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Benzodiazepines

Structure of Benzodiazepines

  1. Benzene ring (A)
  2. Seven member diazepine ring (B)
  3. 5 aryl substitution ring
  4. 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
  1. Act in CNS at different levels
  2. Limbic system or area and reticular activating system
  3. Muscle relaxation is important,  mediated by action on medullary sites
  4. In high doses cause ataxia due to action at cerebellum
  5. Have widespread effects.

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

  1. GABA A receptor –ligand gated Cl- channel.
  2. 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

  1. Anti-anxiety
  2. Amnesia
  3. Sedation
  4. Hypnosis
  5. On I/V admin produce state of anesthesia
  6. Anticonvulsant action
  7. Central muscle relaxation due to depression of polysynaptic reflexes in the spinal cord
  8. Coronary vasodilatation seen with some benzodiazepines on I/V admin
  9. 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):

  1. Hydroxyl ethyl flurazepam
  2. Desalkyl flurazepam
  3. Flurazepam aldehyde

Therapeutic Uses Of Benzodiazepines

  1. 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
  1.   To induce sleep/hypnosis
  1.   To relieve excitement
  2.   For symptomatic treatment of convulsions /epilepsy

Diazepam and Clonazepam are used.

  • Diazepam is used I/V for status epilepticus
  • Clonazepam is used for convulsions
  1. 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.

  1. Pre anesthetic medication
  2. To control ethanol or other sedative/hypnotic withdrawal states
  3. Muscle spasm
  4. 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:

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

Short acting benzodiazepines have more chances of withdrawal symptoms.

Drug interactions
  1. Increase alcohol, barbiturate & other depressants effects
  2. Cimetidine and isoniazid and oral contraceptives are enzyme inhibitors, cytochrome p450 is inhibited, thus they retard benzodiazepine metabolism, increasing their half life.
  3. Benzodiazepines increase phenytoin plasma levels, when given concomitantly.
  4. BDZ may worsen the tremor of parkinsonism treated with levodopa.
Advantages of benzodiazepines over barbiturates
  1. No hyperalgesia
  2. No confusion state in elderly
  3. Selective in nature and do not cause generalized CNS depression. Selective action on:
  • Limbic system
  • Substantia nigra
  • Globus pallidus
  • Cerebral and cerebellar cortex
  1. Safe as compared to barbiturates (high therapeutic index)
  2. No disturbance of sleep pattern.
  3. Less abuse liability
  4. No loss of consciousness
  5. Produce less CVS and respiratory depression
  6. Mild tolerance as compared to barbiturates
  7. Do not induce enzymes, so less severe enzyme interactions

Therapeutic classification

Sedative/ hypnotics

Lormetazepam,

Temazepam,

Nitrazepam,

Flurazepam

Anxiolytics

Diazepam,

Oxazepam,

Lorazepam

Anticonvulsants
Diazepam,

Nitrazepam,

Clonazepam

Lorazepam

Central muscle relaxants

Diazepam,

Flurazepam,

Clonazepam

 Anxiolytics

1Benzodiazepines

Alprazolam

Bromazepam

Lorazepam

Diazepam

2. Imadazopyridine derivative

Zolpidem

3. Pyrazolopyrimidine Derivative

Zaleplon

4. Cyclopyrrolone Derivatives

Eszopiclone, Zopiclone

5. Azapirones

Buspirone

Gepirone

Ispirone

6. Beta- Adrenergic Blockers

            Propranolol

7. Anti-depressants

Amitryptyline

Pharmacological Actions

1. Sedation:

It is the suppression of responsiveness to a constant level of stimulation with decreased spontaneous activity and ideation.

–          Occurs at lowest hypnotic doses.

–          Ability to release punishment suppressed behavior

In animals ( equated with anti anxiety effects)

-Cause anterograde amnesia

-Antipsychotic & Tricyclic antidepressants do not have this effect.

-Behavior disinhibiting effect, although they can cause sedation.

2. Hypnosis:

Increase in dose leads to hypnosis

NREM (70-75%) REM (10-15%) (Cyclic NREM/REM Sleep)

Latency of sleep decrease (time to fall a sleep)

Duration of NREM (stage-2)

Duration of REM increase.

Duration  of slow wave  sleep decrease.

3. Anesthesia

–          Diazepam & midazolam have been tried

–          Not very successful.

–          Cause prolonged respiratory depression

4. Anti Convulsant Effect

-Clonazepam, diazepam, lorazepam, nitrazepam have selective anti seizure activity.

5. Muscle Relaxation

-Exert inhibitory effect on polysynaptic reflexes and internuncial transmission.

-High doses decrease transmission at N.M junction as well

-Decrease Muscle spasm

6. Effects On CVS and Respiration

-Hypnotic dose – no prominent effect

-increase doses – decrease respiration

-Increase doses – decrease CVS functions

-I/V dose more: CVS & respiratory depression

Tolerance

Psychologic & Physiologic dependence

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