Clorazepate

Clorazepate is a prodrug of nordiazepam (desmethyldiazepam), which is the primary active metabolite of diazepam, a benzodiazepine that is used to treat anxiety disorders as well as to temporarily relieve acute alcohol withdrawal symptoms and anxiety symptoms. Clorazepate can be administered off-label for the treatment of a number of illnesses, including premenstrual syndrome, social anxiety, insomnia, and PTSD. Federal and state laws limit clorazepate as an illicit substance because, like other benzodiazepines, it is susceptible to dependency and misuse.

How does clorazepate work?  

The way that clorazepate works pharmacologically in the brain at certain receptor locations may help to explain why it is such an excellent anxiety treatment. Receptors are certain areas on the membrane of nerve cells that receive signals from neurotransmitters, which are neurochemicals. A neurotransmitter attaches to the receptor and travels along the neuron to convert the neurochemical signal into an electrical or other chemical signal. These particular receptors are also referred to as benzodiazepine receptors.

• The neurotransmitter γ-aminobutyric acid (GABA) in that area of the brain is facilitated in its inhibitory effect by the combined action of benzodiazepines on the receptors, which promotes channel opening and neuronal hyperpolarization.

It appears that benzodiazepines’ anxiolytic, sedative, and anticonvulsant effects are due to their interaction with GABA receptors.

 What is the recommended dose of clorazepate?

The usual starting dosage of clorazepate is 15 mg two or three times a day. Depending on the severity of symptoms, the dosage may range from 15 mg/day to 60 mg/day, administered in divided doses. 

• Clorazepate breaks down into an active metabolite in the body. In seniors who have decreased metabolism, clorazepate and its metabolites may be eliminated more slowly and thus accumulate.

 The initial dosage for elderly people should be small, and the dosage should be increased gradually to prevent any untoward reactions.

•  Compared to benzodiazepines with shorter half-lives, such as alprazolam, withdrawal symptoms from clorazepate are often milder due to its prolonged duration of action.  

What happens when you take an overdose of clorazepate?

Oral benzodiazepine overdoses are rarely lethal. Benzodiazepines sometimes cause mortality when taken with other CNS depressants, particularly alcohol, narcotics, and barbiturates.  

Drowsiness, confusion, somnolence, weariness, dropped coordination, clumsiness while walking (ataxia), and sluggish reflexes are some of the mild indications of benzodiazepine overdose. 

When taken alone, benzodiazepines hardly cause death. When some drugs participate in benzodiazepine overdose, severe symptoms such as trouble breathing, a slowing heart rate, and decreased blood pressure, lack of coordination, and loss of consciousness leading to coma and death.

• Every potential overdose should be considered an emergency at the ER. The prescription bottle of the drug along with any extra drugs linked to the overdose should also be brought, as the data on the prescription label can help the treating physician estimate the quantity of pills consumed.

What are the side effects of clorazepate?

Sedation and drowsiness are the most often reported, particularly in the early stages of therapy. Other common symptoms include difficulty focusing and remembering things, a dissociative or “spacey” feeling, and trouble with coordination. 

• Constipation, dizziness, change in appetite, decreased interest in sexual intercourse.
• Suicidal thoughts or behaviors, Hyperventilation, change in consciousness, confusion, loss of memory, Seizure and palpitations

In some individuals, benzodiazepines may possess paradoxical effects. In susceptible individuals, the drug stimulates enthusiasm, aggression, hostility, uncontrolled behavior, and wrath, rather than the expected depressive effects. These reactions are especially common in the elderly, people with brain injuries, and people with personality and impulse control difficulties. Though it is rare with clorazepate.

• Dizziness, headache, nausea, facial or muscle twitching, muscle weakness, balance disorder, Painful or difficult urination, Chills, slow heart rate, slow breathing, and dark urine.

What are the precautions for clorazepate usage?

• Clorazepate, like other benzodiazepines, is categorized as a restricted substance due to its potential for misuse and dependence, according to state and federal laws. 
• The drug impairs awareness and coordination; therefore, patients should use caution when driving or performing other tasks that require alertness while taking this medicine. 

Seniors may be more vulnerable due to impaired coordination and reflexes, perhaps leading to falls and injuries. 

• Co-administration with other central nervous system (CNS) depressants such as alcohol, opioids, and barbiturates may exacerbate these CNS effects. So quit drinking while taking the drug. 
• Prolonged usage of benzodiazepines as clorazepate could end in dependence. When the medicine is abruptly stopped, withdrawal symptoms may appear. Headaches, vomiting, decreased attention, confusion, tremors, muscle cramps, and seizures are among the withdrawal symptoms. 
• Benzodiazepines such as clorazepate are systemically acting depressants that might reduce breathing. This is especially challenging for people with chronic obstructive lung disease and emphysema. The respiratory depressive effect of benzodiazepines may further suppress respiratory drive in these patients, putting them at greater risk for respiratory depression and death. 

If you miss a dose, take it right away. If it is near the next planned dose, cancel the missed dose and resume your normal dosing schedule. Avoid taking double the prescribed dose.

• Clorazepate can be taken before or after meals. 
• Keep the medication in the original labeled, light-resistant container, away from heat and moisture, to avoid drug degradation by them. 
• Keep clorazepate away from your children.

How does clorazepate affect pregnancy and lactation?

• Clorazepate is classified as pregnancy category D.

Benzodiazepines and their metabolites are known to cross the placenta and accumulate in the fetal circulation. 

• They are associated with a risk of congenital malformations when used during pregnancy, causing cleft lip and heart deformities in the fetus. 
• Benzodiazepines such as clorazepate should be avoided during pregnancy, particularly in the first trimester. The use of benzodiazepines during pregnancy should be considered only when the need for the medication outweighs its risk and alternative therapies have failed. 

Nursing mothers should not take clorazepate, because it will pass into breast milk and be ingested by the baby. If stopping the drug is not an alternative, breastfeeding should not be started or should be discontinued.

What are the drugs contraindicated with clorazepate?

Clorazepate is metabolized hepatically by decarboxylation to give an active metabolite(nordiazepam) that with further metabolism by hydroxylation gives oxazepam.

• CNS depressants (alcohol, narcotics, barbiturates, hypnotics) and antihistamines could affect coordination and breathing while increasing drowsiness.

Cimetidine, Nefazodone, Erythromycin, Itraconazole, Ciprofloxacin, fluoxetine, ketoconazole, propranolol, divalproex sodium, propoxyphene; These medications may inhibit the metabolism of clorazepate, thus increasing the level and pharmacological effects of the drug and producing excessive sedation and other adverse CNS effects.