Benzodiazepines

Structure of Benzodiazepines

Benzene ring (A)
Seven member diazepine ring (B)
5 aryl substitution ring
Chemically known as 5-aryl 1,4 benzodiazepine

Position 7 of ring B is substituted with chloride or nitro group.

There are more than 60 benzodiazepine structures differentiated by duration of action and pharmacokinetic profile. Position 7 is important.

Site and Mechanism of Action

Act in CNS at different levels
Limbic system or area and reticular activating system
Muscle relaxation is important, mediated by action on medullary sites
In high doses cause ataxia due to action at cerebellum
Have widespread effects.

GABA is the inhibitory neurotransmitter in CNS, it is of two types:

GABA A receptor –ligand gated Cl- channel.
GABA B receptor –G protein coupled receptor (acts on central muscle relaxants)

Receptor is further divided into alpha, beta and gamma subunits.

Binding site of GABA is beta subunit. Benzodiazepines bind alpha receptor.

GABA receptors are located post-synaptically, mediating post synaptic inhibition. Chloride channels are selectively permeable to chloride channels, it has some negativity and some negative potential.

Benzodiazepines act by enhancing presynaptic/postsynaptic inhibition through a specific BDZ receptor which is an integral part of the GABA receptor chloride channel complex, located on supramolecular complex.

Benzodiazepines are GABAERGIC, they potentiate the inhibitory neuro-transmission of GABA in various parts of CNS.

In absence of GABA, benzodiazepines are inactive.

Benzodiazepines when administered they bind with their own receptors, they Displace GABA modulin from GABA receptors, increase GABA Binding, Increase frequency of opening of Cl- channels – increase influx of chloride through GH Cl channels in neurons membrane, Resulting in hyperpolarizations.

Besides benzodiazepines, other ligands bind as well like barbiturates and antagonists too.

Benzodiazepine Receptor Ligands

1. Agonists

– Facilitate GABA-ergic inhibition & produce anxiolytic & anti-convulsant effect

– Zolpidem & related imidazopyridine are selective agonist at BZ,(omega) receptors

– Endozepines also act on GABA- mediated chloride channels gating in cultured neurons

2. Antagonists
– Block the action BDZ at receptors “Flumazenil”.

3. Inverse Agonists
“Beta carbolines produce anxiety & seizures.

Pharmacological Properties Of Benzodiazepines

Anti-anxiety
Amnesia
Sedation
Hypnosis
On I/V admin produce state of anesthesia
Anticonvulsant action
Central muscle relaxation due to depression of polysynaptic reflexes in the spinal cord
Coronary vasodilatation seen with some benzodiazepines on I/V admin
Neuromuscular blockage, seen only with very high doses

Pharmacokinetics

There are a large number of compounds, administered mainly orally having various rates of absorption.

All members are well absorbed after oral administration, which exception of Oxyzepam and lorezepam, which are absorbed slowly.

They have a strong protein binding, thus have a chance of accumulation in the body fat.

Oral route is preferred. Also given I/V (5-10 mg diazepam for status epilepticus). Not well absorbed by I/M route. Lorezepam is given I/M.

Metabolism:

– By liver microsomal enzymes

– But do not induce enzymes.

– Microsomal oxidation & N. dealkylation (phase 1 reactions) & aliphatic hydroxylation

– Glucuronidation (Phase II reactions )

– Excretion in urine

Chlordiazepoxide has been removed from market because of chances of respiratory and cardiac depression.

Clorazepate is a prodrug

Desmethyldiazepam is an active metabolite

Oxazepam and Lorazepam are short acting, used for daytime sedation

Flurazepam is converted into three active metabolites (hypnotic use):

Hydroxyl ethyl flurazepam
Desalkyl flurazepam
Flurazepam aldehyde

Therapeutic Uses Of Benzodiazepines

To relieve anxiety & related states

Response to stress is reduced –calming effect
Spontaneous activity is decreased
Prolongation of reaction time with stimulus
Decrease in responsiveness to stimulus
amnesia-forgetfulness
Hasten onset of sleep
Restlessness is reduced
Night terrors are decreased
Total sleep time is increased
Stage 2 of sleep is increased, 3 and 4 are somewhat decreased
Individual gets up after a refreshing sleep
REM lessened but has less effect
Sleep shifts –less goes into stage 1
Duration of sleep is increased

To induce sleep/hypnosis

To relieve excitement
For symptomatic treatment of convulsions /epilepsy

Diazepam and Clonazepam are used.

Diazepam is used I/V for status epilepticus
Clonazepam is used for convulsions

Central muscle relaxation

Increase in tone of muscles is a common feature of anxiety; benzodiazepines produce relaxation by acting on medullary areas.

Relaxant effect is clinically important. Diazepam is frequently used for muscle relaxing property with antianxiety effect.

Pre anesthetic medication
To control ethanol or other sedative/hypnotic withdrawal states
Muscle spasm
Use in anesthesia induction, maintenance & amnesia

Even at highest dose, complete anesthesia is not produced, as there is some awakening.

Adverse effects

Safest drugs if used rationally. Side effects are of hypnotic doses these include:

Dizziness, vertigo, ataxia, disorientation, prolongation of reaction time, impaired psychomotor skills
Weakness, blurring of vision
Dry mouth
Urinary incontinence
Paradoxical stimulation, irritability and sweating (with Flurazepam)
Nightmares, behavioral alterations (Nitrazepam)
Tolerance to sedative effects
Administration during labor may cause flaccidity, respiratory depression in neonates leading to floppy baby syndrome
Tolerance and dependence (Physiologic and psychological) –long acting have less chances of tolerance, short acting have rebound phenomenon.
Performance & alertness decrease ( Ist week of treatment) (driver & machine operator)
Potentiation of effects alcohols & similar drugs
Rebound insomnia
Anterograde amnesia.
I/V injection may cause apnea & cardiac arrest
Behavior disorder is a contraindication
Teratogenic

Short acting benzodiazepines have more chances of withdrawal symptoms.

Drug interactions

Increase alcohol, barbiturate & other depressants effects
Cimetidine and isoniazid and oral contraceptives are enzyme inhibitors, cytochrome p450 is inhibited, thus they retard benzodiazepine metabolism, increasing their half life.
Benzodiazepines increase phenytoin plasma levels, when given concomitantly.
BDZ may worsen the tremor of parkinsonism treated with levodopa.