Clonazepam
Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72. Clonazepam is a benzodiazepine derivative (a chlorinated derivative of nitrazepam and therefore a nitrobenzodiazepine). It is available in US, UK and other countries.

Benzodiazepines are sedative-hypnotic drugs that help to relieve nervousness, tension, anxiety symptoms and seizures by slowing the central nervous system.

Pharmacology : Clonazepam has anticonvulsant, muscle relaxant and anxiolytic properties.

Pharmacokinetics
Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations are reached within 1 to 4 hours after oral administration. The elimination half-life of clonazepam is typically 30 to 40 hours.

Mechanism of action :
Clonazepam is an anti-anxiety medication in the benzodiazepine family, the same family that includes diazepam, alprazolam, lorazepam, flurazepam and others. Clonazepam and other benzodiazepines act by enhancing the effects of gamma-aminobutyric acid (GABA) in the brain. GABA is a neurotransmitter that inhibits brain activity. It is believed that excessive activity in the brain may lead to anxiety or other psychiatric disorders.

Indications

• Anxiety
• Panic disorders
• Some types of epilepsy
• To treat social phobia, mania, and post-traumatic stress disorder
• Certain types of seizures, specifically petit mal seizures, akinetic seizures, and myoclonus, as well as Lennox-Gastaut syndrome.

Panic disorder is characterized by recurrent unexpected panic attacks, i.e. a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Recommended dosage :
For panic disorder, the initial recommended dose is 0.25 mg twice daily. This dose can be increased every three days in increments of 0.125–0.25 mg twice daily. The target dose for panic disorder is 1.0 mg per day, although some people benefit from doses up to a maximum of 4 mg per day.

For the treatment of post-traumatic stress disorder, doses in the range of 0.25–3 mg daily appears to help treat symptoms of this disorder. Daily dosages for the treatment of social phobia range from 1.0–2.5 mg, while the dosage to control mania may be as high as 10 mg daily.

Maximum recommended daily dose is 20 mg.

If clonazepam is taken continuously for longer than a few months, stopping therapy suddenly may produce seizures, tremors, muscle cramping, vomiting and/or sweating. Therefore, discontinuation usually is accomplished by reducing the dose gradually.

Side effects :
Sedation, dizziness, impaired coordination, depression, sleeps disturbance, fatigue and behavior changes.

In few cases : sinus problems and upper respiratory tract infections, increased salivation, anorexia, dry mouth, blurred vision.

Precautions : Renal disease, respiratory disease or an impaired gag reflex

Contraindications :
Pregnancy, lactation, allergic reaction to it or another benzodiazepine drugs, people with narrow-angle glaucoma or severe liver disease.

Drug interactions :
Because clonazepam is a nervous system depressant, it should not be taken with other drugs such as alcohol, other sedatives, sleeping pills, or tranquilizers, opiates, antihistamines.

Medications that make clonazepam ineffective include phenobarbital, phenytoin, carbamazepine , theophylline, rifampin, and rifabutin.

Warning : They should not drive, operate dangerous machinery, or engage in hazardous activities that require mental alertness.

Clonazepam Efficacy :

Panic Disorders :
In chest pain patients with panic disorder and normal coronary arteries, eight of twelve (67%) clonazepam treated patients responded with reduction of panic attacks by week four to zero per week or half of initial frequency compared to seven of fifteen (47%) placebo treated patients. The results show a generally good outcome in chest pain patients with panic disorder, and they provide suggestive evidence for the efficacy of clonazepam compared to placebo. The International Journal of Psychiatry in Medicine Volume 29, Number 1 / 1999: 97 – 105

Four hundred thirteen patients with panic disorder were randomly assigned to receive placebo or one of five fixed daily dosages of clonazepam (0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, and 4.0 mg). After 3 weeks of dose escalation, the fixed dose was given for 6 weeks (the dose-maintenance phase) and then was tapered during a 7-week discontinuance phase. Dose-response analysis showed that daily dosages of 1.0 mg and higher were equally efficacious in reducing the number of panic attacks. All treatments were well tolerated. Daily dosages of 1.0 to 2.0 mg of clonazepam offered the best balance of therapeutic benefit and tolerability. J Clin Psychopharmacol 1997;17:390-400.

To assess the effectiveness of clonazepam, in a fixed dose (2 mg/day), compared with placebo in the treatment of 24 panic disorder patients with agoraphobia. At the therapeutic endpoint, only one of 9 placebo patients (11.1%) were free of panic attacks, compared with 8 of 13 (61.5%) clonazepam patients. The results provide evidence for the efficacy of clonazepam in panic disorder patients. Arq. Neuro-Psiquiatr. vol.58 n.4 São Paulo Dec. 2000

The inhalation of 35% carbon dioxide has consistently been shown to provoke panic attacks in panic disorder patients. In the clonazepam group (2 mg dose) (n=11) two patients (18.2%) had a mild panic attack and in the placebo group (n=11) nine patients (81.8%) had a moderate to severe panic attack in the CO2 challenge test. The findings suggest the efficacy of an acute dose of clonazepam in attenuating panic attacks induced by carbon dioxide inhalation. Psychiatry Research, Volume 94, Issue 2, Pages 179-184

In seizures control :
Clonazepam is a new benzodiazepine anticonvulsant recently approved for the treatment of typical absence, infantile myoclonic, atypical absence, myoclonic, and akinetic seizures. Arch Neurol. 1976;33(5):326-332.
A patient with multi-infarct dementia and associated hypomanic features was treated effectively with clonazepam to control logorrhea, hyperactivity, agitation, intrusiveness, and impulsive violence and to promote cooperation and manageability. Plausible mechanisms include the ability of clonazepam to stimulate serotonin synthesis, to bind highly and specifically to the active benzodiazepine binding site, and to raise the seizure threshold. J J Geriatr Psychiatry Neurol 1988;1:47-48

In a controlled clinical investigation based on ten patients with simple absences and ten patients with myoclonic atonic seizures, all patients who had insufficient response to conventional antiepileptic treatment received clonazepam combined with previous antiepileptic drugs. In a daily dose of usually 3 to 6 mg, depending on patient age, the antiepileptic effect of clonazepam was significantly superior to placebo and was estimated as remarkably good. Arch Neurol. 1976;33(5):322-325.

In convulsions and seizures : Superior than doazepam – Animal study
The experimental convulsions and focal electroencephalographical and clinical seizures in cats shows a significant increase in the bemegride threshold as well as a signicant decrease in focal epileptic activity. Clonazepam comparable dose is ten times smaller to that of diazepam and with less side-effects. Clonazepam was much superior to diazepam in suppressing focal seizures and focal spiking. Epilepsia 5 Nov 2007 Volume 14 Issue 2 Pages 195 – 202.

In chronic, nonmalignant pain :
A randomized, double-blind controlled trial is reported comparing phenobarbital and clonazepam for the purpose of sedative-hypnotic taper in inpatients with chronic, nonmalignant pain. The findings support the superiority of clonazepam over barbiturates for sedative-hynotic taper for symptoms of withdrawal. Annals of Clinical Psychiatry, Volume 5, Issue June 1993 , pages 123 – 128.

Clonazepam –Superior than alprazolam

• Longer half life
• Free from interdose rebound symptoms In a 6 week placebo controlled trial comparing clonazepam and alprazolam, also found that clonazepam (mean=2.5mg/day) and alprazolam (mean=5.3mg/day) , as compared to placebo, significantly reduced panic attacks and improved global functioning. 50% of the clonazepam group, 46% of the alprazolam group, and 14% of the placebo group were panic free for two consecutive weeks. Clearly, Clonazepam is a reasonable alternative to alprazolam. The advantages of clonazepam therapy are primarily due to its long half life, allowing for less frequent dosing and decreased probability of interdose rebound symptoms. Smit S., Sinha et al., Pharmacotherapy of Panic Disorder Forty-eight consecutive patients treated for panic disorder with alprazolam, but with presumed interdose anxiety symptoms, were switched to clonazepam. Forty-one patients made the “switch” according to a protocol, and 82% rated clonazepam “better” because of decreased frequency of administration and lack of interdose anxiety. J Clin Psychopharmacol. 1987 Jun;7(3):175-8.