CLONAZ 0.5

Indications

• All forms of epilepsy
• Myoclonus
• Panic disorders (with or without agoraphobia) resistant to antidepressant therapy

Dosage

Children: Child 1–11 months: Initially 250 micrograms once daily for 4 nights, dose to be increased over 2–4 weeks, usual dose 0.5–1 mg daily, taken at night; may be given in 3 divided doses if necessary.

Adults: Initially 1 mg once daily for 4 nights, dose to be increased over 2–4 weeks, usual dose 4–8 mg daily, adjusted according to response.

Mechanism of action

Clonazepam binds to benzodiazepine receptors associated with GABA(a) receptors in the central nervous system. This binding increases the affinity of GABA for its receptor, enhancing chloride ion conduction across neuronal membranes. The resultant hyperpolarization of the neuron decreases its excitability, leading to reduced neuronal firing and contributing to its anticonvulsant effects.

Pharmacodynamics

Clonazepam exhibits common pharmacodynamic properties of benzodiazepines, including anticonvulsive, anxiolytic, sedative, and muscle relaxant effects. It effectively suppresses various types of paroxysmal activity in the brain, including generalized spike-wave discharges in absence seizures and minor motor seizures. It is particularly effective in reducing generalized EEG abnormalities.

Pharmacokinetics

Clonazepam is well absorbed after oral administration, with peak plasma concentrations typically reached within 1-4 hours. It is metabolized primarily in the liver and has a half-life ranging from 18 to 50 hours, allowing for once-daily dosing in many cases. The drug's effects can persist for several hours due to its active metabolites.

Contra-indications

• Coma
• Current alcohol abuse
• Current drug abuse
• Respiratory depression
• Acute porphyrias
• Severe airway obstruction

Adverse effects

• Alopecia
• Increased bronchial secretions (in children)
• Impaired coordination
• Abnormal drooling (in children)
• Gastrointestinal disorders
• Hypersalivation (in children)
• Incomplete precocious puberty

Interactions

• Nevirapine may decrease clonazepam concentration

Precautions

• Caution in patients with depression
• Caution in patients with spinal ataxia
• Monitor for decreased effectiveness after prolonged use

Pregnancy

Clonazepam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is associated with risks of congenital malformations when taken in the first trimester.

Breast-feeding

Clonazepam 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

• Clonazepam 0.5 mg tablet
• Clonazepam 1 mg tablet
• Clonazepam 2 mg tablet
• Clonazepam oral suspension (various concentrations)

Mechanism of action

Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons. Subsequently, benzodiazepines like clonazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors. This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors. This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells. Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. In particular, when out of the ordinary rapid and repetitive electrical signals are released in the CNS, it is proposed that the brain can become over-stimulated and ordinary functions are disrupted - resulting in seizure activity. By enhancing the neuro-inhibitory activity of GABA, it is believed that clonazepam can facilitate in decreasing any excessive electrical nerve activity in the CNS that might be contributing to seizures. Concurrently, it is also believed that clonazepam's actions in enhancing GABA effects may inhibit neuronal activity proposed to occur in amygdala-centered fear circuits - therefore assisting in the management of anxiety or panic.

Pharmacodynamics

The pharmacodynamic properties of clonazepam are common among benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations, as well as irregular spikes and waves. Moreover, the agent can also decrease the frequency, amplitude, duration, and spread of discharge in minor motor seizures. Generalized EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalized and focal epilepsies.