ANAFRANIL 25

Indications

• Obsessive-compulsive disorder (OCD)
• Depressive disorders
• Panic disorder
• Chronic pain management, especially neuropathic pain

Dosage

Children: Refer to the BNF

Adults: Refer to the BNF for specific adult dosing recommendations as they can vary based on the condition being treated and patient-specific factors.

Mechanism of action

Clomipramine functions as a strong, but not completely selective serotonin reuptake inhibitor (SRI). Its active metabolite, desmethyclomipramine, acts preferentially as an inhibitor of norepinephrine reuptake. It also blocks sodium channels and NMDA receptors, which may contribute to its effectiveness in treating chronic neuropathic pain. The exact mechanism for its efficacy in OCD remains unclear, although its pronounced serotonin reuptake inhibition is a significant factor.

Pharmacodynamics

As a tricyclic antidepressant, clomipramine's primary action involves the inhibition of norepinephrine and serotonin reuptake. However, while its reuptake inhibition occurs immediately, the therapeutic effects on mood may take weeks to manifest. This delay is attributed to changes in receptor sensitivity within the cerebral cortex and hippocampus, affecting presynaptic alpha and beta receptors, which ultimately influence mood and emotional responses. Additionally, clomipramine is recognized for its analgesic effects in neuropathic pain.

Pharmacokinetics

Clomipramine is well absorbed from the gastrointestinal tract, with peak plasma concentrations achieved within a few hours post-administration. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, leading to the formation of its active metabolite, desmethyclomipramine. The elimination half-life of clomipramine is approximately 21 hours, although this can vary significantly among individuals. It is primarily excreted in urine, with both unchanged drug and metabolites present.

Contra-indications

• Hypersensitivity to clomipramine or any of its components
• Acute or severe myocardial infarction
• Concurrent use of monoamine oxidase inhibitors (MAOIs)
• Severe liver impairment

Adverse effects

• Sedation
• Dry mouth
• Constipation
• Urinary retention
• Blurred vision
• Weight gain
• Dizziness
• Orthostatic hypotension
• Cardiac arrhythmias

Interactions

• Fluvoxamine: Moderate interaction, increases exposure to clomipramine

Precautions

• Use with caution in patients with a history of seizures
• Monitor closely in patients with cardiovascular disorders
• Caution in elderly patients due to increased risk of side effects
• Avoid abrupt withdrawal to prevent withdrawal symptoms

Pregnancy

Clomipramine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It is categorized as a pregnancy category C medication.

Breast-feeding

Clomipramine is excreted in breast milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Capsules

Indications

• Depression
• Emotional lability in multiple sclerosis

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Initially 10–25 mg daily; increased, if tolerated, in steps of 10–25 mg every 1–7 days; maximum 75 mg per day.

Mechanism of action

Clomipramine is a potent inhibitor of the reuptake of norepinephrine and serotonin in the synaptic cleft, leading to increased concentrations of these neurotransmitters. This action contributes to its antidepressant effects and its ability to stabilize mood in patients with emotional lability. Additionally, clomipramine exhibits anticholinergic properties, which can affect various neurotransmitter systems in the brain.

Pharmacodynamics

Clomipramine's antidepressant effects are attributed to its action on the noradrenergic and serotonergic systems. By inhibiting the reuptake of serotonin and norepinephrine, it increases their availability in the synaptic cleft, enhancing mood and emotional regulation. The drug's anticholinergic effects can lead to side effects such as dry mouth and sedation, which are common with tricyclic antidepressants.

Pharmacokinetics

Clomipramine is well-absorbed following oral administration, with peak plasma concentrations occurring approximately 2 to 6 hours post-dose. It undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, and has a long half-life, allowing for once-daily dosing in many cases. The drug's metabolites are excreted predominantly via the urine. The pharmacokinetics may vary in patients with hepatic impairment, necessitating caution and possible dose adjustments.

Contra-indications

• Arrhythmias during manic phase treatment
• Heart block
• Immediate recovery period after myocardial infarction
• History of bipolar disorder
• Psychosis
• Severe hepatic impairment
• Increased intraocular pressure
• Angle-closure glaucoma
• Phaeochromocytoma
• Urinary retention
• Prostatic hypertrophy
• Pyloric stenosis

Adverse effects

• Drowsiness
• Anticholinergic syndrome
• QT interval prolongation
• Dry mouth
• Constipation
• Dizziness
• Nausea
• Headache
• Mood altered
• Myocardial infarction
• Delirium
• Delusions
• Eosinophilia
• Gynaecomastia
• Hyperhidrosis
• Hypertension
• Hypotension
• Hyponatraemia
• Movement disorders
• Visual disturbances

Interactions

• Alcohol (enhanced effects)
• MAO inhibitors (serious interactions)
• Other CNS depressants (enhanced sedation)
• Anticholinergic drugs (increased anticholinergic effects)
• Sympathomimetics (risk of arrhythmias)
• Antihypertensives (effects may be attenuated)

Precautions

• Caution in patients with cardiovascular disease
• Caution in patients with chronic constipation
• Caution in patients with diabetes
• Caution in patients with epilepsy
• Elderly patients may be more susceptible to side effects
• Close monitoring required for patients with a history of suicide risk

Pregnancy

Clomipramine should only be used in pregnancy if the potential benefits justify the potential risks to the fetus. Consult relevant guidelines for specific recommendations.

Breast-feeding

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

Storage

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

Formulations

• Tablets: 10 mg, 25 mg

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.