Clobazam

7-Chloro- 1-methyl- 5-phenyl- 1,5-benzodiazepine- 2,4(3H)-dione

INTRODUCTION

• synthesized in 1972 by modification of the 1,4-diazepine structure

• The resulting 1,5 structure retained 20% of the the anxiolytic activity of diazepam,10-15 % of diazepam's sedative effects .

• introduced as an anti-anxiety agent about half as potent as diazepam and producing less psychomotor side-effects than diazepam.

• later found to have major antiepileptic effects

CHEMISTRY

• white hygroscopic powder with MW 300.73.• It has a bitter taste, is relatively insoluble in water • cannot be given as intravenous or intramuscular

injection.• It is a weak organic acid and forms water-soluble

salts at acidic pH. • At physiological pH its lipid solubility is about 40%

of that of diazepam

Mode of action

• Clobazam exerts its anxiolytic and anticonvulsant action at the benzodiazepine binding site of the Gamma-aminobutyric acid A (GABA -A) receptor complex by increasing the likelihood of opening of the ligand-gated Cl~ ion channel in response to given concentration of GABA.

• less affinity for the ω1-allosteric binding site on the GABAA

receptor compared to the 1,4-benzodiazepines.• selective affinity for the ω2 site, where it has agonistic

activity.• action at a lower affinity membrane site which probably

involves an increase in the population of sodium channels in the inactive state, limiting the repetitive firing of neurones.

• A decrease of voltage-sensitive Ca conductance is also observed, limiting Ca(++) entry presynaptically and decreasing neurotransmitter release

Pharmacokinetics

• absorbed rapidly and almost completely. • Mean absorption half-life is 20 min. • It is unaffected by age or sex. • The rate of absorption is reduced when the

drug is taken with or after meals, but the extent of absorption is not .

• The drug is highly lipophilic and, after absorption, is rapidly distributed in fat and cerebral grey matter.

• Maximal plasma concentration after a single dose is seen after 1-4 h• half-lives varies from 11 to 77 h in healthy subjects, with the

longest half-life in the elderly .• The half-life of clobazam's major metabolite, Ndesmethylclobazam

is even longer, about 50 h .• At clinical doses , plasma concentration of the metabolite (300-

3500ng/mL) is usually 10-fold greater than clobazam concentrations (20-350 ng/mL) .

• good correlation between plasma concentration and dose in the individual patient but large interindividual variations.

• Measurements of serum levels, however, have not been found useful clinically.

• Plasma protein binding of the benzodiazepines varies from nearly 99% for diazepam to 70% for alprazolam.

• Clobazam protein binding is 83%. • The protein bound fraction is independent of

plasma concentration of clobazam• only changed by lowered protein content, which

may be of importance in hepatic and renal diseases and other conditions with lowered protein, e.g. in the elderly.

Drug interactions

• has a complex pattern of interactions, with marked interindividual variability.

• increase or decrease in the blood levels of phenobarbital, phenytoin or carbamazepine .

• Phenytoin toxicity in patients on maximal tolerable phenytoin doses when clobazam was added

• levels of all enzyme-inducing antiepileptic drugs can alter in susceptible patients.

• The combination of valproate in doses of 1500-2000 mg and clobazam leads to an increase in serum valproate levels often with toxic-confusional states

• These rather unpredictable interactions may be the explanation for the aversion to clobazam shown by some patients with chronic epilepsy on antiepileptic polytherapy.

• Clobazam levels are generally lower and norclobazam levels higher in patients who are comedicated with enzyme-inducing antiepileptic drugs.

• Comedication with carbamazepine seems to induce the epoxidation of this drug

• Conversely, it has also been reported that clobazam levels can be raised in bitherapy with phenobarbital, phenytoin and carbamazepine .

• Concomitant administration of alcohol and cimetidine can also lead to a significant increase in clobazam levels.

Biotransformation• Clobazam is metabolized to least 12 metabolites.• biotransformation of clobazam is by oxidation in the liver to

desmethylclobazam (norclobazam), an active metabolite.• Norclobazam may be responsible for the effects of clobazam . serum

concentrations are usually over 10-fold higher than the parent drug.• Studies in baboons have shown antiepileptic effects 5-6 h after IV

infusion, by which time clobazam plasma concentrations have fallen to low levels.

• the lipophilicity of norclobazam is lower than that of clobazam, and the affinity for the benzodiazepine receptor is more than 10-fold lower than that of clobazam.

• Desmethylclobazam is further metabolized by conjugation and excreted in bile as glucuronate and in bile and urine as the sulphate

Toxicity

• sedation, development of tolerance and withdrawal symptoms can limit the use of 1,4 benzodiazepines in chronic treatment of epilepsy,

• clobazam has less detrimental effects on psychomotor performance than these drugs .

• Impairment on a few cognitive tests, mainly retrieval processes and mental rapidity has been reported .

• Muscle fatigue or weakness is an effect apparent in dynamic work situations where a disorderly recruitment of motor units is seen .

• Significant toxicity includes sedation, dizziness, headache, nausea, amnesia, ataxia and blurred vision or diplopia.

• In chronic institutionalized patient populations increased irritability, depression and disinhibition occurs and behaviour disturbance may be seen. .

• Drowsiness and dizziness were the most common side-effects. • Gelastic seizures,Urticaria ,Rashes,are rare side effects• side-effects were mild and transient, and seems well tolerated. • The plasma concentration of the metabolite norclobazam is

increased significantly in polytherapy, and this may be the cause of some of the sedative side-effects

Tolerance

• Tolerance or 'escape' is usually measured as an increase of seizure frequency in the last half of a treatment period,

• Tolerance is increased by high doses, and decreased by intermittent treatment

• In patients with temporal lobe epilepsy tolerance was found to be increasing slowly from 3% after 1 month to 35% after 2 years and did not seem to increase further

• Used as monotherapy in childhood epilepsy, tolerance was noted in7 .5%, as compared to 4.3% for carbamazepine and 6.7% for phenytoin monotherapy .

• Tolerance to sedation develops more quickly than tolerance to the anticonvulsant or anxiolytic effects

withdrawal

• Withdrawal symptoms with irritability, restlessness and difficulty to concentrate appears in 5-10% during the first 14 days after termination of treatment.

• Tapering will in most cases prevent this.

Antiepileptic effectiveness

• tried in patients with refractory epilepsy of long standing as an addition to other antiepileptic treatment.

• Patients of all ages, aetiologies and seizure types responded.

• Some consider partial seizures to do best, and others secondarily generalized attacks.

• It has been claimed that patients with symptomatic epilepsy, most often with partial seizures without secondary generalization and without mental retardation, respond best to clobazam , but this is an uncontrolled observation which has not been replicated

adjunctive therapy in • complex partial seizures• myoclonic, • myoclonic-absent, • simple partial,• non-status absence seizures

Open studies reported a beneficial and even astounding effect in

• non-convulsive status, • startle seizures ,• Lennox-Gastaut syndrome • alcoholic withdrawal seizures , Studies of clobazam used as monotherapy are

very few. Clobazam has, however, been used in open

studies as the only drug in benign childhood partial epilepsy and found of value even in carbamazepine-resistant cases .

Uncontrolled observations (as well as routine clinical experience) show good efficacy

• acute epilepsy, • clusters, • serial seizures • prophylaxis (e.g. on days when it is important to avoid a

seizure such as when travelling, taking examinations, interviews, etc.).

• Clobazam is the drug of first choice for such intermittent therapy

• intermittent therapy in catamenial epilepsy

Dose and clinical therapeutics

• 5 to 140 mg/day. • There is now general agreement that doses between 10 and 20

mg/day (in adults) are usually best, • few patients who continue to have seizures respond better to

higher doses, • Dose adjustments are not usually needed in patients

comedicated with other antiepileptic drugs. • The frequency of side-effects increases sharply with higher

doses (above 30mg/day). • The usual daily dose for acute prophylaxis is lOmg.• Clobazam withdrawal should be carried out slowly in a staged

fashion.