maprotiline hydrochloride

• 塩酸マプロチリン

関

Ludiomil、maprotiline

WordNet

1. a complex consisting of an organic base in association with hydrogen chloride

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/09/24 10:10:15」(JST)

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Maprotiline

Systematic (IUPAC) name
N-Methyl-9,10-ethanoanthracene-9(10H)-propanamine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682158
Pregnancy cat.	? (US)
Legal status	Prescription Only (S4) (AU) ℞-only (US)
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 Y
ATC code	N06AA21
PubChem	CID 4011
IUPHAR ligand	2402
DrugBank	DB00934
ChemSpider	3871 Y
UNII	2U1W68TROF Y
KEGG	D02566 Y
ChEMBL	CHEMBL21731 Y
Chemical data
Formula	C20H23N
Mol. mass	277.403 g/mol
SMILES c1ccc3c(c1)C4c2ccccc2C3(CC4)CCCNC
InChI InChI=1S/C20H23N/c1-21-14-6-12-20-13-11-15(16-7-2-4-9-18(16)20)17-8-3-5-10-19(17)20/h2-5,7-10,15,21H,6,11-14H2,1H3 Y Key:QSLMDECMDJKHMQ-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Maprotiline (sold as Deprilept, Ludiomil, Psymion) is a tetracyclic antidepressant (TeCA). However, Maprotiline's fourth ring is spurious, as formed by a bridge across the central tricyclic ring. 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 : H₁
• Moderate : 5-HT₂, alpha₁
• Weak : D₂, mACh

The pharmacologic profile of Maprotiline explains its antidepressant, sedative, anxiolytic, and sympathomimetic 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'.

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

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.

• 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 systematically explored and its use is not 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

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 (which are less prominent than those of most tricyclic antidepressants) and antihistaminergic effects. Most often seen are:

• Dizziness
• Drowsiness
• Somnolence
• fatigue
• Dry mouth (and complications of long-term uncontrolled dry mouth such as dental caries)
• Constipation
• Vertigo
• Nausea (rare, incidence of ~2%) and vomiting
• Increased appetite and weight gain
• Orthostatic hypotension, hypertension, sinus tachycardia, heart-block, arrhythmias and other cardiac effects
• Sexual dysfunction in men: impotence, priapism, delayed ejaculation, anejaculation, decreased libido.
• Sexual dysfunction in women: decreased libido, vaginal dryness, painful sexual intercourse, anorgasmia.
• Allergic skin reactions such as rash or urticaria (more often than with other antidepressants). Rarely, severe skin reactions such as erythema multiforme can occur.
• Photosensitivity
• Agitation, confusion
• Induction of hypomania or mania in patients suffering from underlying bipolar affective disorder
• Psychotic symptoms
• Tremor
• Extrapyramidal symptoms
• Headache
• Peripheral neuropathy damage to nerves outside the central nervous system (very rare).
• Seizures (at high doses)
• Rare haematological complications: leukopenia and agranulocytosis (dangerous fall in white blood cells)
• Liver damage (rare)
• Galactorrhoea
• Hypoglycaemia
• Testicular swelling
• Fever
• Urinary retention

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

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 for 2–4 weeks of initial treatment with Maprotiline (until significant remission). Prescribing of benzodiazepines is NOT recommended in patients that have suicidal thoughts or have had suicidal attempts, due to the increased risk of death due to overdose in conjunction with Maprotiline.

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-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 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

• 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

Brand names

• Ludiomil, Deprilept Psymion
• Generics

External links

• Maprotiline drug information
• rxlist.com
• Schweizer Arzneikompendium (German)
• List of suppliers

References

• B. Bandelow, S. Bleich, S. Kropp : Handbuch Psychopharmaka (German), 2nd. edition, 2004
• Benkert, Hippius : Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. edition, 2003

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 成人における単極性うつ病と三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、
  および副作用 unipolar depression in adults and tricyclic and tetracyclic drugs pharmacology administration and side effects
• 2. パニック障害の薬物療法 pharmacotherapy for panic disorder
• 3. 終末期医療：うつ病の評価および管理 end of life care assessment and management of depression
• 4. 身体化：治療および予後 somatization treatment and prognosis
• 5. 慢性疼痛の治療の概要 overview of the treatment of chronic pain

English Journal

• Effects of gender and age on serum concentrations of antidepressants under naturalistic conditions.

• Unterecker S, Riederer P, Proft F, Maloney J, Deckert J, Pfuhlmann B.SourceDepartment of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany, Unterecker_S@klinik.uni-wuerzburg.de.
• Journal of neural transmission (Vienna, Austria : 1996).J Neural Transm.2013 Aug;120(8):1237-46. doi: 10.1007/s00702-012-0952-2. Epub 2012 Dec 20.
• Therapeutic drug monitoring (TDM) data of antidepressant drugs are often evaluated using homogeneous samples of selected individuals without psychiatric or somatic comorbidity. These data may have limitations in transferability to everyday clinical practice. Hence, studies under naturalistic conditi
• PMID 23254926

• Inhibitory Effects of Psychotropic Drugs on the Acetylcholine Receptor-Operated Potassium Current (IK.ACh) in Guinea-Pig Atrial Myocytes.

• Okada M, Watanabe S, Matada T, Asao Y, Hamatani R, Yamawaki H, Hara Y.SourceLaboratory of Veterinary Pharmacology, Kitasato University, Towada, Aomori 034-8628, Japan.
• The Journal of veterinary medical science / the Japanese Society of Veterinary Science.J Vet Med Sci.2013 Jul 1;75(6):743-7. Epub 2013 Jan 24.
• Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by a
• PMID 23343658

• Multiple pharmacological actions of Yiqi Huatan Decoction in a model of depression in rats.

• Zhou HH, Chen SD, Xu Y, Han YZ, Hu JY.SourceDepartment of Traditional Chinese Medicine, Medical College of Xiamen University, Xiamen, Fujian Province 361005, China.
• Chinese journal of integrative medicine.Chin J Integr Med.2013 Mar;19(3):200-5. doi: 10.1007/s11655-012-1024-z. Epub 2012 Mar 14.
• OBJECTIVE: To investigate the influence of Yiqi Huatan Decoction (, YHD) on a model of depression in rats under different pathological conditions.METHODS: Thirty-two male SD rats were randomly divided into 4 groups of 8: normal, model, YHD, and maprotiline. The model group, YHD group and maprotiline
• PMID 22415138

Japanese Journal

• 新規抗うつ薬Ｍｉｌｎａｃｉｐｒａｎ　ｈｙｄｒｏｃｈｌｏｒｉｄｅ（ＴＮ‐９１２）の脳波および循環器に対する作用

• 川崎 博己 [他],山本 隆一,占部 正信,貫 周子,田崎 博俊,高崎 浩一朗
• 日本薬理学雑誌 98(5), 345-355, 1991
• … 新規抗うつ薬，milnacipran hydrochloride(TN-912)の脳波および循環器に対する作用をimipramine(IMP)およびmaprotiline(MPT)の作用と比較した．TN-912(10～100mg/kg)の経ロ投与は無麻酔・無拘束ラットの自発脳波と音刺激による脳波覚醒反応に対して，著明な変化を示さなかったが，IMP(10～100mg/kg)およびMPT(10～100mg/kg)の高用量投与は自発脳波の徐波成分の増加傾向と脳波覚醒反応の軽度抑制を生じた．無麻酔-無拘束ラット …
• NAID 130000758808

Related Links

• Maprotiline Hydrochloride Monograph for Professionals ...

Maprotiline Hydrochloride reference guide for safe and effective use from the American Society of Health-System Pharmacists (AHFS DI). ... Cautions for Maprotiline Hydrochloride Contraindications Concurrent or recent (i.e., within 2 ...

• | Maprotiline Hydrochloride - BioPortfolio — the Biotechnology ...

| Maprotiline Hydrochloride. BioPortfolio Medication Database ... A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an ...

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maprotiline

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薬理学

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「hydrochloride」

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