Maprotiline
Encyclopedia
Maprotiline is a tetracyclic antidepressant
Tetracyclic antidepressant
Tetracyclic antidepressants are a class of drugs used primarily as antidepressants that were first introduced in the 1970s. They are named after their chemical structure which contains four rings of atoms and are closely related to the tricyclic antidepressants which contain three rings of...

 (TeCA). It is a strong norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...

 with only weak effects on serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 reuptake.

It exerts blocking effects at the following postsynaptic receptors:
  • Strong : H1
  • Moderate : 5-HT2, alpha1
  • Weak : D2, mACh


The pharmacologic profile of Maprotiline explains its antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....

, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...

, and sympathomimetic activities. Additionally, it shows a strong antagonism against Reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...

-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 improve mood in nondepressed persons.

History

Maprotiline was developed and has been marketed by the Swiss manufacturer Geigy (now Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

) since the early 1980s under the brand name Ludiomil. Generics are widely available.

Indications

  • Treatment of depressions
    Clinical depression
    Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

     of all forms and severities (endogenous, psychotic, involutional, and neurotic)
  • Treatment of the depressive phase in bipolar depression
  • For the symptomatic relief of anxiety
    Anxiety
    Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

    , tension
    Stress (medicine)
    Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...

     or insomnia
    Insomnia
    Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...



N.B. The use of maprotiline in the treatment of enuresis
Enuresis
Enuresis refers to an inability to control urination. Use of the term is usually limited to describing individuals old enough to be expected to exercise such control.Types of enuresis include:* Nocturnal enuresis* Diurnal enuresis...

 in pediatric patients has so far not been systematically explored and its use is not recommended.

Absolute

  • Hypersensitivity to Maprotiline or to other tri-/tetracyclic antidepressants
  • Hypertrophy of the prostate
    Prostate
    The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....

     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

Animal studies showed delayed bone development. Maprotiline should be used during pregnancy only if needed.

Maprotiline should not be given to nursing mothers.

Side effects

The side-effect profile is comparable to other tri-/tetracyclic antidepressants and many of the following are due to anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 effects. Most often seen are:
  • Dizziness
    Dizziness
    Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

    , drowsiness, fatigue
  • Dry mouth
    Xerostomia
    Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...

    , obstipation
    Constipation
    Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

  • Increased appetite and weight gain
  • Orthostatic hypotension
    Orthostatic hypotension
    Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...

    , sinus tachycardia
    Sinus tachycardia
    Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...

     or other arrhythmias
  • Sexual dysfunction
    Sexual dysfunction
    Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....

     in men: impotence
    Erectile dysfunction
    Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

    , priapism
    Priapism
    Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...

    , delayed ejaculation
    Delayed ejaculation
    Delayed ejaculation is the inability to ejaculate or persistent difficulty in achieving orgasm despite the presence of normal sexual desire and sexual stimulation...

    , anejaculation
    Anejaculation
    Anejaculation is the pathological inability to ejaculate in males, with or without orgasm.It can depend on one or more of several causes, including ':*Sexual inhibition*Pharmacological inhibition...

    , decreased libido.
  • Sexual dysfunction in women: decreased libido, vaginal dryness, painful sexual intercourse
    Dyspareunia
    Dyspareunia is painful sexual intercourse, due to medical or psychological causes. The symptom is reported almost exclusively by women, although the problem can also occur in men. The causes are often reversible, even when long-standing, but self-perpetuating pain is a factor after the original...

    , anorgasmia
    Anorgasmia
    Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...

    .
  • Allergic skin reactions such as rash
    Rash
    A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...

     or urticaria
    Urticaria
    Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...

     (more often than with other antidepressants). Rarely, severe skin reactions such as erythema multiforme
    Erythema multiforme
    Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...

     can occur.
  • Photosensitivity
    Photosensitivity
    Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...

  • Agitation, confusion
  • Induction of hypomania
    Hypomania
    Hypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...

     or mania
    Mania
    Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...

     in patients suffering from underlying bipolar affective disorder; aggravation or induction of psychotic
    Psychosis
    Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...

     symptoms in patients suffering from an underlying psychiatric disorder likely to cause psychosis, such as schizophrenia
    Schizophrenia
    Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

     or type I bipolar affective disorder
    Bipolar I disorder
    Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well...

    . These two effects (induction of mania and psychosis) are due to the dopamine reuptake inhibition effect of maprotilide, leading to a higher dopaminergic activity in the brain and will therefore aggravate conditions due to excess dopaminergic activity.
  • Seizure
    Seizure
    An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

    s (at high doses)
  • Rare haematological complications: leukopenia
    Leukopenia
    Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

     and agranulocytosis
    Agranulocytosis
    Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

     (dangerous fall in white blood cells)
  • Liver damage
    Hepatotoxicity
    Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...

     (rare)
  • Polyneuritis: damage to nerves outside the central nervous system (very rare).


Other uncommon side effects have been observed.

Maprotiline causes a strong initial sedation (first 2 to 3 weeks of therapy) and is therefore indicated to treat agitated patients or those with suicidal risks. It causes anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 side effects (dry mouth, constipation, confusion, tachycardia) with a lower incidence than amitritypline. Originally, the manufacturer claimed that maprotiline is better tolerated than other tri-/tetracyclic drugs. However, 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 blood cell counts. At-risk patients need 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. The decision may be made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or Chlorprothixene
Chlorprothixene
Chlorprothixene is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized...

 for 2–4 weeks of initial treatment with Maprotiline (until significant remission).

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, so cautionary measures are recommended.

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.

Contraindications

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

Patients with bipolar affective disorder should not receive antidepressants whilst in a manic phase, as antidepressants can worsen mania.

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, constipation 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:
  • Guanethidine, Reserpine, Guanfacine : antihypertensive effects decreased
  • Clonidine : 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, Carbamazepine and oral anticonceptive drugs, enhance the elimination of Maprotiline and decrease its antidepressant effects. Additionally the blood-concentrations of Phenytoin or Carbamazepine may be increased, leading to a higher incidents of side effects.
  • 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.
  • Maprotiline may amplify the actions of coumarin
    Coumarin
    Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

    -type anticogulants (e.g. Warfarin, Phenprocoumon). The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings.
  • Maprotiline can increase the actions of oral antidiabetic drugs (sulfonylureas) and Insulin. Diabetic patients should have regular assessments of their blood-glucose-levels.
  • The concomitant application with Fluoxetine or Fluvoxamine may lead to significantly increased plasma-levels of Maprotiline with a high incidence of Maprotiline side effects. Due to the long half-lives of Fluoxetine and Fluvoxamine this effect may persist.

Chemistry



The first step in the preparation of the antidepressant maprotiline takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (1) with ethyl acrylate and a relatively mild base leads to the Michael adduct; saponification of the ester group gives the corresponding acid (2). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the first-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (3). Diels–Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (4). The final steps involve the construction of the typical antidepressant side chain. The acid in (4) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (5). Reduction to a secondary amine completes the synthesis of (6).

Overdose

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 to counteract central and peripher anticholinergic effects and Diazepam to control convulsion. Symptomatic measures are stabilization of blood pressure and correction of water- and electrolyt-deficits. Lidocaine can be given intravenously in small doses against cardial arrhythmias.

Due to milder anticholinergic and cardiotoxic effects of Maprotiline the acute lethal dose may be higher compared with other classical antidepressants (e.g. Amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...

, Doxepin
Doxepin
Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal, the original preparation by Boehringer-Mannheim, now part of the Roche group; Adapine, Doxal , Deptran, Sinquan and Sinequan...

). Maprotiline is more toxic than the other tetracyclic drugs Mianserin
Mianserin
Mianserin is a psychoactive drug of the tetracyclic antidepressant chemical class which is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine effects...

 and Mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...

.

Dosage

  • Oral: Usually, treatment is started with 3 times 25 mg or 75 mg in a single dose at bedtime. The daily dose is gradually increased to 150 mg daily (2 times 75 mg or 3 times 50 mg). Doses up to 225 mg 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 150 mg are 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 Tablets, 10 mg, 25 mg, 50 mg, and 75 mg
  • Injectable concentrate, 25 mg

External links

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