Benzodiazepine

[SH(H)2:p133, SH4:Chp5]

Overview

Benzodiazepine = a benzene ring fused to a seven-membered diazepine ring

5 principle effects

1. Anxiolysis
2. Sedation
3. Anticonvulsant
4. Spinal-cord mediated skeletal muscle relaxation
   * Not sufficient for surgical procedure
   * No influence on dose requirement of muscle relaxant
5. Anterograde amnesia
   * Inability to store new information
   * Amnestic effect is greater and more prolonged than the sedative effect
   * No retrograde amnesia

NB:

• AAASS - anxiolysis, amnesia, anticonvulsant, sedation, skeletal muscle relaxation

Benzodiazepine vs barbiturate

Comparing with barbiturates, benzodiazepines have

• Less tendency to produce tolerance and addiction
• Less potential for abuse
• Greater margin of safety after overdose
• Fewer and less serious drug interaction
• No induction of hepatic microsomal enzyme
• Antagonist available
  * i.e. Flumazenil

Structures

• Benzodiazepine refers to the structure composed of a benzene ring fused to a diazepine ring
• All important benzodiazepines have a 5-aryl substituent, and a 1,4-diazepine ring

NB:

• 1,4 refers to nitrogen on carbon 1 and carbon 4
• Aryl = any group derived from a simple aromatic ring
• Diazepine ring is a 7 membered heterocyclic compound with 2 nitrogen, and 3 double bonds

Differences between benzodiazepines

All benzodiazepines are:

• Highly lipid soluble
• Highly absorbed from GIT
• Highly bound to plasma protein (especially albumin)
  * Both midazolam and diazepam = 96-98% protein bound
  * Haemodialysis is of limited efficacy in overdose
  * Increased sensitivity in cirrhosis and uremia
• Differences are due to differences in
  * Potency (affinity to receptors)
  * Lipid solubility
  * Pharmacokinetics

Pharmacodynamics

Mechanism of action

[SH4:p140]

• Facilitate the action of GABA in CNS
  * Binds to alpha subunit (GABA binds to beta subunit)
  * Does not directly activate GABAa receptor
  * Instead enhance the affinity of the GABAa receptor for GABA
  * Build-in ceiling effect, thus more safe
• Activation of GABAa receptor
  --> Increase chloride conductance
  --> Hyperpolarisation
  --> Postsynaptic cells more resistant to excitation

NB:

[MCQ:Q175] [???]

• Midazolam (and other benzodiazepines) increases frequency of Cl- channel opening
  * Does not increase duration of opening
  * Barbiturate increases duration of opening

Binding sites

[GABA receptors]

• GABAa receptor has separate binding sites for GABA, benzodiazepines, barbiturate, etomidate, propofol, neurosteroids, and alcohol
• Benzodiazepine, barbiturate, and alcohol act via different sites
  --> Synergism
• Activation of alpha-1 subunits of GABAa receptor --> Sedation
  * More abundent
  * 60% of GABAa receptors in the brain
• Activation of alpha-2 subunits of GABAa receptor --> Anxiolysis
  * Mainly in the hippocampus and amygdala

Other actions of benzodiazepine

• Inhibition of nucleoside transporter
  --> Decreased adenosine degradation
  --> Slower HR and better coronary vasodilation
  --> Cardioprotection
• Decrease alpha activity and increased beta (low voltage, rapid) activity on EEG
• Benzodiazepine cannot produce an isoelectric EEG
  * Unlike barbiturates and propofol

Side effects of benzodiazepines

• Fatigue
• Drowsiness
• Decreased motor coordination
• Impairment of cognitive function
• Anterograde amnesia
  * Exacerbated by concomitant use of alcohol
• Dependence
• Inhibition of platelet aggregation
• BP may decrease
  * More so in hypovolaemia
  * Due to benzodiazepine-induced peripheral vasodilation
• Ventilation may be depressed

Drug interaction

• Synergistic effect with other CNS depressants
• Decreased anaesthetic requirement
• Potentiation of respiratory depressant effect of opioids
• Reduced analgesic effects of opioids
• Depression of hypothalamic-pituitary adrenal axis
  * More so with alprazolam

Age

• Aging and liver disease affect glucuronidation less than oxidative metabolic pathways
• Lorazepam, oxazepam, and temazepam are metabolised only by glucuronidation
  * Also have no active metabolites
  --> May be preferable in elderly patients
• Elderly patients may be more sensitive to benzodiazepine
  * Due to both pharmacodynamic and pharmacokinetic reasons

Pharmacokinetics

[MCQ:Q177] [???]

• Benzodiazepines are completely absorbed orally --> 100% absorption
• Oral bioavailibility is 90%

Individual benzodiazepine agents

Also see [Diazepam] and [Midazolam]

Benzodiazepines

	Midazolam	Diazepam	Lorazepam
Equivalent dose (mg)	0.15-0.3 mg	0.3-0.5 mg	0.05 mg
Vd (L/kg)	1-1.5 L/kg	1-1.5 L/kg	0.8-1.3 L/kg
Protein-binding	96-98%	96-98%	96-98%
Clearance	6-8 mL/kg/min	0.2-0.5 mL/kg/min	0.7-1.0 mL/kg/min
Elimination half-time (hr)	1-4 hours	21-37 hours	10-20 hours

Lorazepam

[SH4:p150]

• More potent sedative and amnesic than diazepam and midazolam
• Lorazepam metabolism is by glucuronidation:
  * Slower than oxidative hydroxylation (of midazolam)
  * BUT LESS affected by changes in hepatic function, age, P450 inhibitors (e.g. cimetidine)
• Metabolites are inactive
  * c.f. Midazolam and diazepam both can produce active metabolites
• Slower onset due to lower lipid solubility
• Absorption after oral and IM are reliable
  * Unlike diazepam
• Obesity
  --> Prolonged elimination due to increased Vd
• Limited usefulness due to slow onset, and prolonged duration of action

Action profile

• After oral administration (50 microgram/kg PO)
  * Peak concentration occurs in 2-4 hours
  * Therapeutic for up to 24-48 hours
• After IV administration (1-4 mg)
  * Onset of action = within 1-2 minutes
  * Peak effect = 20-30 min
  * Duration of sedation = 6-10 hours

Oxazepam

• Slightly shorter duration of action
• Metabolite is inactive
• Slow onset
• Elimination half-time = 5-15 hours
• Metabolism is by glucuronidation
  * Like lorazepam, metabolism is less affected by changes in hepatic function or enzyme inhibitors
  * Glucuronidated conjugates are excreted in urine
• Slow absorption
  * Useful for insomnia with early awakening
  * Not for insomina with difficulty falling asleep

Alprazolam

• Significant anxiolysis
• Good for primary anxiety and panic attacks
• Inhibition of adrenocorticotrophic hormones and inhibition of cortisol secretion may be more prominent

Clonazepam

• Particularly effective in seizures
  * Especially myoclonic and infantile spasms
• Long elimination half-time
  = 24-48 hours

Flurazepam

• Used exclusively for treatment of insomnia
• Decreases REM sleep
• Principal metabolite is desalkylflurazepam
  * Active
  * Prolonged elimination half-time
  --> May cause hangover effect and cumulative sedation

Temazepam

• Used exclusively for treatment of insomnia
• Residual drowsiness unlikely
• Good oral absorption
  --> Peak plasma concentration does not occur until about 2.5 hours
• Metabolite have very weak to no activity
• Elimination half-time = 15 hours
  --> But still unlikely to cause hangover effect
• Does NOT alter REM sleep
• Tolerance and withdrawal do not occur, even after 30 days of consecutive use

Triazolam

• Used mainly for treatment of insomnia
• Metabolites have very little activity
• Elimination half-time = 1.7 hours
  --> One of the shortest-acting benzodiazepines
• Residual daytime effect unlikely
• Does NOT alter REM sleep
• Rebound insomnia can occur on discontinuation
• Elderly are more sensitive to triazolam due to decreased clearance and higher plasma concentration
  --> 50% dosage reduction recommended

Short-acting hypnosedatives

e.g. zaleplon, zolpidem, opiclone