Chemistry of Benzodiazepines
Benzodiazepines are composed of benzene rings fused to seven membered diazpine ring.
The substitution of halogen or nitro gp at position-7 produce more sedative and hypnotic compounds.
Mode of Action of Benzodiazepines
- Binding of GABA to its receptors on cell membrane triggers an opening of chloride channel which leads to an increase in chloride conductance.
- Benzodiazepine bind to specific, high affinity sites on cell membrane (benzodiazepine receptors) which are separate from but adjacent to GABA receptor.
- The benzodiazepine receptors are found only in CNS.
- The binding of benzodiazepine enhances the affinity of GABA receptors for neurotransmitter, resulting in more frequent opening of adjacent cl– channels.
Pharmacological Actions of Benzodiazepines
I. Sedative Effect
Most of benzodiazepines act as sedative when given in small doses.
II. Hypnotic Effect
Benzodiazepines produce sleep resembling natural sleep if high enough doses are given. Benzodiazopines produce this effect by:
- The latency of sleep onset is decreased
- The duration of stage 2 NREM sleep increased
- The duration of REM sleep is decreased
- The duration of stage 4 NREM slow-wave sleep is decreased
III. Anticonvulsant Effect
Benzodiazepines are capable of inhibiting the development and spread of epileptiform activity in the CNS.
Benzodiazepines are effective in the treatment of tonic-clonic seizures.
IV. General Anaesthesia
In large doses, benzodiazepines may cause anaesthesia due to CNS depression.
V. Effect on CVS
These effects are minimum when drug is administered orally.
Pharmacokinetics of Benzodiazepines
- Benzodiazepines when administered orally exhibit various rates of absorption:
Cmax for diazepam is 1 hour.
Cmax for lorazepam is 3 hour.
Cmax for oxazepam is 4 hour.
- Benzodiazepines are biotransformed in liver to active metabolites.
- Benzodiazepines are distributed throughout the body.
- Bnezodiazepines are excreted in urine as glucoronides or oxidized melabolites.
Clinical Uses of Benzodiazepines
- Benzodiazepines are used as anxiolytic
- Benzodiazepines are used as hynotic
- Benzodiazepines are used for sedation and amnesia before medical and surgical procedures
- Benzodiazepines are used for anaesthetic premedication
- Benzodiazepines are used for skeletal muscle relaxation
- Benzodiazepines are used in the treatment of epilepsy
- Benzodiazepines are used in acute mania
- Benzodiazepines are used in myoclonus
- Benzodiazepines are used in tetanus
- Benzodiazepines are used in pannic disorders
- Benzodiazepines are used in rapid eye movement disorders
- Benzodiazepines can be useful for short-term treatment of inasomnia
- Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification
Adverse Effects of Benzodiazepines
- Impaired judgement
- Myocardial depression
- Respiratory depression
- Change in appetite
- Blurred vision
- Lack of coordination
- Liver toxicity
Benzodiazepines Withdrawl Symptoms
Psychological and physical dependence on benzodiazepines can develop if high doses of drug are given over a prolonged period. Abrupt discontinuation of benzodiazepines result in withdrawl symptoms including:
- Muscle spasm
- Suicidal behaviour
Mangement of Withdrawl Symptoms of Benzodiazepines
- Withdrawl is best managed by transferring the physical dependent patients to an equivalent dose of diazepam because it has the longest half life of all benzodiazepines is metabolised into long acting active metabolites.
- Chlordiazepoxide, which also has a long half life and long acting active metabolised can be used as alternative.
- Alcohol is cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another.
- Chlorpromazine cna worsen withdrawl effects.
Drug Interactions of Benzodiazepines
- Oral contraceptives antibiotics like rifampici, anticonvulsants like phenytoin accelerate elimination of benzodiazepines and decreases their actions when given with benzodiazepines.
- Use of alcohol, opioids and other CNS antidepressants with benzodiazepines potentiates their action.
- Antacids may reduce the rate of absoption of benzodiazepines from the intestine when given with benzodiazepines.
Contraindications of Benzodiazepines
Benzodiazepines are contraindicated in the people with :
- Myasthenia gravis
- Sleep apnea
- Personality disorders
- Major depression
- Pregnancy (It crose the placental barrier and affects the growth and development of fetus)
- Liver disease
- Kidny disease