Anxiolytics, sedatives & hypnotics Flashcards
How is GABA metabolised?
GABA –> succinic semialdehyde (SSA) by GABA transaminase SSA –> succinic acid by SSA dehydrogenase Mitochondrial enzymes
What receptor is involved in GABAergic central neurotransmission?
GABA A receptor complex
Explain the GABA A receptor complex
Cl- ionophores - cause hyperpolarisation: GABA modulin + GABA R protein + Barbiturate R protein + BDZ R protein in ring with Cl- channel protein in middle
What are the principal clinical uses of barbiturates?
Sedatives/hypnotics
What are the principal clinical uses of benzodiazepines?
- Long-acting = anxiolytics, e.g. diazepam - Short-acting = sedatives/hypnotics, e.g. temazepam
What are the adverse effects of barbiturates?
- Enzyme inducers - Alter natural sleep (reduce REM) –> hangover, irritability - Depress respiration (tf low safety margins) - O.d. is lethal - Dependence - withdrawal syndrome - Tolerance - Potentiate effects of other CNS depressants (alcohol)w
What are the adverse effects of benzodiazepines?
- Dependence - withdrawal syndrome (less intense than barbs) - Tolerance (less than barbs) - Potentiate other CNS depressants (alcohol, barbs) - Sedation, confusion, amnesia, ataxia
What drugs can increase free [plasma] of benzodiazepines?
Aspirin Heparin
What are the advantages of benzodiazepines over barbiturates?
- Mild effect on REM sleep - Don’t induce liver enzymes - Wide safety margin - overdose –> prolonged rousable sleep –> flumazenil
Why do the pharmacokinetics of benzodiazepines determine clinical use?
- 20+ different benzodiazepines with very small differences in structure (3 rings, differ in R1, R2, R3, R4) - Same mechanisms of action - Similar potency - Tf pharmacokinetics determine clinical use
Summarise the pharmacokinetics of benzodiazpepines
- Duration of action - varies - short or long-acting - Admin - peak [plasma] in 1h, well-absorbed orally, i.v. for status epilepticus - Distribution - binds PPs strongly, highly lipid soluble –> wide distribution - Extensive hepatic metabolism
What do hypnotics do?
Induce sleep
What do anxiolytics do?
Remove anxiety without impairing mental or physical activity
What do sedatives do?
Reduce mental and physical activity without producing loss of consciousness
What would an ideal benzodiazepine or barbiturate do?
- Produce natural sleep - Not depress respiration - Have a wide margin of safety - Not produce hangovers or dependence - Not interact with other drugs
How does GABA binding affect the GABA A receptor complex?
- Linkage of GABA receptor protein and BDZ receptor protein mediated by GABA modulin - Enhances BDZ binding - Momentary opening of Cl- channel
How does BDZ binding affect the GABA A receptor complex?
- Facilitates action of GABA on Cl- channel - Enhances GABA binding - increases affinity
How does Barb binding affect the GABA A receptor complex?
- Enhances GABA binding - Direct agonist of Cl- channel - Enhances GABA action on Cl- channel
How do barbiturates and benzodiazepines differ?
- Different binding sites and mechanisms: BZs increase frequency of openings, barbs increase duration, opening caused by GABA - Barbs are less selective - other membrane effects, decrease excitatory transmission (may explain induction of surgical anaesthesia and low margin of safety)
Why do benzodiazepines and barbiturates have no activity alone?
They are positive allosteric modulators Only increase freq or duration of opening caused by GABA
How is GABA synthesised?
Glutamate –> GABA by glutamate decarboxylase
What are the clinical uses of benzodiazepines and barbiturates?
- Sedatives/hypnotics - Anxiolytics - Anaesthetics - barbs - Anti-convulsants - Anti-spastics
What can long-acting benzodiazepines be metabolised into?
Short-acting benzodiazepines
