Benzodiazepines

Question 1

Benzodiazepines - general principles

Answer 1

• All benzodiazepines have a benzene ring and a diazepine ring
• Binds to GABAA receptor at specific BZD binding site, which is located between the alpha and gamma subunits
• BZ1 (spinal cord, cerebellum) - anxiolysis
• BZ2 (spinal cord, hippocampus, cerebral cortex) - sedative, anticonvulsants
• Binding of benzodiazepines facilitates the effect of GABA in opening the receptors ligand-gated chloride channel, which hyperpolarizes the cell
• Weak bases
• Highly protein bound ~95%

Question 2

Midazolam

Answer 2

• Tautomeric
• At pH 3.5 its diazepine ring structure is open, resulting in an ionized molecule which is water soluble
• At pH >4, the diazepine ring structure is closed, and it becomes lipid soluble
• PKa = 6.5, so is 90% unionized at physiological pH
• Metabolized by hydroxylation to active compound 1-alpha hydroxymidazolam, which is conjugated with glucoronic acid before renal excretion

Question 3

Diazepam

Answer 3

• Metabolized in liver to desmethyldiazepam, oxazepam and temazepam - all of which are active
• Lowest clearance of benzodiazepines, half life significantly increased by use as infusion (context-sensitive half-time)

Question 4

Lorazepam

Answer 4

• Inactive metabolites