long halflives of Fluoxetin and Fluvoxamin this effect may last for a long time.

Overdose

If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222.

Canadian residents should call their local poison control center directly. Symptoms of overdose may include flushing, fast or irregular heartbeat, dry mouth, drowsiness, confusion, agitation, enlarged pupils, seizures, and loss of consciousness.

Drugs commonly used to treat overdose are Physostigmine (N.B. increased risk of seizures in Physostigmine treated patients) to counteract central and peripher anticholinergic effects and Diazepam (cautiously, may deepen central depression!) against convulsion. Symptomatic measures are stabilization of blood pressure and correction of water- and electrolyt-deficits. Lidocaine can be given intravenously in cautious doses against cardial arrhythmias. The patient should be treated and monitored in an intensive care unit for several days.

Due to milder anticholinergic and cardiotoxic effects of Maprotiline the acute lethal dose may be higher compared with other classical antidepressants (e.g. Amitriptyline, Doxepin). Maprotiline is definitely more toxic than the other tetracyclic drugs Mianserin and Mirtazapine.

Dosage

  • Oral: Usually, treatment is started with 3 times 25mg or 75mg in a single dose at bedtime. The daily dose is gradually increased to 150mg daily (2 times 75mg or 3 times 50mg). Doses up to 225mg are possible, but carry the risk of a higher incidence of seizures.
  • Parenteral: i.m.-injections and slow iv.-infusions with total daily doses of 75 to 150mg are possible. Switch to oral forms as soon as possible. Parenteral treatment may lead to an earlier onset of action of Maprotiline but may also be associated with an increased risk of seizures.

Dose Forms

  • Coated Pills, 10mg, 25mg, 50mg, and 75mg
  • Injectable concentrate, 25mg

Brand Names

  • Ludiomil®, Deprilept® Psymion®
  • Generics


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External links


Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine
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