Maprotiline

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Maprotiline
Maprotiline.svg
Maprotiline3Dan.gif
Systematic (IUPAC) name
N-Methyl-9,10-ethanoanthracene-9(10H)-propanamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a682158
Pregnancy cat.
Legal status
Routes oral, intramuscular, intravenous (infusion)
Pharmacokinetic data
Bioavailability 66 to 70%
Protein binding 88%
Metabolism hepatic
Half-life 27-58 hours
Excretion biliar (30%) and urine (57%) as gluconurides, 3 to 4% as unchanged drug
Identifiers
CAS number 10262-69-8 YesY
ATC code N06AA21
PubChem CID 4011
IUPHAR ligand 2402
DrugBank DB00934
ChemSpider 23719117 N
UNII 2U1W68TROF YesY
KEGG D02566 YesY
ChEMBL CHEMBL21731 YesY
Chemical data
Formula C20H23N 
Mol. mass 277.403 g/mol
 N (what is this?)  (verify)

Maprotiline (sold as Deprilept, Ludiomil, Psymion) is a tetracyclic antidepressant (TeCA).

History[edit]

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

Pharmacokinetics[edit]

After oral use absorption is good. It binds to plasma proteins 80-90 %. Maximal plasma concentration is reached 6 hours after use. The mean time to peak is 12 hours. The half-life of elimination averages 51 hours.

Pharmacology[edit]

Activity profile[edit]

Maprotiline exhibits strong effects as a norepinephrine reuptake inhibitor with only weak actions the reuptake of serotonin and dopamine.[1][2] It is also a strong antagonist of the H1 receptor, a moderate antagonist of the 5-HT2 and α1-adrenergic receptors, and a weak antagonist of the D2 and maCh receptors.

Maprotiline has also more recently been identified as a potent antagonist of the 5-HT7 receptor, with this action potentially playing an important role in its antidepressant effectiveness.[3]

Discussion[edit]

The pharmacological profile of maprotiline explains its antidepressant, sedative, anxiolytic, and sympathomimetic activities. In accordance to the pharmacological characteristics it is used in the treatment of depression, such as depression associated with agitation or anxiety. Additionally, it shows 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'.

The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacological action is thought to be primarily responsible for the drug's antidepressant and anxiolytic effects. It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake. At higher doses however, maprotiline increases serotonergic transmission and increases the level of serotonin available.[4]

Indications[edit]

Maprotiline is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide.[5]

  • Treatment of depressions of all forms and severities (endogenous, psychotic, involutional, and neurotic) especially for depression associated with agitation or anxiety
  • Panic disorder
  • Neuropathic pain
  • 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 systematically explored and its use is not recommended.[2]

Side effects[edit]

The side-effect profile is comparable to other tri-/tetracyclic antidepressants and many of the following are due to anticholinergic (which are less prominent than those of most tricyclic antidepressants) and antihistaminergic effects.[2] Most often seen are:

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 side effects (dry mouth, constipation, confusion, tachycardia) with a lower incidence than amitriptyline. 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[edit]

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.

Drug abuse and dependence[edit]

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[edit]

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.

Absolute[edit]

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

Special caution needed[edit]

  • 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[6]

Suicidal patients[edit]

Same as other antidepressants, Maprotiline increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Maprotiline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Maprotiline is not approved for use in pediatric patients.[7]

Special populations[edit]

Pregnancy[edit]

Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Maprotiline. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers[edit]

Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when Maprotiline hydrochloride is administered to a nursing woman.

Pediatric Use[edit]

Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of Maprotiline in a child or adolescent must balance the potential risks with the clinical need.

Elderly Patients[edit]

In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts.[8][9]

Necessary examinations during therapy[edit]

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.

Interactions[edit]

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-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[edit]

Maprotilin synthesis.png
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.[10][11]

Overdose[edit]

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 peripheral 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, Doxepin). Maprotiline is more toxic than the other tetracyclic drugs Mianserin and Mirtazapine.

Dosage[edit]

  • 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[edit]

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

Brand names[edit]

  • Ludiomil, Deprilept Psymion
  • Generics

External links[edit]

References[edit]

  1. ^ Peng, Wen-Huang; Kuan-Lin Lo, Yi-Hsuen Lee, Tai-Huang Hung, Ying-Chih Lin (2007). "Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice". Life Sciences 81 (11): 933–938. doi:10.1016/j.lfs.2007.08.003. PMID 17804020. 
  2. ^ a b c "DRUGDEX Evaluations - Maprotiline". Retrieved 25 April 2013. 
  3. ^ Matthys A, Haegeman G, Van Craenenbroeck K, Vanhoenacker P (June 2011). "Role of the 5-HT7 receptor in the central nervous system: from current status to future perspectives". Mol. Neurobiol. 43 (3): 228–53. doi:10.1007/s12035-011-8175-3. PMID 21424680. 
  4. ^ Miyake K, Fukuchi H, Kitaura T, Kimura M, Kimura Y, Nakahara T (1991). Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline. J Pharm Sci.;80(12):1114-8.
  5. ^ Delini-Stula A, Mikkelsen H, Angst J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". J Affect Disord 35 (1-2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID 8557884. 
  6. ^ Simeon J, Maguire J, Lawrence S (1981). Maprotiline effects in children with enuresis and behavioural disorders. Progress in Neuro-Psychopharmacology 5 ( 5–6), 495–8.
  7. ^ http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682158.html. Retrieved 29 September 2013
  8. ^ http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682158.html. Retrieved 29 September 2013.
  9. ^ http://www.drugs.com/pro/maprotiline.html. Retrieved 29 September 2013.
  10. ^ Miyake K, Fukuchi H, Kitaura T, Kimura M, Kimura Y, Nakahara T (1991). Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline. J Pharm Sci.;80(12):1114-8.
  11. ^ Wilhelm, M.; Schmidt, P.; Helv. Chim. Acta 1969, 52, 1385.
  • B. Bandelow, S. Bleich, S. Kropp : Handbuch Psychopharmaka (German), 2nd. edition, 2004
  • Benkert, Hippius : Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. edition, 2003