ANAFRANIL TABLETS 25MG

Indications

• Obsessive-Compulsive Disorder (OCD)
• Depression
• Neuropathic Pain
• Chronic Pain Syndromes

Dosage

Children: For children aged 5 years and older, the initial dose is typically 1 mg/kg body weight daily, which can be increased based on clinical response and tolerability, with a

Adults: The usual adult dosage for depression is 75 mg daily, which may be increased to a maximum of 250 mg daily, depending on the clinical response and tolerability.

Mechanism of action

Clomipramine acts primarily as a serotonin reuptake inhibitor, while its active metabolite, desmethyclomipramine, inhibits norepinephrine reuptake. It also blocks sodium channels and NMDA receptors, contributing to its analgesic effects and its efficacy in chronic pain management. The precise mechanism for its effectiveness in OCD remains unclear, although its actions on serotonin receptors are significant.

Pharmacodynamics

Clomipramine's pharmacodynamics involves the modulation of neurotransmitter systems, particularly serotonin and norepinephrine. It leads to changes in receptor sensitivity in brain regions such as the cerebral cortex and hippocampus, which are associated with mood regulation. This results in sensitization of alpha-1 and beta-1 receptors, and desensitization of alpha-2 receptors, ultimately enhancing noradrenaline production. Despite immediate effects on neurotransmitter reuptake, mood improvement typically takes several weeks.

Pharmacokinetics

Clomipramine is well absorbed from the gastrointestinal tract and exhibits high plasma protein binding. It undergoes extensive hepatic metabolism, primarily by CYP2D6, leading to the formation of active metabolites, including desmethyclomipramine. The elimination half-life varies, generally ranging from 20 to 40 hours. It is excreted mainly in urine as metabolites. Steady-state concentrations are usually achieved within one to two weeks.

Contra-indications

• Hypersensitivity to clomipramine or any of its components
• Acute recovery phase after myocardial infarction
• Concurrent use with monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Drowsiness
• Dry mouth
• Constipation
• Blurred vision
• Weight gain
• Increased sweating
• Orthostatic hypotension
• Cardiac arrhythmias
• Seizures

Interactions

• Increased risk of toxicity with other central nervous system depressants
• Potentiation of effects with alcohol
• Concomitant use with MAOIs can lead to serious reactions
• May interact with anticholinergic drugs, increasing adverse effects
• Effects may be altered with CYP450 enzyme inducers or inhibitors

Precautions

• Use with caution in patients with a history of seizures
• Monitor for signs of serotonin syndrome, particularly when used with other serotonergic drugs
• Caution in patients with cardiovascular disorders due to potential arrhythmias
• Risk of suicidal thoughts and behavior in young adults and children

Pregnancy

Clomipramine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Limited data suggests a risk of congenital malformations.

Breast-feeding

Clomipramine is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 25 mg, 50 mg, 75 mg
• Capsules: 25 mg, 50 mg
• Oral solution: 5 mg/5 ml

Mechanism of action

Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α₁-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. The pharmacology of clomipramine is complex and in many ways resembles that of other antidepressants, particularly those agents (eg, selective serotonin-reuptake inhibitors, trazodone) that predominantly potentiate the pharmacologic effects of serotonin (5-HT). Although clomipramine's principal pharmacologic effect in vitro is the selective inhibition of serotonin reuptake, in vivo the drug's pharmacologic activity is not so selective because of the action of its demethylated metabolite, desmethylclomipramine, as an inhibitor of norepinephrine reuptake. As a result of this and other effects, clomipramine also shares the pharmacologic profile of other tricyclic antidepressants. The precise mechanism of action that is responsible for the efficacy of clomipramine in the treatment of obsessive-compulsive disorder is unclear. However, because of its pronounced potency in blocking serotonin reuptake at the presynaptic neuronal membrane and its efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition. The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that clomipramine is effective because it corrects this imbalance. Clomipramine and its principal metabolite, desmethylclomipramine, have been shown to block the reuptake of serotonin and norepinephrine, respectively, at the presynaptic neuronal membrane. The effects of serotonin and norepinephrine may thus be potentiated. However, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. During long-term therapy with most antidepressants (eg, tricyclic antidepressants, monoamine oxidase [MAO] inhibitors), these adaptive changes generally consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of beta-adrenergic receptors; such effects on noradrenergic receptor function commonly are referred to as "down-regulation." In addition, some antidepressants reportedly decrease the number of 5-HT binding sites following chronic administration. Clomipramine's principal metabolite, desmethylclomipramine, is an inhibitor of norepinephrine reuptake. Clomipramine decreases the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, in CSF in patients with obsessive-compulsive disorder. Patients with depressive affective (mood) disorders (e.g., major depressive episode) also exhibit decreases in concentrations of 5-HIAA and MHPG in CSF during treatment with clomipramine. The decrease in the concentration of 5-HIAA in CSF was correlated with inhibition of the in vitro uptake of 3H-serotonin in plasma. The change in concentration of MHPG in CSF during clomipramine therapy was correlated with amelioration of depression. For more Mechanism of Action (Complete) data for Clomipramine (10 total), please visit the HSDB record page.

Pharmacodynamics

Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α₁ and β₁ receptors are sensitized, α₂ receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.