FunMed: PBL 5 (Groggy Grandmother - Benzodiazepines) Flashcards
Define ‘allosteric’
Binding of molecule to enzyme at site other than active site –> modulation of enzyme by causing change in shape
Define ‘first order elimination’
Decrease in drug levels which is dependent on plasma concentrations (substrate is rate limiting factor) - exponential graph
Define ‘zero order elimination’
Decrease in drug levels independent of plasma concentration (straight line)
What are benzodiazepines?
Psychoactive drug which enhances effect of GABA (inhibitory neurotransmitter) at the GABAa receptor to cause sedative, anticonvulsant and muscle relaxant properties
Define ‘anxiolytic’
Reducing anxiety effect
What are the 3 main subclasses of benzodiazepines?
Hypnotics, anxiolytics and general
What is GABA?
Chief inhibitory neurotransmitter in CNS; works to reduce neuronal excitability
Describe the mode of action of benzodiazepines
Binding of drug to GABAa receptor on post-synaptic membrane has positive allosteric effect (promotes binding of GABA to receptor) to increase chloride ion influx –> hyperpolarisation
Describe the GABAa ion channel
Present on post-synaptic neuronal membranes, and consists of 5 subunits (2 alpha, 2 beta, 1 gamma) and is achloride ion channel with 2 binding sites for GABA and 1 for benzodiazepines
Where are GABAa receptors located?
Cerebellum, limbin system and cerebral corx
What are side effects of benzodiazepines?
Poor memory, sedation, hypotension, dizziness, seizure, agitation –> falls, shoplifting
What are the main differences between different benzodiazepines?
Half-lives and potency
What is the effect of benzodiazepines with greater half-lives?
Longer half-life will promote greater sedation through the night, so is better for sleeping, but has greater risk of residual effects next day
Describe the metabolism of benzodiazepines
Diazepam can be hydroxylated to temazepam (active metabolite) in liver or demethylated to form desmethyldiazepam. Desmethyldiazepam can then be hydroxylated to oxazepam. Both oxazepam and temazepam then undergo glucuronide conjugation –> excretion
What is the difference between diazepam and temazepam?
Temazepam can be directly conjugated (no need for metabolism) whereas diazepam requires metabolsim
What is the significance of desmethyldiazepam?
Active metabolite of diazepam (and many other benzodiazepines) which has a half-life over 40 hours, so has long duration of action
What does phase I metabolism involve?
Biotransformation: oxidation, reduction and hydrolysis (and adding polar molecules)
What does phase II metabolism involve?
Conjugation (to increase water solubility) with glucuronide, sulfate, methyl or acetyl groups
Define ‘bioavailability’
Proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect
What factors affect the rate of drug absorption?
Gastrointestinal motility (peristaltic action), intestinal absorption, size of drug (smaller = easier to diffuse), whether food has been consumed
What is ‘first pass effect’?
All drugs absorbed by GI tract –> portal blood –> liver –> metabolism –> systemic blood
Which enzymes (broadly) metabolise benzodiazepines and which enzyme is most commonly used (phase I reactions)
CYP450 enzymes (cytochrome) and specifically, CYP3A4
Why are the elderly more prone to adverse effects of benzodiazepines?
They have reduced metabolic capability, renal excretion and increased sensitivity to effects
Why may there be issues with drug compliance?
Patient feels better, no faith in doctor, office visiting time restrictions, medication cost, ineffective communication of side-effects, motivation to recover
