SEDATIVE-HYPNOTIC DRUGS OBJECTIVES Define the following terms: ‘© Sedation © Hypnosis © REMsleep © Tolerance * Physical dependence + Anxiolytic ‘+ Psychologic dependence You should be able to: «Identify the major clinical classes of sedative-hypnoties. * Describe the sequence of CNS effects of a typical sedative-hypnotic over the entire dose range. © Describe the pharmacodynamics of benzodiazepines, including interactions with neuronal membrane receptors. * Compare the pharmacokinetics of commonly used benzodiazepines and barbiturates and understand how differences between them apply to clinical use. © Describe the clinical uses of sedative-hypnoticsANXIOLYTIC AND HYPNOTIC DRUGS CLASSES OF ANXIOLYTIC AND H TIC DRUG * Benzodiazepines, the most important clas insomnia, are used for treating both anxiety states and * S-HTia- receptor agonists have been recently introduced and show anxiolytic activity with little sedation © The P-adrenoceptor agonists are used mainly to reduce physical symptoms of anxiety (tremor, palpitations, etc.); they have no effect on the affective component * Miscellaneous other agents (e.g. methaqualone, chloral hydrate) are still used occasionally to treat insomnia (benzodiazepines are preferable in most cases). ‘* Barbiturates are now largely obsolete as anxiolytic/sedative agents. ZODIAZEPINES * Act by binding to a specific regulatory site on the GABAs-receptor, Subtypes of the GABAs receptor exist in different regions of the brain and differ in their sensitivity to benzodiazepines. * Anxiolytic benzodiazepines are agonists at this regulatory site. Other benzodiazepines (e.g. flumazenil) are antagonists and prevent the actions of the anxiolytic benzodiazepines. A further class of inverse agonists is recognised, which reduce the effectiveness of GABA and are anxiogenic; they are not used clinically. * Endogenous ligands for the benzodiazepine-binding site are believed to exist. They include peptide and steroid molecules, but their physiological function is not yet understood. * Benzodiazepines cause: reduction of anxiety and aggression sedation, leading to improvement of insomnia muscle relaxation and loss of motor coordination suppression of convulsions (antiepileptic effect) anterograde amnesia tocolysis + Differences in the pharmacological profile of different benzodiazepines are minor; clonazepam appears to have more anticonvulsant action in relation to its other effects Different GABA, receptor isoforms are believed to mediate sedative and axiolytic effects. + Benzodiazepines are active orally and differ mainly in respect of their duration of action, Short-acting agents (e.g. lorazepam and temazepam, half-lives 8-12 hours) are metabolised to inactive compounds and are used mainly as sleeping pills. Some long- acting agents (e.g. diazepam and chlordiazepoxide) are converted to a log-lasting active metabolite (nordazepam) * Some are used intravenously, e.g. diazepam in status epilepticus, midazolam in anesthesia. Zolpidem is a short-acting drug that is not a benzodiazepine but acts similarly Benzodiazepines are relatively safe in overdose. Their main disadvantage are interaction with alcohol, long-lasting hangover effects, withdrawal symptoms vVvVVVYCharacteristics of benzodiazepines in humans HALF LIFE oF ACTIVE PARENT | METABOLITE COMP (H) OVERALL DURATION OF ACTION MAIN USES ira (<6h) Ultra short @ b) short Hydroxylated derivative Hypnotic, midazolam used as Triazolam®, midazolam intravenous anesthetic Zolpidem™* Lorazepam, oxazepam, temazepam, lormetazepam Hypnotic Short (12-18h) | Anxiolytic, hypnotic ‘Medium (24h) Medium Tiydronylated derivative a Alprazolam Anxiolytic, antidepressant ‘Nitrazepam Hypnotic, anxiolytic _ ‘Anxiolytic, muscle relaxant Diazepam used intravenously as anticonvulsant _ Diazepam, chlordiazepoxide Nordazepam Long (24-48h) Desimethyi- ‘lurazepam No Fhurazepam Anxiolytic ‘Anticonvulsant, anxiolytic [especially mania) Clonazepam ‘+ *Triazolam has been withdrawn from use in UK on account of side-effects, * *Zolpidem is not a benzodiazepine but acts at the same site BARBITURATES + Barbiturates are non-selective CNS depressants that produce effects ranging from sedation and reduction of anxiety to unconsciousness and death from respiratory and cardiovascular failure. Therefore, they are dangerous in overdose They act partly by enhancing action of GABA but are less specific than benzodiazepines. Barbiturates are mainly used in anesthesia and treatment of epilepsy; use as sedative/hypnotic agents is no longer recommended. * They are potent inducers of hepatic drug-metabolising enzymes, especially cytochrome 450 system, so are liable to cause drug interactions. They also precipitate attacks of acute porphyria in susceptible individuals. Tolerance and dependence occur. S-HT,, AGONISTS AS ANXIOLYTIC DRUGS Buspirone is a potent (though non-selective) agonist at S-HT1A-receptors Ipsapirone and gepirone are similar Anxiolytic effects take days or weeks to develop Side-effects appear less troublesome than with benzodiazepines, but not sedation or loss of coordination