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15/04/2009
Padma Priya
Overview
• Developed in the 1960’s to replace oral barbiturates
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Overview
• Diazepam • Flumazenil
• Midazolam
• Lorazepam
• Temazepam
• Oxazepam
• Clonazepam
• Triazolam
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Chemical classification
• 1, 4 benzodiazepines
• 1 benzene ring
• 7 member diazepam
ring
• Substitutions at
various points affect
potency and
The basic benzodiazepine skeleton: biotransformation
A. benzene ring
B. the 1,4-diazepine ring
C. phenyl ring at the 5-position
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Mechanism of action
• Binds to a specific site on
GABAA receptor
• Enhanced opening of Clˉ
gating channels
• ↑ Clˉ conductance
• Hyperpolarisation of
postsynaptic cell
membrane
• Renders postsynaptic
GABA: Gamma Aminobutyric Acid neurons more resistant to
•principle inhibitory CNS neurotransmitter excitation
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Mechanism of action
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Relationship between the effects seen with
benzodiazepines and receptor occupancy
Anxiolysis 20-30
Amnesia
Muscle relaxation
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Mechanism of action
• Benzodiazepine compounds which are ligands at
receptor but have inverse agonist activity cause cerebral
excitement
– Paradoxical reaction in the elderly
– Exacerbated by increasing dose
– Reversed by flumazenil
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Pharmacokinetics
• Absorption
– Routes: PO, IV,IM, PR
– Weakly basic drugs
– Effective absorption at high pH of duodenum
• Distribution
– Diazepam: lipid soluble → rapidly crosses blood brain barrier
– Lorazepam: moderately lipid soluble → slower brain uptake & onset of
action
– Midazolam: has imidazole ring which remains open at low pH (water
soluble) and closed at physiological pH (lipid soluble)
– All 3 are highly protein bound
– Fairly rapid redistribution → responsible for awakening
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Pharmacokinetics
• Biotransformation & excretion
Hepatic metabolism
– Phase I : microsomal oxidation
• Affected by age, hepatic disease, drug interactions &
cytochrome p450 alterants
– Phase II : glucoronide conjugation
Renal excretion
– Accumulation of metabolites in renal dysfunction
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Effects
CNS
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Effects
• Muscle relaxation:
– Not mediated at NMJ but at spinal cord level
– Mild reduction in muscle tone
• Useful in mechanical ventilation @ ICU
• Reducing articular dislocation
• Endoscopic procedures
– Might cause airway obstruction
• Anaesthesia
– High dose
– Slower loss of consciousness and longer recovery compared to
thiopental/ propofol
– No direct analgesic properties
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Effects
CVS
• Minimal depressant effects
• Arterial blood pressure, cardiac output and peripheral
vascular resistance ↓ slightly
• Occasional increase in heart rate
Respi
• ↓ ventilatory response to CO2
• Caution in pts with hypoventilation syndrome & Type 2
respi failure
• Synergism with opioids- titrate dose accordingly
• Ventilation must be monitored in all pts receiving IV
benzodiazepines & resuscitation equipment must be
available
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Drug interactions
• Benzodiazepines ↓ MAC
of volatile anaesthetics ≈
30%
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Drug interactions
• Midazolam
– Erythromycin inhibits metabolism
– 2 to 3 fold prolongation and intensification of its effects
• Diazepam
– Metabolism ↓ by Cimetidine
• binds to cytochrome p450
– Heparin ↑ free drug concentration
• protein binding site displacement
– + opioids :
• ↓ ↓ arterial BP & peripheral vascular resistance
• esp in IHD/ valvular heart disease pts
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Diazepam
• First benzodiazepine for IV use
• Insoluble in H2O
– Prepared with propylene glycol (venoirritant) / as
lipid emulsion
• Active metabolite has long half life (36-
200 hrs)
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Midazolam
• Has replaced diazepam for use in preop medication and
conscious sedation
• 2 to 3 times more potent than diazepam
• Imidazole ring which remains open at low pH (water
soluble) & closes at physiological pH (lipid soluble)
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Midazolam
• Minimal to no
discomfort during
IV/IM injection
• Compatible with
Hartmann’s
• Can be mixed with
acidic salts of other
drugs e.g opioids,
anticholinergics
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Midazolam
Pharmacokinetics
• Rapid GI tract absorption
• Slow effect site equilibrium time compared to
thiopental/propofol
– Space IV doses of mida for peak effect before considering
repeat dose
• Only 50% of oral mida reaches systemic circulation
• Bound to plasma proteins
• Short duration of action of single dose d/t rapid
redistribution and hepatic clearance
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Midazolam
Pharmacokinetics (con’t)
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Midazolam
Effects on organ systems:
CNS
• ↓ cerebral metabolic oxygen requirements
• Cerebral vasomotor responsiveness to CO2 is preserved
during mida anaesthesia
• Little or no change in ICP (does not prevent ↑ ICP during
laryngoscopy)
• Potent anticonvulsant
• Paradoxical excitement occurs in <1% of pts
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Midazolam
Ventilation
• Dose dependent decreases in ventilation
– worse in COPD pts
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Midazolam
CVS
• ↓ BP & HR
– Changes d/t ↓ systemic vascular resistance
– Cardiac output not altered
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Midazolam
Clinical use
• Oral premedication:
– Sedation & anxiolysis without delayed awakening
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Midazolam
• Induction of anaesthesia (0.1-0.4 mg/kg)
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Midazolam
• Maintenance of anaesthesia
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Lorazepam
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Lorazepam
Clinical use
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Lorazepam
• Sedation in ICU
• Continuous IV infusion
• Dose titrated to clinical response (max 4mg/hr)
• Advantages over mida infusion:
– Half life of mida is extended during long term infusion
• Worsened by hepatic and renal dysfunction
– Cheaper than mida
• 0.7 mg lorazepam equipotent to 10mg mida
• Average cost 10x cheaper with lorazepam
– No difference in recovery between mida and lorazepam
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Uses and doses of commonly used
benzodiazepines
Agent Use Route Dose (mg/kg)
Diazepam Premedication oral 0.2-0.5
Sedation IV 0.04-0.2
Induction IV 0.3-0.6
Midazolam Premedication Oral, IM 0.07- 0.15
Sedation IV 0.01-0.1
Induction IV 0.1-0.4
Lorazepam Premedication Oral 0.053
IM 0.03-0.05
Sedation IV 0.03-0.04
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Flumazenil
• Benzodiazepine antagonist
– High affinity competitive antagonist for all other ligands @
benzodiazepine receptor
• Rapid reversal of CNS effects of benzodiazepines and
other potentially dangerous adverse physiological effects
– Respi, CVS, airway obstruction
• Rapidly cleared from plasma
– Metabolised by liver
– Short elimination half life (< 1 hr)
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Flumazenil
• Duration of action depends on dose administered, identity & dose of
agonist
– 20mins to 2 hrs
• Potential for resedation
– Close observation necessary
– Repeated doses
Indication
• Reversal of sedation
– Also used in reversal of prolonged sedation in ICU d/t accumulation of
midazolam in renal impaired pts
• Self poisoning
– Repeated doses or continuous infusion until plasma concentrations of
agonist have decreased
– Diagnostic tool in coma of unknown cause
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Flumazenil
Dosage and administration
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References
• G. Edward Morgan, Jr. Maged S. Mikhail, Michael J. Murray, CIinical
Anaesthesiology (2006)
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Thank
you
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