Pharmacology 18b - Anxiolytics, sedatives and hypnotics
- List the principal clinical uses (with routes of administration) of the benzodiazepines and the barbiturates.
- What are the main undesirable effects of the benzodiazepines? How do these compare with the unwanted effects of the barbiturates?
- Do individual benzodiazepines differ in terms of
- their mechanisms,
- their profiles,
- their durations of action?
- How do differences in durations of action influence the therapeutic usefulness of these compounds?
- Give examples.
- Define the term ‘anxiolytic drug’. State three classes of drugs which have useful anxiolytic properties.
- Name three drugs widely used for their hypnotic effects. Why is diazepam not used in this capacity?
Benzodiazepines and Barbiturates
Benzodiazepines and barbiturates have no action on their own. They only exert a pharmacological effect when they are combined i.e. they have an allosteric reaction.
They do however have different binding sites and have different actions at those sites:
NB: both bind to GABAA receptors
-Benzodiazepines increase frequency of Cl- channel openings.
-Barbiturates increase duration of Cl- channel openings.
Barbiturates are less selective than benzodiazepines and therefore have other membrane effects. This may explain their use in surgical anaesthesia.
•Anaesthetics (Barbs Only : Thiopentone)
•Anticonvulsants (Diazepam; Clonazepam; Phenobarbital)
•Anxiolytics – remove anxiety
•Sedatives – inhibit mental and physical activity
•Hypnotics – induce sleep.
There is a sliding scale; high dose anxiolytics will have hypnotic effects and low dose hypnotics will have anxiolytic effects.
Thiopentone, Phenobarbital, amobarbital.
Generally not used as first treatment
-general anaesthetics - thiopentone
-anticonvulsants (treat epilepsy) - phenobarbital
-sedative - amobarbital
-hypnotic - amobarbital
Mode of Action – non-selective CNS depressant. Binds to Cl- channels causing them to increase in duration of opening. This causes more Cl- to enter postsynaptic neurones and hence inhibit firing of action potentials. They can induce surgical anaesthesia and have a low margin of safety due to their non-selective properties.
low safety margins: depress respiration
alter natural sleep (decrease REM) hangovers/ irritability
potentiate effect of other CNS depressants (e.g. alcohol)
tolerance (pharmacokinetic & tissue)
dependence : withdrawal syndrome
Diazepam, temazepam, oxazepam.
Mode of Action – these are selective for GABAA receptors. They only act on the postsynaptic neurone terminal and increase the frequency of Cl- channel opening in response to GABA. Their duration of action and pharmacokinetics determine their use.
-Diazepam is long acting (32hrs) – anxiolytic
-Temazepam and oxazepam are short acting (8hrs) – sedative.
Side Effects and Pharmacokinetics
Well absorbed orally
Peak plasma concentration at 1hr (oxazepam is slower onset)
IV use in status epilepticus (prolonged excessive and not self limiting seizures)
Binds strongly to plasma proteins and is highly lipid soluble to has a wide distribution
Cab be displaced by other plasma protein binding drugs
- Metabolism and excretion:
Hepatic metabolism – conjugation with glucuronide
Excreted in the urine
Shown below – as can be seen diazepam for example has to be metabolised to temazepam and oxazepam before glucuronide conjugation
- Duration of action:
Slow acting – e.g. temazepam, oxazepam (singe step to glucuronide conjugation t1/2 = 8hrs)
Long acting – slow metabolism and/or active metabolites. E.g. diazepam (2 steps to glucoronide conjugation t1/2 = 32hrs)
They are better than barbiturates because they:
They have a wide margin of safety
Have a mild effect on REM sleep
Do not induce liver enzymes.
•sedation, confusion, ataxia (impaired manual skills)
•potentiate other CNS depressants (alcohol; barbs)
•tolerance (less than barbs; ‘tissue’ only)
•dependence withdrawal syndrome similar to barbs (less intense)
•Increased levels in the plasma by aspirin and heparin.
•Wide Margin Of Safety )
Propranolol (β blocker)
•Improves Physical Symptoms
•Slow Onset Of Action (Days / Weeks)