Clomipramine
Anafranil®
Classification:
Psychotropic Agents
- Antidepressants
- Tricyclic antidepressants
Description: Clomipramine is similar in structure to the tricyclic antidepressant drugs imipramine and desipramine and is the first drug approved for the treatment of obsessive-compulsive disorder. Anticholinergic and orthostatic hypotensive adverse effects are more pronounced for clomipramine than for the other tricyclic antidepressants. Clomipramine is the most specific of all the tricyclic antidepressants with regard to its ability to inhibit serotonin reuptake versus norepinephrine reuptake. Although clomipramine is used clinically to treat obsessive-compulsive disorder, it is occasionally used off-label for major depression. It was approved by the FDA for the treatment of OCD in 1991. On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: The concise action of tricyclic antidepressants is not fully understood, but it is believed that their most important effect is to enhance the actions of norepinephrine and serotonin by blocking the reuptake of these neurotransmitters at the neuronal membrane. Of the tricyclic antidepressants, clomipramine is the most selective and potent inhibitor of serotonin (5-HT) reuptake. (Fluoxetine and related agents are also serotonin-specific.)
Recent evidence suggests that the upset of monoamine output exhibited by depressed patients may be regulated by long-term antidepressant treatment due to action on beta-adrenergic receptors. This action on beta-receptors may be a better explanation than the reuptake theory of these agents’ antidepressant effects. Monoamine oxidase is not inhibited by clomipramine. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, and the seizure threshold can be lowered. Anticholinergic activity is moderate. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose can result from clomipramine’s effect on the endocrine system.
Pharmacokinetics: Clomipramine is well absorbed from the GI tract, but there can be considerable variation in individual response. The full effects may take several weeks to stabilize, although adverse effects can be seen within a few hours. Peak plasma concentrations are obtained within 2 - 6 hours following oral administration. Tricyclic antidepressants are highly protein-bound in plasma and tissues. Because tricyclic antidepressants are long-acting, a single daily dose can be given once dosage is established to improve patient compliance.
Clomipramine is well distributed into CSF and the brain. Clomipramine may cross the placenta and is distributed into breast milk. Metabolism of clomipramine takes place in the liver to produce desmethylclomipramine, one of several metabolites. About 66% is excreted in the urine and the remainder in the feces. Elimination of the parent drug is about 36 hours, but the major metabolite, desmethylclomipramine, can have an elimination half-life of between 4 and 233 days.
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[ Revised 11/9/2005 12:35:00 PM ]
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