Jan/20: Updated information on Clonazepam (from StatPearls/PubMed)

"Clonazepam"

https://www.ncbi.nlm.nih.gov/books/NBK556010/#article-19617.s1

Indications

Clonazepam is a long-acting and high potency benzodiazepine. It behaves both as a GABA-A receptor agonist and also as a serotonin agonist. Clonazepam has anticonvulsant and anxiolytic effects. It is FDA-approved for the treatment of seizure disorders and panic disorders.[1][2] It also has off label use as monotherapy or adjunctive therapy for the treatment of mania, restless leg syndrome, insomnia, tardive dyskinesia, and REM sleep behavior disorder.[3][4][5][4][3]

Seizure Disorders

Clonazepam has a broad range of activity against different types of seizure disorders. Its primary indications are for acute management of epilepsy and acute treatment of non-convulsive status epilepticus (complex partial seizures or absence seizures). It is also very effective in controlling the minor motor seizures of childhood, particularly petit mal absences, Lennox-Gastaut syndrome, and infantile spasm.[6] Clonazepam is also useful in the treatment of psychomotor, myoclonic epilepsies, grand mal, and focal motor seizures. However, it is not used as first-line therapy for these conditions. It can be used in patients resistant to standard treatment. 

Panic Disorder

Clonazepam causes a significant improvement in patients who have panic disorders with or without agoraphobia. It is efficacious in the short-term management of panic disorder due to the risk of developing withdrawal symptoms and abuse. However, it is also less likely to cause rebound anxiety upon cessation than other benzodiazepines because of its longer half-life. Clinicians also use it for the acute treatment of panic attacks.[7]

Acute Mania

Clonazepam has anticonvulsant and serotonin agonist activity, both of which are associated with its antimanic effect. Therefore, it is sometimes helpful for the treatment of acute mania. Research found it to be significantly more effective than lithium in reducing manic symptoms, and fewer patients required PRN administration of haloperidol, as well as the number of days on which haloperidol was needed, was lower during clonazepam treatment. This way, the clonazepam not only reduces the need for antipsychotic drugs in the treatment of acute mania but also decreases the risk of side effects in these patients.[2]. Nowadays, a combination of a benzodiazepine and antipsychotic haloperidol is considered the most effective treatment of acute agitation in the emergency department.[8]

Miscellaneous Uses

Clonazepam is also a side option for the treatment of akathisia, restless leg syndrome, rapid eye movement behavior disorder, and bruxism.[9][10][11][12]

Mechanism of Action

Clonazepam is highly potent and a long-acting benzodiazepine. It exerts its pharmacological effects by acting as a positive allosteric modulator on GABA-A receptors. The GABA-A receptor is a ligand-gated chloride ion-selective channel whose endogenous ligand is GABA (gamma-aminobutyric acid). Benzodiazepines (BZDs) facilitate GABA-A action by increasing the frequency of chloride channel opening resulting in hyperpolarization of the neurons and decreased firing, thus producing calming effects on the brain by reducing the excitability of the neurons.

GABA is an inhibitory neurotransmitter that is present in abundance in the cortex and limbic system. There are three types of GABA receptors A, B, and C. However, BZDs act only on GABA-A receptors. Each receptor complex has 2 GABA-binding sites and 1 BZD-binding site and is made of five subunits two alpha, two beta, and one gamma. BZDs do not bind to the same receptor site on the receptor complex as the endogenous ligand GABA but bind to distinct BZD-binding sites situated at the interface between the alpha and gamma subunits. The binding results in a conformational change in the GABA-A receptor's chloride channel that results in the hyperpolarization of the cell and accounts for GABA's inhibitory effect throughout the central nervous system.[13]

GABA receptors also classify into various BZDs receptors based on the isoforms of the alpha subunit. The benzodiazepine type-1 receptors (BZ1), which contain alpha-1 subunits, are present in abundance in the cortex, thalamus, and cerebellum are responsible for their anticonvulsant and sedative effects. Whereas benzodiazepine type-2 receptors containing alpha-2 subunits, mostly concentrated in the limbic system, motor neurons and dorsal horn of spinal cord, mediate the anxiolytic effects of BZDs.

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