Benzodiazepines

15/04/2009
Padma Priya
 Overview
• Developed in the 1960’s to replace oral barbiturates

• Five principle pharmacological effects:

– Anxiolysis
– Sedation
– Anticonvulsant
– Spinal cord mediated skeletal muscle relaxation
– Anterograde amnesia

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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

Midazolam dose Effect Receptor Flumazenil dose to

occupancy % reverse
Low dose Anticonvulsant 20-25 Low dose

Anxiolysis 20-30

Slight sedation 25-50

Reduced attention 25-50

Amnesia

Intense sedation 60-90

Muscle relaxation

High dose Anaesthesia High dose

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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

• Chronic benzodiazepine use causes down regulation of

receptors → tolerance

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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

• General: ↓ cerebral oxygen consumption, CBF & ICP

• Anxiolysis: at low dose
• Sedation:
– dose dependent
– cortical > medullary depression
– Upper airway obstruction and loss of protective reflexes occur
before profound sedation
• Anterograde amnesia: useful as premedication
• Anticonvulsant: Prevention of subcortical spread of seizure
activity

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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%

• Ethanol, barbiturates &

other CNS depressants ↑
sedative effect of
benzodiazepines

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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)

• Elimination half life : 1 to 4 hrs

• May be doubled in elderly pts (decreased hepatic blood
flow, enzyme activity)
• ↑ volume of distribution (Vd) in elderly and obese d/t
enhanced distribution of drug into peripheral adipose
tissue
• ↑ clearance – mental function returns to normal within 4
hrs

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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

• Transient apnea can occur after rapid bolus of large doses

– esp in combination with an opioid

• ↓swallowing reflex and upper airway activity

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 Midazolam
CVS
• ↓ BP & HR
– Changes d/t ↓ systemic vascular resistance
– Cardiac output not altered

• Enhanced BP ↓ in presence of hypovolemia (similar to

other induction drugs)

• Does not prevent BP & HR ↑ during tracheal intubation

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 Midazolam
Clinical use

• Oral premedication:
– Sedation & anxiolysis without delayed awakening

• IV sedation : 0.01- 0.1mg/kg

– Effective for regional anaesthesia sedation and brief therapeutic
procedures
– Rapid onset, more amnesia & less post-op sedation compared
to diazepam
– Synergistic effects with opioids/propofol advantageous
– Caution in elderly pts

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 Midazolam
• Induction of anaesthesia (0.1-0.4 mg/kg)

– Given over 30-60s

– Thiopental 50-100% faster than mida
– ↑ onset when fentanyl (50-100 mcg) precedes IV mida by 1 to 3
mins
– ↓ dose if premed has been given, or in elderly pts

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 Midazolam
• Maintenance of anaesthesia

– May be administered to supplement opioids, propofol and/or

inhaled agents
– ↓anaesthetic requirement for volatile anaesthetics
– Awakening after GA is 1 to 2 .5 times longer than when
thiopental is used as induction agent
– Rarely assoc. with nausea, vomiting or emergence excitement
– 1 hr post-op pts are equally alert with either mida or thiopental
( no difference in discharge time )

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 Lorazepam

• More potent amnesiac than midazolam and diazepam

• Similar to other benzodiazepines in terms of effects on
ventilation, CVS and skeletal muscle

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 Lorazepam
Clinical use

• Maximal plasma concentration: 2 to 4 hrs

– Persists at therapeutic levels up to 24 to 48 hrs
• Premedication : 50 mcg/kg, not to exceed 4mg
– Maximal anterograde amnesia lasting up to 6 hrs
– Use limited d/t prolonged duration of action
• Anaesthesia/ sedation/ anticonvulsant
– Limited use d/t low onset
– Limits emergence reactions after ketamine administration

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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

• 1 ampoule = 500 mcg in 5 ml

• Clinical effective dose 0.2-1mg given as 0.1-0.2 mg
boluses & repeated at 1 min intervals.
• Dose in diagnosis of coma should not exceed 3 mg

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 References
• G. Edward Morgan, Jr. Maged S. Mikhail, Michael J. Murray, CIinical
Anaesthesiology (2006)

• Alan R. Aitkenhead, David J. Rowbotham, Graham Smith, Textbook of

Anaesthesia (2001)

• Robert K. Stoetting, Pharmacology and Physiology in Anaesthetic

Practice (1999)

• EL Swart, RJM Strack van Schijndel, AC van Loenen and LG Thijs

Continuous infusion of lorazepam versus midazolam in patients in the
intensive care unit: Sedation with lorazepam is easier to manage and
is more cost-effective Crit Care Med 1999, 27: 1461-1465

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 Thank
you
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