Trimipramine
Encyclopedia
Trimipramine is a tricyclic antidepressant
(TCA). It has antidepressant
, anxiolytic
, antipsychotic
, sedative
, and analgesic
effects.
as well as the antipsychotic levomepromazine
(Nozinan).
Trimipramine's mechanism of action
differs from other TCAs. It is only a moderate reuptake inhibitor
of norepinephrine
, and a weak reuptake inhibitor of serotonin
and dopamine
. Its main effects are due to considerable receptor
antagonism
as follows:
The spectrum of effects (strong antidepressant activity, sedation and anxiolysis) and side effects (strong anticholinergic
and antiadrenergic symptoms) is similar to those of doxepin
. It is also a more effective sedative than amitriptyline
. Trimipramine is the only effective drug against insomnia known so far that does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to brighten during treatment. However, this can occasionally go too far, as nightmares are an uncommon but possible side effect of the drug. Its relatively strong antagonistic activity at postsynaptic D2 receptors led to a clinical study trying trimipramine as atypical neuroleptic. There it exerted good antipsychotic activity with a low incidence of extrapyramidal
and other side effects. But this study encompassed only 28 patients, so the use of trimipramine as a neuroleptic needs further confirmation and can currently not be recommended. Trimipramine also shows useful activity against chronic pain.
Treatment should be initiated at the lowest recommended dose and increased gradually, noting carefully the clinical response and any evidence of intolerance. Days to weeks may elapse before optimal therapeutic effects of Trimipramine are seen. Increasing the dosage usually does not shorten this latent period and may increase the incidence of side effects and patient non-compliance.
In elderly or debilitated patients it may be necessary to check blood pressure and cardiac rhythm, particularly in patients who have unstable cardiovascular function.
Once a satisfactory response has been obtained, the dosage is normally adjusted to the lowest level required to maintain remission and avoid relapse. Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement. Afterwards, prophylactic treatment for 1 to 2 years may be indicated, but there are different opinions regarding the optimal dose and length of remission maintenance treatment.
dd
compound with two enantiomer
s. CYP2C19 is responsible for the demethylation
of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP
2D6 is responsible for the 2-hydroxylation
of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.
Relative:
Withdrawal symptoms frequently seen when treatment with trimipramine 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 trimipramine 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.
. Trimipramin was applied as his racemate.
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
(TCA). It has 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;...
, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effects.
Indications
- Endogenous and neurotic depression with prominent agitation and anxiety
- Depressive and non-depressive insomnia (suitable for long-term treatment)
- Adjunctive therapy of alcohol and opioid withdrawal
- Chronic pain of malignant and non-malignant origin
Pharmacology
Trimipramine is chemically similar to other TCA antidepressants such as imipramineImipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
as well as the antipsychotic levomepromazine
Levomepromazine
Levomepromazine in Germany and Methotrimeprazine in America is an aliphatic phenothiazine neuroleptic drug...
(Nozinan).
Trimipramine's mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
differs from other TCAs. It is only a moderate reuptake inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and a weak reuptake inhibitor of 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...
. Its main effects are due to considerable receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
antagonism
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
as follows:
- Extremely strong: H1
- Strong: 5-HT2, mACh, α1-adrenergicAlpha-1 adrenergic receptorThe alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
- Moderate: D2Dopamine receptor D2Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
- Weak: 5-HT1, α2-adrenergicAlpha-2 adrenergic receptorThe alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
The spectrum of effects (strong antidepressant activity, sedation and anxiolysis) and side effects (strong 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....
and antiadrenergic symptoms) is similar to those of 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...
. It is also a more effective sedative than 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...
. Trimipramine is the only effective drug against insomnia known so far that does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to brighten during treatment. However, this can occasionally go too far, as nightmares are an uncommon but possible side effect of the drug. Its relatively strong antagonistic activity at postsynaptic D2 receptors led to a clinical study trying trimipramine as atypical neuroleptic. There it exerted good antipsychotic activity with a low incidence of extrapyramidal
Extrapyramidal symptoms
The extrapyramidal system can be affected in a number of ways, which are revealed in a range of extrapyramidal symptoms , also known as extrapyramidal side-effects , such as akinesia and akathisia .Extrapyramidal symptoms are various movement disorders such as acute dystonic reactions,...
and other side effects. But this study encompassed only 28 patients, so the use of trimipramine as a neuroleptic needs further confirmation and can currently not be recommended. Trimipramine also shows useful activity against chronic pain.
Forms
- Tablets/capsules (10, 12.5, 25, 50, 75, 100, 150 mg)
- Liquid concentrate (40 mg/ml)
- Injectable concentrate (25 mg)
Dosage
Whilst some standard suggested dosages are published for the treatment of depression, the proper dosage for treatment of insomnia in non-depressive patients, those on alcohol/opioid withdrawal and those with chronic pain may vary greatly and should be discussed with your physician.Treatment should be initiated at the lowest recommended dose and increased gradually, noting carefully the clinical response and any evidence of intolerance. Days to weeks may elapse before optimal therapeutic effects of Trimipramine are seen. Increasing the dosage usually does not shorten this latent period and may increase the incidence of side effects and patient non-compliance.
In elderly or debilitated patients it may be necessary to check blood pressure and cardiac rhythm, particularly in patients who have unstable cardiovascular function.
Once a satisfactory response has been obtained, the dosage is normally adjusted to the lowest level required to maintain remission and avoid relapse. Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement. Afterwards, prophylactic treatment for 1 to 2 years may be indicated, but there are different opinions regarding the optimal dose and length of remission maintenance treatment.
dd
Parenteral usage
Intramuscular injections and slow i.v.-infusions are possible, but have the disadvantage of intensified anticholinergic and antiadrenergic side effects. The advantage may be an earlier onset of action compared to oral dosage. Decreased doses are sufficient with parenteral treatment.Metabolism
Trimipramine is a racemicRacemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
compound with two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s. CYP2C19 is responsible for the demethylation
Demethylation
Demethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP
CYP
CYP is a three-letter abbreviation which may refer to:* CINOP Young Professionals* Calbayog, in the Philippines * Crystal Palace railway station, the national railway code for a railway station in London, UK* Cape York Peninsula, Australia...
2D6 is responsible for the 2-hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.
Contraindications
Absolute:- Concomitant treatment with monoamine oxidase inhibitorMonoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (MAOIs) - Known allergy or hypersensitivity to trimipramine or other TCAs
- Acute delirum tremens
- Untreated closed angle glaucoma
- HypertrophyHypertrophyHypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
of the prostate with urine retention - Paralytic ileus
Relative:
- HypertrophyHypertrophyHypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
of the prostate without urine retention - Reduced function of the bone marrow
- Organic brain disorders
- Increased risk of seizures, pre-existing epilepsy
- Pre-existing cardial damage, particular some arrhythmias (impulse conductive disorders)
Abuse & dependence
Trimipramine is not an abusable substance nor does it cause psychological dependence.Withdrawal symptoms frequently seen when treatment with trimipramine 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 trimipramine gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
(e.g., lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
, clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
, or alprazolam
Alprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.
Formation
Trimipramine is synthesised by treatment of 10,11,Dihydro-5H-dibenz[b,f]azepine and with 3-N,N-Dimethylamino-2-methylpropylchloride in a nucleophilic substition in present of Sodium amideSodium amide
Sodium amide, commonly called sodamide, is the chemical compound with the formula NaNH2. This solid, which is dangerously reactive toward water, is white when pure, but commercial samples are typically gray due to the presence of small quantities of metallic iron from the manufacturing process...
. Trimipramin was applied as his racemate.