1. MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics-
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,
Pure anesthetic ??
anxiolysis,
sedation,
anticonvulsant actions,
spinal cord-mediated skeletal muscle relaxation,
anterograde (acquisition or encoding of new information) amnesia

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
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
Benzene

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. Pictures taken from net for closed academic purpose only
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
Pain
durat
Excitation

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. 4.Post op and ICU sedation –
In CNS
1.Premedicant-
2. Anesthetic adjuvant –
3.Anesthetic –
4.Post op and ICU sedation –
5.Status epilepticus –
6. Tetanus --
Decreased CMRO2.
No change in ICP
No iso electric EEG
No neuro protective effect
But better anticonvulsant
Amnesia and sedation -- √

24. Malignant hyperthermia safety
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

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. Effect on limbic system more than cortex
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. Amnesia, anticonvulsant, anesthesia, sedation CVS stability – same
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