Benzodiazepines

Classification of benzodiazepines

1. Diazepam

2. Lorazepam

3. Midazolam

4. Clonazepam

5. Nitrazepam

6. Clorazepate dipotassium

7. Clobazam

MOA of benzodiazepines

MOA

• All the benzodiazepines produce their functional effects by positive allosteric modulation of GABA a receptors; results in chloride influx → hyperpolarisation

PK of benzodiazepines

PK

Well absorbed after oral administration

Are lipophilic - widely distributed in the body esp CNS

PPB - 80-90%

Clobazam has a half-life of 10-30 hours

• It is metabolized in the liver by

CYP & non-CYP transformations, with up to 14 metabolites; > However, the major metabolite is N-desmethylclobazam. (norclobazam) which is produced by CYP3A4

Norclobazam is then mainly metabolized by CYP2C19 except in CYP2C19-poor metabolizers with a CYP2C19 inactive allele.

• With long-term administration of clobazam, levels of norclobazam, which has a longer half-life than clobazam, are 8-20 times higher than those of the parent.

eliminations primarily in the kidneys

ADRS of benzodiazepines

AEs

• Tolerance to clobazam is not a prominent issue in clinical Rx.

• Side effects that occur in a dose-dependent fashion include

somnolence

sedation

dysarthria , drooling

behavioral changes, including aggression.

• Withdrawal symptoms may occur with abrupt discontinuation.

DIs of benzodiazepines

DIs

• Cannabidiol inhibits CYP2C19 to cause a threefold increase in plasma concentrations of norclobazam

• When cannabidiol is added, the clobazam dose may require reduction to avoid excessive sedation.

• Clobazam is a moderate inhibitor of CYP2D6 & significantly increases the levels of drugs metabolized by this isoenzyme such as phenytoin & carbamazepine.

> Reduced dosing may be required when these drugs are used in combination with Clobazam

Aspects that limit the usefulness of benzodiazepines - 2

Clinical use of benzodiazepines

• Two prominent aspects of benzodiazepines limit their

usefulness in the chronic therapy of epilepsy.

1. Their pronounced sedative effects;

›However, in children, there may be a paradoxical hyperactivity, as is the case with other sedative agents such as barbiturates.

2. Tolerance with chronic dosing, whereby seizures may respond initially but recur within a few months.

• As a result of these limitations, benzodiazepines are rarely used in the chronic Rx of epilepsy.

Clinical use of clobazam

1. Clinical use of Clobazam

• It is used for the Rx of

i. Focal seizures

ii. Seizures associated with Lennox- Gastaut syndrome in patients > 2 years of age.

• Norclobazam has antiseizure activity, although it is weaker than clobazam.

> However, because norclobazam levels are so much higher at steady state, seizure protection during chronic therapy is likely mainly due to norclobazam.

Clinical use of diazepam

i. Diazepam given IV is a first-line Rx for status epilepticus.

ii. It is also used in a rectal gel formulation or nasal spray for the Rx of acute repetitive seizures (seizure clusters).

• Diazepam is occasionally given orally on a long-term basis

-However, it is not very effective in this application because tolerance limits its efficacy.

Clinical use of larazepam

• Lorazepam is more commonly used in the Rx of status epilepticus because it has a more prolonged duration of action after bolus IV injection.

• Lorazepam is also available as an oral concentrate that may be administered buccally.

• A sublingual tablet is also available & Lorazepam can also be administered nasally-

Clinical use of midazolam

4. Clinical use of Midazolam

i. IM midazolam is well absorbed from muscle & is rapidly acting.

> It is preferred in the out-of-hospital Rx of status epilepticus because the delay required to achieve IV access may be avoided.

ii. Midazolam is available as a nasal spray for the Rx of acute repetitive seizures (seizure clusters) & in buccal (oromucosal) dosage form

Clinical use of clonazepam

5. Clinical use of Clonazepam

• Clonazepam is a long-acting benzodiazepine that on a milligram basis is one of the most potent antiseizure agents known.

• It has efficacy in the Rx of absence, atonic, and myocionic seizures.

• As is the case for all benzodiazepines, sedation is prominent, especially on initiation of therapy;

• Starting doses should be small.

• Maximal tolerated doses are usually in the range of 0.1-0.2 mg/kg/d, but many weeks of gradually increasing daily doses may be needed to achieve these dosages in some patients.

• IV clonazepam is frequently used as a first-line therapy for status epilepticus

Clinical use of Nitrazepam

• It is used for infantile spasms and myoclonic seizures.

Clinical uses of clorazepate dipotassium

• It is approved for the Rx of focal seizures.

• Drowsiness and lethargy are common adverse effects,

-However, if the drug is increased gradually, dosages a high as 90 mg/d can be given.