Sedatives and Hypnotics

• Sedatives and hypnotics- drugs used to induce sleep.

• Anxiolytics- drugs used to reduce anxiety.

• The action of hypnotics and anxiolytics often overlap.

Broad types.

• Benzodiazepines

• Non benzodiazpine ligands

• Barbiturates

• Other

Benzodiazepines

• Commonly used as both an anxiolytic and/or hypnotic.
• Benzodiazepines with a short t ½ (usually high potency) are preferred to for anxiety.
• Benzodiazepines with a longer t ½ are used as hypnotics.

Examples of benzodiazepines:
Diazepam                       
Chlordiazepoxide                   
Lorazepam                       
Temazepam                       
Alprazolam
Triazolam

Pharmocokinetics:

• Absorption:  rapidly absorbed.
• Strongly bound to plasma proteins.
• Lipophilic; cross blood brain barrier easily.
• Metabolism:  Liver.  Many metabolites formed.  BDZ with long half lives are broken down into ACTIVE metabolites, which continue to act therapeutically.  
• Excretion:  Conjugates in urine.

Benzodiapines- mode of action?
Acts as a positive allosteric modulator at the GABA-A receptor complex.

Actions of benzodiazepines

• Sedative and hypnotic action.

• Anxiolytic

                         E.g. used for anxiety disorders, such Generalized Anxiety Disorder.

• Muscle relaxant

                        E.g. may be used in general anaesthesia.

• Anticonvulsant

                         E.g. used to treat epilepsy.


Side effects of benzodiazepines

• Drowsiness ( e.g. ‘Hangover’ effect).

• Poor coordination, ataxia, dizziness (falls, injuries- e.g. in elderly).

• Confusion and/or brief amnesia- esp in elderly.

• Sometimes- Disinhibition.

• Tolerance and Dependence with prolonged use;  can get physical withdrawal when stopping prolonged treatment. Therefore limit use to short term (ideally less than 1 week; continuous use for over 3 weeks – sig. risk of dependence).

Toxic effects in overdose…

• Respiratory depression.

• Additive effect with other drugs that depress the CNS, such as alcohol.

Flumazenil (iv)

• BDZ receptor antagonist.

• Blocks actions of BDZ.

• Useful in reversing acute toxicity.

Non benzodiazepine ligands :
Relatively new;  commonly used as hypnotics.
E.g.
Zopiclone  (half life: 4-6 hours)
Zolpidem   (half life: 1.5- 2 hours)
Zaleplon    (half life:  1- 1.5 hours)

Act at/ close to the benzodiazepine receptor site.

Side effects include:

• Residual effects, e.g. drowsiness next day.

• Risk of tolerance and dependence?  seem less.

Barbiturates

1. Used widely in the past as a hypnotic and anxiolytic.  Use less now, due to side effects.
2. Unwanted effects:

• Similar to BDZ, but more prominent.

• E.g. Drowsiness, ataxia, irritability.

• Dependence and withdrawal symptoms marked.

• At large doses- significant risk of respiratory depression.