3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.3. IV anaesthetic agents
 3.1.3.3.6. Benzodiazepine 

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