Anxiolytics and Hypnotics Flashcards
What are the four main proteins that make up the GABA-A receptor?
GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein
What protein links the GABA receptor protein and the benzodiazepine receptor protein?
GABA modulin
Describe the normal physiological action of GABA.
GABA binds to the GABA receptor protein
GABA modulin links the GABA receptor protein + benzodiazepine receptor protein
Results in opening of the chloride ion channel, causing hyper polarisation of the cell
Name a competitive antagonist of the GABA A receptor protein.
Biciculline
Name a competitive antagonist of the benzodiazepine receptor protein. When is this used therapeutically?
Flumazenil
Used to treat Benzodiazepine OD
What are the two main effects of benzodiazepines that facilitate GABA neurotransmission?
Facilitate GABA-mediated opening of cl- channel
Increase affinity of GABA to the GABA binding site– reciprocated with enhanced BZ binding
What are the three main effects of barbiturates that facilitate GABA neurotransmission?
Enhance normal physiological action of GABA
Enhance GABA binding to the GABA receptor protein (NOT reciprocated)
At higher concs, BARBs can directly open Cl- channel
What is the key difference in the mechanism of action of barbiturates and benzodiazepines?
Benzodiazepines: increase frequency of cl- channel opening
Barbiturates: increase duration of cl- channel opening
What is the relative difference in selectivity between barbiturates and benzodiazepines?
Barbiturates are LESS selective
May explain why barbiturates induce surgical anaesthesia + are less safe than benzodiazepines
Barbiturates also reduce excitatory transmission
Name a barbiturate that is used as an anaesthetic.
Thiopentone
Name 3 barbiturates and benzodiazepines that are used as anti-convulsants.
Diazepam
Clonazepam
Phenobarbital
Name a benzodiazepine that is used as an anti-spastic.
Diazepam
What are two other clinical uses of benzodiazepines and barbiturates?
Anxiolytics
Sedatives/ Hypnotics
Define anxiolytic.
Remove anxiety without impairing mental or physical activity
Define sedative.
Reduce mental + physical activity without producing loss of consciousness
Define hypnotic.
Induces sleep
What structure is common to all barbiturates?
6-membered ring (4 carbons + 2 nitrogens)
Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly? What is it used for? What is the half-life of this drug?
Amobarbital
Severe intractable insomnia
20-25 hours
What are 6 unwanted effects of barbiturates?
Low safety margin (depresses respiration, OD = lethal)
Alters natural sleep (reduced REM, causes hangovers)
Enzyme inducers (cause faster metabolism of other drugs + thus decreases their efficacy)
Potentiates action of other CNS depressants (e.g. alcohol)
Tolerance (Tissue + pharmacokinetic)
Dependence (withdrawal syndrome results)
What structure is common to all benzodiazepines?
They are tricyclic
What are the three key benzodiazepines?
Diazepam
Oxazepam
Temazepam
What is the difference between all the benzodiazepines that are in clinical use?
Their pharmacokinetics
Describe the administration of benzodiazepines.
Well absorbed per orally
Peak plasma concentration after ~ 1 hour
When would you give IV benzodiazepines?
Treatment of status epilepticus
Describe the distribution of benzodiazepines.
Bind strongly to plasma proteins
Highly lipid soluble, results in wide distribution
Describe the metabolism of benzodiazepines.
Extensively metabolised in the liver
Describe the excretion of benzodiazepines.
Excreted in the urine as glucuronide conjugates
Describe the duration of action of benzodiazepines.
Varies a lot
Allows classification as short- + long-acting
What makes long-acting benzodiazepines have a long duration of action?
Have slower metabolism
Generate active metabolites
Name two short-acting benzodiazepines.
Oxazepam
Temazepam
Name a long-acting benzodiazepine.
Diazepam
Describe the metabolism of oxazepam.
Metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)
Describe the metabolism of temazepam.
Metabolised to oxazepam, then to the glucuronide conjugate
Describe the metabolism of diazepam.
Metabolised via temazepam + oxazepam to the glucuronide conjugate
Some diazepam is metabolised to nordiazepam + then oxazepam
Name three drugs that are used as anxiolytics.
General rule: long-acting benzodiazepines
Diazepam
Chlordiazepoxide
Nitrazepam
Under what condition would you use a short-acting benzodiazepine as an anxiolytic?
Hepatic impairment: means BZs are metabolised more slowly
Use oxazepam
Name two drugs that are used as sedatives/hypnotics.
General rule: short-acting benzodiazepines
Oxazepam
Temazepam
Name a long acting drug that might be used as a sedative/hypnotic. Why would this be used?
Nitrazepam (t1/2 = 28 hours)
If waking early or anxiolytic effect desired in day
What are 5 advantages of benzodiazepines over barbiturates?
Wide margin of safety
OD causes prolonged sleep (but is rousable)
Flumezanil can be given IV if a patient has OD
Mild effect on REM sleep
Do NOT enhance liver enzymes
What are 7 unwanted effects of benzodiazepines?
Sedation
Confusion
Ataxia
Potentiate other CNS depressants (e.g. alcohol)
Tolerance (tissue only)
Dependence (less intense withdrawal syndrome than BARBs)
Free plasma conc. can be increased by giving aspirin + heparin
Name a sedative/ hypnotic that isn’t a benzodiazepine. What class of drug does this fall into?
Zopiclone: a cyclopyrrolone + it’s short-acting (t1/2 = 5 hours)
acts on BZ receptor but not a BZ
Has fewer hangover effects but dependency is still an issue
What drug is used to control the physical symptoms of anxiety? What symptoms in particular?
Propranolol
Tachycardia
Tremor
Name a new drug that has started being used as an anxiolytic. What are its advantages and disadvantages?
Buspirone: 5HT1A agonist
Relatively few side effects + causes less sedation than BZs
Downside: slow onset of action (max. anxiolytic effects not seen for days/weeks)
What is the precursor molecule to GABA? What enzyme causes the conversion to GABA?
Glutamate
Glutamate decarboxylase GAD
What are GABA-B receptors?
GABA auto receptors on presynaptic nerve terminals
Regulate GABA release into synapse
What type of GABA receptor is found on the post-synaptic membrane?
GABA-A receptors
Describe the metabolism of GABA. What type of enzymes mediate this?
GABA reuptake into pre-synaptic or glial cells
GABA-T converts GABA to Succinic semialdehyde
SSDH converts this to Succinic acid
Mitochondrial enzymes
What happens if metabolism of GABA is inhibited?
Increased inhibition of the brain
Used in treatment of epilepsy
Why are barbiturates and benzodiazepines referred to as positive allosteric modulators?
Without GABA they have no action
They enhance action of GABA at GABA receptor
What other classes of drugs can be used as anxiolytics?
Some antidepressants e.g. SSRIs Some antiepileptcs e.g. Valproate Some antipsychotics e.g. Quetiapine Propanolol Busiprone
