Benzodiazepines or BDZ are compounds have largely replaced the barbiturates as hypnotics and act as sedatives, anticonvulsants, muscle relaxants and anesthetic agents.
Mechanism of action of Benzodiazepines or BDZ
Benzodiazepines or BDZ bind selectively to the a subunit of the GABA-A receptors surrounding the chloride channels in the CNS, a site distinct from that to which barbiturates bind, and designated as benzodiazepine receptors (BDZ receptors).
They modulate the effects of GABA, thereby increasing the frequency of chloride channel opening, and increasing the chloride ion concentration in the neuron.
This causes hyperpolarization of the neuronal membrane, making it more difficult for the excitatory neurotransmitters to depolarize the cell. They enhance the effectiveness of GABA by lowering the concentration of GABA required for opening the chloride channels.
Although all the Benzodiazepines or BDZ have similar pharmacological properties, they differ in their selectivity and vary in their clinical usefulness owing to the existence of multiple BDZ receptor subtypes in the CNS.
For example, the anti-spasticity effect appears to involve the GABA-A receptors in the brain stem and the spinal cord, whereas the sedative and anticonvulsant actions are localized to the limbic system.
Pharmacological actions of Benzodiazepines
Benzodiazepines act as
- Hypnotics and Sedation
- Muscle relaxants
- Anesthetic action
In small doses, Benzodiazepines produce relief from anxiety and in larger doses, they induce sleep. All benzodiazepines arc qualitatively similar in their effects on the important sleep parameters.
Thus, they decrease the time to onset of sleep, prolong stage 2 of sleep, and shorten stages 3 and 4 and REM sleep. The total sleep time is increased.
Clinically, Benzodiazepines are preferred as hypnotics because they:
- Induce sleep which is more refreshing and with fewer hangover symptoms such as drowsiness, dysphoria, and mental or motor depression.
- Preserve near-normal sleep, remain effective as hypnotics for longer periods of time, and cause less rebound of REM sleep after withdrawal.
- Can induce sleep even in the presence of pain.
- Do not exert significant action on respiration and CVS even in large doses, in normal subjects.
- Have higher therapeutic index; and
- Cause fewer drug interactions and have less potential than barbiturates for drug abuse.
- All can induce anterograde amnesia, where there is impairment of memory for events after the drug.
Muscle relaxant and anti-convulsion actions:
They have a central muscle relaxant action. They increase the seizure threshold and act as anticonvulsants.
They may lower the BP and decrease the respiratory rate.
Absorption, fate and excretion of Benzodiazepines
The various Benzodiazepines differ from each other in their pharmacokinetic characteristics. Given orally, diazepam and cholrazepate are most rapidly and completely absorbed from the proximal small intestine; prazepam and oxazepam arc the least rapidly absorbed; flurazepam and lorazepam fall in between these two groups.
The absorption of chlordiazepoxide and diazepam given IM is slow, incomplete and erratic. The only BDZ with reliable absorption from the IM site are lorazepam and midazolam. Rectal route for diazepam is generally used in the convulsing patient.
The duration of action following a single dose depends upon the rate and extent of drug distribution and of metabolic degradation. BDZ are metabolized by hepatic microsomal CYP450 enzymes, and hepatic damage prolongs their action.
The t1/2 is prolonged in subjects over 60 years age and in infants due to reduced hepatic clearance; hence, dosage should be reduced under such conditions. Depending on their elimination t1/2, they can be grouped.
Some of the BDZ are bio transformed to clinically active metabolites, some of them with longer half-life than the parent compound. Thus, desmethylduizepam (t1/2 36-200 hours), a major metabolite, plays an important role in the clinical effects of cholrdiazepoxide, diazepam, prazepam, chlorazepate and medazepam.
Clorazepate and prazepam are in fact pro-drugs and reach the systemic circulation only as desmethyldiazepam. Flurazepam is converted to the active metabolite desalkylflurazepam.
Multiple dose therapy with such drugs leads to accumulation of the long half-life, active metabolites, resulting in prolongation of the effect, and may cause unwanted daytime sedation.
However, it should be noted that the clinical drug effects do not necessarily increase in direct proportion to plasma concentration because of development of tolerance.
Because of long half-life, clinically important amounts of chlordiazepoxide, diazepam or desmehtyl-diazepam may persist in the blood and in the body for many days/weeks after termination of prolonged therapy.
This could be beneficial in anxiety state as it prevents the rapid return of anxiety and delays the development of withdrawal symptoms.
BDZ with short t1/2 such as oxazepam, lorazepam, temazepam arc preferred hypnotics when residual daytime effect is undesirable. Oxazepam and lorazepam lack active metabolites and are preferred in the elderly.
Adverse reactions of Benzodiazepines or BDZ
Benzodiazepines in general are well tolerated. The common side effects are due to dose related depression of CNS: drowsiness, lethargy and ataxia. They also cause impairment of visual-motor coordination, behavioral changes, daytime sedation, and anterograde amnesia.
The drugs may occasionally produce personality changes and may cause a paradoxical increase in hostility, irritability and anxiety especially in the elderly. They should be used cautiously in the presence of respiratory, liver and cardiac diseases.
Rarely, BDZ cause leucopenia allergy, photosensitization, vertigo, headache, impaired sexual function and menstrual irregularities.
Patients develop tolerance to the sedative (but not to the anxiolytic) action, as well as physical and psychic dependence.
Withdrawal symptoms include insomnia, agitation and rarely convulsions. The withdrawal symptoms are more intense following the discontinuation of shorter acting BDZ than of longer acting BDZ. The treatment is similar to that of barbiturate dependence.
Administration of BDZ to the mother before delivery can cause apneic spells, reluctance to feed, hypotonia and hypothermia in the newborn (floppy baby syndrome).
Drug interactions: They may produce bizarre interactions with alcohol, MAO inhibitors, barbiturates and amitriptyline. H2 receptor blockers like cimetidine and the anti-tuberculosis drug INH retard the elimination of diazepam by inhibiting the hepatic microsomal enzymes. However, serious drug interactions are rare.
Therapeutics uses of Benzodiazepines
- As hypnotics
- In anxiety states and neuroses
- During withdrawal of alcohol
- As anticonvulsants
- As anesthetic medication: Short half-life midazolam may be used IV in anesthesia