Tricyclic antidepressants (TCAs)

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Chapter: Medicinal Chemistry : Antidepressants

Antidepressants - Tricyclic antidepressants (TCAs) - SYNTHESIS AND DRUG PROFILE - 1. Imipramine (Synonym: Tofromil, Imavate, Microdep, Antidep, Depsol) 2. Trimipramine (Surmontil) 3. Desipramine 4. Clomipramine (Aneprnil)


SYNTHESIS AND DRUG PROFILE


Tricyclic antidepressants (TCAs)

Mode of action: Tricyclic antidepressants inhibit the active reuptake of biogenic amines, that is, NE and 5-HT into their respective neurons, and thus, potentiate them. Following the release of NE by depolarization in the presence of Ca2+, NE interacts with postsynaptic α and β adrenergic receptors as well as presynaptic α2 auto-receptors. Inactivation of transsynaptic communication occurs primarily by active transport (inhibited by tricyclics); secondary deamination by mitochondrial MAO, blockade and inactivation of NE  by tricyclics, initially, leads to α2 receptor mediated inhibition of the firing of neurons, and gradually on long-term administration of TCA, desensitize the α2 -auto receptors and sensitizes the pre and postsynaptic NA/5-HT receptors and produces enhanced adrenergic and seretonergic transmission.


1. Imipramine (Synonym: Tofromil, Imavate, Microdep, Antidep, Depsol)


Synthesis


Properties and uses: Imipramine HCl is the lead compound of the TCAs. It is also closely related to the antipsychotic phenothiazines compounds. The compound has a tendency towards a high 5-HT/NE uptake block ratio. It is useful in treating endogenous depression particularly manic-depressive and involutional psychosis. It is also used routinely to treat nocturnal enuresis (bed wetting) in children aged 6 years and above.

Dose: Usual dose is 50–150 mg daily, in divided doses.


2. Trimipramine (Surmontil)


Synthesis


Properties and uses: It exists as white crystals, has bitter taste and slightly soluble in water or in alcohol, but freely soluble in chloroform. Replacement of hydrogen with an α-methyl substituent produces a chiral carbon. It is used as a racemic mixture. Biological properties reportedly resemble those of imipramine.

Dose: For Depression: Adult: Initially 50–75 mg daily, increased gradually as necessary to 150–300 mg daily. It may be given in divided doses during day or as a single dose at night. For elderly: Initially 50–75 mg daily, increased gradually if necessary. Maximum: 100 mg daily.


3. Desipramine


Synthesis


Properties and uses: It exists as white to off-white crystalline powder, odourless, with bitter taste, unstable after long exposure to light, heat, and air, soluble in water, alcohol, chloroform, or ether. It has few anticholinergic effects or (a low level of sedation). Used as an antidepressant with less antianxiety and sedative properties.


4. Clomipramine (Aneprnil)


Synthesis


Properties and uses: It is a TCA with high sedative and intense antimuscarnic effects, causing hypotension and weight gain. Initially, indicated only for obsessive-compulsive disorder.

Dose: Usual dose is 25 mg twice or thrice/day.


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