Benzodiazepines

Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip.

Software statistics- PhD ( physiology), IDRA

Class of five

• anxiolysis,• sedation, • anticonvulsant actions, • spinal cord-mediated skeletal muscle

relaxation, • anterograde (acquisition or encoding of new

information) amnesia

Pure anesthetic ??

When we compare

The answer is

Barbiturates Benzodiazepines

Sedation more Amnesia more

Anesthetic Anxiolysis

Safety – less More

Tolerance – yes less

Addiction potential – yes

No

Hepatic microsome Yes

no

Antagonist – No Flumazenil

Withdrawal effects No

Withdrawal effects Yes

Structure

• Benzene + diazepine

• Benzene ring (5 carbon atoms) fused to a seven-member diazepine ring (2 • nitrogen atoms, 5 carbon atoms);

• side groups are responsible for the property variations between drugs of this class

Benzene

Diazepine

• Benzodiazepines enhance fast inhibitory neurotransmission via modulating the activity of GABA A receptors in postsynaptic membranes

• Increased chloride ( hyperpolarization ) • Increased sodium is depolarization • Inhibition of neurons – same as thio but why

diazepam is safe ??

• The benzodiazepines do not activate the GABA A receptors by themselves; rather, benzodiazepines modulate the response to GABA by enhancing the affinity of the receptor for GABA

• It needs the neurotransmitter GABA – • They are GABA facilitators than THIO ( GABA

mimetics) • Hence the safety

That’s the safety factor !!

Other mechanisms

• benzodiazepines may be working by non-GABA mechanisms such as inhibition of adenosine reuptake

• inhibition of neuronal Ca2+ currents.• (Anti convulsant predominant)• agonist activity at the glycine receptor, an

important inhibitory neurotransmitter in the spinal cord

GABA A receptors

Pictures taken from net for closed academic purpose only

Supplied as

• Diazepam and lorazepam are “classic” benzodiazepines

that are lipid soluble and difficult to solubilize for

injection.

• Diazepam injection is supplied as a 0.5% solution in 40%

propylene glycol and 10% ethanol.

• Lorazepam is supplied as a 0.4% solution in 80% propylene

glycol, 18% polyethylene glycol, and 2% benzyl alcohol.

Induction doses Dose Onset durat Excita

tion Pain

• Elderly, debilitated , liver disease – 25 % less • Repeat doses , opioid addition- 25 % less • Alcohol !!

• Sedation on induction – midazolam • 1 -2 mg IV bolus , 5 minutes , titrate with 0.75

to 1 mg bolus to get the desired effect

Routes

• Oral , IM and IV routes are available• The intravenous solution can be mixed with

fruit juice or flavored syrup-- • But IM diazepam ?? • IM midaz and ketamine are the two induction

agents • Nasal, sublingual, intrathecal – Yes for

midazolam

Rectal

• 0.4 mg / kg midazolam • 0.75 mg/ kg of diazepam

• Rarely sublingual and skin patches have been used

• Febrile fits in chubby child !!

Intrathecal Benzodiazepines - Midazolam

• GABA 2 receptors in dorsal horn

• Also delta receptors

• 1 -2 mg – motor block , early post op analgesia

• ? Prolongation of anaesthesia

• 12 mg / day – chronic pain

• Can be combined with opioids and clonidine

• Early - neuro toxicity - ? Possibly addition of 10 % HCl in

preparation – now proved as nil

In CNS

• Decreased CMRO2. • No change in ICP • No iso electric EEG • No neuro protective effect • But better anticonvulsant

• Amnesia and sedation -- √

1.Premedicant-2. Anesthetic

adjuvant –

3.Anesthetic –

4.Post op and ICU sedation –

5.Status epilepticus –

6. Tetanus --

• Ceiling effect on CNS depression

• CNS receptors occupancy• 20 % – anxiolysis, anticonvulsant • 30 % sedation • 50 to 70 % hypnosis • 95 % - deep anesthesia • Differing actions - Other than the other receptor

theory

Malignant hyperthermia

safety

Debatable

• benzodiazepines can reduce anxiety at doses that are not highly sedating.

• Of note, the same effects may not occur in surgical patients.

• Many patients scheduled for surgery do not have high levels of self-rated anxiety,

• effect of midazolam is more likely to produce dizziness or sleepiness

Clinical tips • Tolerance – yes • Anticonvulsant in status but tolerance – chronic

seizure prophylaxis ??? • Emergence delirium; prophylaxis and treatment • Withdrawal of abuse drugs • Cardiac cath, reduce hallucinations after ketamine • Midazolam (0.5 to 1 mg IV) may be an effective

treatment for the paradoxical vocal cord motion that may manifest postoperatively.

Other effects

• Benzodiazepines produce a mild reduction in muscle tone, which may be advantageous

• Dislocations • Mechanical ventilation • Endoscopies

• Internuncial neurons in spinal cord • No effect in NMJ

Effect on limbic system

more than cortex

MAOi – OK

Other effects

• No effect on blood pressure • No effect on myocardial contractility• dose-dependent decrease in hypoxic ventilatory

drive, also CO2 drive • Sub hypnotic doses given alone rarely cause

apnea. • Make unconscious – then apnea is comparable

with thiopentone • No nausea

Metabolism • Midaz – hydroxy midaz – can accumulate in infusion ,

but high clearance for shorter duration of action of midazolam

• Diazepam is principally metabolized by hepatic microsomal enzymes using an oxidative pathway of N-demethylation.

• The two principal metabolites of diazepam are des methyl diazepam and oxazepam, with a lesser amount metabolized to temazepam.

• That’s why - the drowsiness • It is absorbed on the plastic and cannot be removed

by dialysis.

All three drugs are extensively protein bound–

but midaz All are lipid soluble to act in

the brain

Lorazepam

• Higher affinity for receptors

• But less lipid soluble than others • Cross slowly – slow onset • Glucuronic acid and excreted • Ideal drug for patients with liver disease and

alcohol withdrawal symptoms

Side effects • Fatigue • Drowsiness • Decreased motor coordination • Impairment of cognitive function• Anterograde amnesia (accentuated by concomitant

ingestion of alcohol)• Paradoxical agitations ( beware of periop agitation-

hypoxia, inadequate reversal, full bladder etc,, ) • Suicidality • Worsen depression

Drug interactions

• Synergistic effects with other CNS depressants • Decreased anesthetic requirements • Potentiation of ventilatory depressant effects of

opioids • Reduced analgesic effects of opioids • Suppression of the hypothalamic-pituitary adrenal

axis • Dependence

Diazepam Midazolam

Preparation Lipid soluble Water soluble

Pain on injection Yes Ring closure – no pain

Dose 4-5 mg 1 mg ( potency)

Metabolites Yes – hence infusion no Not very active – inf. Yes

Routes Oral . IV rectal + IM, intrathecal, buccal nasal

Protein bound More A little less

Duration More with slurredRecovery

Less with clear head

Resp depression Less Slightly more

Amnesia, anticonvulsant, anesthesia, sedation CVS stability – same

Summary

• Structure • Drugs • Preparation • Effects and uses • Advantages • Side effects