Download Benzodiazepines

Benzodiazepines
Dr. S. Parthasarathy
MD., DA., DNB, MD (Acu), Dip. Diab.
DCA, Dip. Software statisticsPhD ( physiology), IDRA
Class of five
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anxiolysis,
Pure anesthetic ??
sedation,
anticonvulsant actions,
spinal cord-mediated skeletal muscle
relaxation,
• anterograde (acquisition or encoding of new
information) amnesia
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 no
Yes
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
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 nonGABA 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
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Decreased CMRO2.
No change in ICP
No iso electric EEG
No neuro protective effect
But better anticonvulsant
• Amnesia and sedation -- √
1.Premedicant2. Anesthetic
adjuvant –
3.Anesthetic –
4.Post op and
ICU sedation –
5.Status
epilepticus –
6. Tetanus --
• Ceiling effect on CNS depression
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Malignant
hyperthermia
safety
CNS receptors occupancy
20 % – anxiolysis, anticonvulsant
30 % sedation
50 to 70 % hypnosis
95 % - deep anesthesia
Differing actions - Other than the other receptor
theory
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
Effect on
• Mechanical ventilation
limbic system
more than
• Endoscopies
cortex
• Internuncial neurons in spinal cord
• No effect in NMJ
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
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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
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Side effects
Fatigue
Drowsiness
Decreased motor coordination
Impairment of cognitive function
Anterograde amnesia (accentuated by concomitant
ingestion of alcohol)
• Paradoxical agitations ( beware of periop agitationhypoxia, 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 slurred
Recovery
Less with clear head
Resp depression
Less
Slightly more
Amnesia, anticonvulsant, anesthesia, sedation CVS stability – same
Summary
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Structure
Drugs
Preparation
Effects and uses
Advantages
Side effects