Benzodiazepines are a class of drugs that enhance the effects of the neurotransmitter GABA at GABA-A receptors in the brain, producing anxiolysis, sedation, anticonvulsant effects, muscle relaxation and amnesia. Common benzodiazepines include diazepam, midazolam and lorazepam. They are used for premedication, anesthesia, sedation, status epilepticus and withdrawal symptoms. While effective, they can cause side effects like fatigue, drowsiness, impaired cognition and paradoxical reactions with prolonged use.

1. Benzodiazepines
Dr. S. Parthasarathy
MD., DA., DNB, MD (Acu), Dip. Diab.
DCA, Dip. Software statistics-
PhD ( physiology), IDRA

2. Class of five
• anxiolysis,
• sedation,
• anticonvulsant actions,
• spinal cord-mediated skeletal muscle
relaxation,
• anterograde (acquisition or encoding of new
information) amnesia
Pure anesthetic ??

3. When we compare
The answer is

4. 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

5. 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

6. Diazepine

8. • 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 ??

9. • 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

10. That’s the safety factor !!

11. 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

12. GABA A receptors
Pictures taken from net for closed academic purpose only

13. 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.

14. Induction doses
Dose Onset
durat
Excita
tion
Pain

16. • 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

17. 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

19. 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 !!

21. 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

23. 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 --

24. • 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

25. 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

26. 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.

27. 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

28. 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

29. 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.

30. All three drugs are
extensively protein bound–
but midaz
All are lipid soluble to act in
the brain

31. 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

32. 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

33. 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

34. 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 slurred
Recovery
Less with clear head
Resp depression Less Slightly more
Amnesia, anticonvulsant, anesthesia, sedation CVS stability – same

35. Summary
• Structure
• Drugs
• Preparation
• Effects and uses
• Advantages
• Side effects