Benzodiazepines (BZDs)

BZDs have become more popular because :

High therapeutic index [50 times therapeutic doses à no death].

No CVS , respiratory depression, & less action on body systems

Less distortion sleep architecture; no rebound phenomena

Low abuse potential, low tolerance, less withdrawal symptoms, low physical & psychological dependence

Additional muscle relaxant property

Specific antidote Flumazenil in poisoning

BZD Pharmacology

BZDs qualitatively similar but different selectivity & duration of action. Anxiolytic, hypnotic, muscle relaxant & anticonvulsant. Decreases time to fall asleep & night awakenings increase duration. Decreases REM but less than barbiturates [Nitrazepam increases REM]. Less Night terrors & body movements; Stages I & 0 are lessened. Skeletal muscle relaxants without impairing voluntary activity. Tolerance develops to anticonvulsant action of Clonazepam & Diazepam à limited use in epilepsy

Mechanism of action of BZDs

Acts on ascending reticular formation [wakefulness] & limbic system [emotions]

BZDàMedulla / Cerebellumà muscle relaxation / ataxia

BZDà BZD receptor of GABA-A receptor Cl- channel

BZD à increase Cl- channel opening (GABA Facilitatory)

BZD action is indirect; mediated via GABA-A receptor

Kinetics

Varied; lipid solubility differ > 50 fold. Slow elimination: Flurazepam, Diazepam, Nitrazepam. Long T1/2; flurazepam is good for night awakenings. Rapid: Temazepam: good for sleep onset difficulty. Ultra rapid: Triazolam ; rapid, good for sleep induction. Midazolam: peak action in 20 min [also i.v anesthetic]

Adverse reactions of BZDs

Vertigo, ataxia, disorientation, amnesia, ­reaction time,¯psychomotor skills [no driving!]. Rarely paradoxical stimulation; irritability, sweating, nightmares & behavioural changes [especially nitrazepam]. Slow tolerance & cross tolerance with CNS depressants. Low potential for Dependence, addiction, drug seeking

Drug Interactions

Synergy with Alcohol, CNS depressants. Valproate à psychotic symptoms. Cimetidine, INH & oral contraceptives à decreases metabolism

Uses of BZDs

1.Hypnotic: ¯sleep latency, ¯night awakenings, ¯anxiety [Not for regular use; better to treat the root cause].

2. Anxiolytic for day time sedation.

3. Anticonvulsant; especially status-epilepticus, febrile convulsions, tetanus.

4. Central muscle relaxant.

5. Pre-anaesthetic medication.

6. Before ECT, Cardiac catheterisation, endoscopies, obstetrics, minor procedures, [ideal for calming + muscle relaxant action]

7. Alcohol withdrawal.

8. With analgesics, NSAIDs, etc.

BZD antagonist

FLUMAZENIL:

Competitive BZD receptor antagonist: no intrinsic action Abolishes BZD action

Use: Overdose of BZD; reverses BZD induced anaesthesia /sedation; abolishes hypnogenic, psycho-motor, cognitive actions of BZD [safe & well tolerated]

ZOPICLONE:

Cyclopyrolone derivative. Potentiates GABAA By binding to some other site. Used in short term insomnia

ZOLPIDEM:

Imidazopyridine derivative. Does not act on BZD receptors

Low abuse potential, Short acting drug

Category: Pharmacology Notes