Sedative-Hypnotic DrugsDepartment of Pharmacology Zhang YanmeiNormal sleep consists of distinct stages,based on three physiologic measures: the electroencephalogram, the electromyogram, and the electronystagmogram.Non-rapid eye movement(NREM) sleep: 70%- 75%Stage 1,2Stage 3,4:slow wave sleep, SWS Rapid eye movement(REM) sleepNormal sleepBASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose. Graded dose-dependent depression of central nervous system function is a characteristic of sedative- hypnotics.CHEMICAL CLASSIFICATION Benzodiazepines: not to lead general anesthesia, raraly death. Barbiturates: the older sedative-hypnotics, general depression of central nervous system. With such drugs, an increase in dose above that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, it may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Other classes of drugs: chloral hydrate, buspirone, et al. .Benzodiazepines The first benzodiazepine, chlordiazepoxide, was synthesised by accident in 1961.Benzodiazepines Derivative of 1,4- benzodiazepines. About 20 are available for clinical use. They are basically similar in their pharmacological actions, though some degree of selectivity has been reported. It is possible that selectivity with respect to two types of benzodiazepine receptor may account for these differences. From a clinical point of view, difference in pharmacokinetic behaviour are more important than difference in profile of activity. PHARMACOLOGICAL EFFECTS1. Reduction of anxiety and aggression :affects the hippocampus and nucleus amygdalae2. Sedation and induction of sleep:(1) the latency of sleep onset is decreased; (2) the duration of stage 2 NREM sleep is increased;(3) the duration of slow-wave sleep is decreased.PHARMACOLOGICAL EFFECTSReasons for their extensive clinical use: (1) great margin of safety;(2) little effect on REM sleep;(3) little hepatic microsomal drug- metabolizing enzymes;(4) slight physiologic and psychologic dependence and withdrawal syndrome;(5) less adverse effects such as residual drowsiness and incoordination movement.3. Anticonvulsant and antiseizure They are highly effective against chemically induced convulsions caused by leptazol, bicuculline and similar drugs but less so against electrically induced convulsions.The can enhance GABA-mediated synaptic systems and inhibit excitatory transmission.4. Muscle relaxationrelax contracted muscle in joint diease or muscle pasm.5. Other effectslead to temporary amnesiadecrease the dosage of anesthetic; depress respiratory and cardiovascular fuction.MECHANISM OF ACTION Benzodiazepines act very selectively on GABAA-receptors, which mediate the fast inhibitory synaptic response produced by activity in GABA-ergic neurons. The effect of benzodiazepines is to enhance the response to GABA, by facilitating the opening of GABA-activated chloride channels (an increase in the frequency of channel opening, but no change in the conductance or mean open time).MECHANISM OF ACTION Benzodiazepines bind specifically to a regulatory site on the receptor, distinct from the GABA binding site, and enhanced receptor affinity for GABA. The GABAA-receptors is a ligand-gated ion channel consisting of a pentameric assembly of subunits.PHARMACOKINETIC ASPECTS Well absorbed when given orally; They bind strongly to plasma protein, and their high lipid solubility cause many of them to accumulate gradually in body fat. Distribution volumes is big. Metabolic transformation in the microsomal drug-metabolizing enzyme systems of the liver, eventually excreted as glucuronide conjugates in the urine. They vary greatly in duration of action, and can be roughly divided into Short-acting compounds: triazolam, oxazepam(15-30min, t1/2 2-3 h) Medium-acting compounds: estazolam, nitrazepam (40min, t1/2 5-8 h) Long-acting compounds: diazepam, flurazepam(50h)ADVERSE DRUG REACTION Acute toxicity: Benzodiazepines in acute overdose are considerably less dangerous than other sedative-hypnotic drugs. Cause prolonged sleep,without serious depression of respiration or cardiovascular. The availability of an effective antagonist, flumazenil.ADVERSE DRUG REACTION Side-effects during therapeutic use: drowsiness, confusion, amnesia, impaired coordination. Main disadvantages are interaction with alcohol, long-lasting han