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RBIP, Mohali , Punjab CONTENTS: CONTENTS INTRODUCTION SLEEP CYCLE MOLECULAR PHARMACOLOGY OF GABA RECEPTOR CLASSIFICATION OF SEDATIVE- HYPNOTIC DRUGS MECHANISM OF ACTION OF DRUGS THERAPEUTIC USE PHARMACOKINETICS ADVERSE EFFECTS DRUG INTERACTIONS SEDATIVE: SEDATIVE A drug that subdues excitement and calms the subject without inducing sleep is called sedative. Sedation refers to decreased responsiveness to any level of stimulation. It is associated with some decrease in motor activity. HYPNOTIC: HYPNOTIC A drug that induces and/or maintains sleep, similar to normal arousable sleep is called hypnotic. Hypnotic effects involve more pronounced depression of the CNS than sedation. SLEEP CYCLES: SLEEP CYCLES Sleep is divided into two phases: Non–rapid eye movement (NREM)sleep. Rapid eye movement (REM) sleep. Humans typically experience four to six cycles of NREM and REM sleep, with each cycle lasting between 70 and 120 minutes. NREM SLEEP : NREM SLEEP STAGE 0: From lying down to falling asleep and occasional nocturnal awakenings , constitutes 1-2% of sleep time. STAGE 1: Eye movements are reduced but there may be bursts of rolling. Neck muscles relax. Occupies 3-6% of sleep time. STAGE 2 : Little eye movements , subjects are easily arousable , this comprises 40-50% of sleep time. STAGE 3 : Eye movements are few , subjects are not easily arousable ; comprises 5-8% of sleep time. STAGE 4 : Eyes are practically fixed , subjects are difficult to arouse. It comprises 10-20% of sleep time. REM (PARADOXICAL) SLEEP: REM (PARADOXICAL) SLEEP REM sleep involves a dramatic physiological change from stage 4 NREM slow-wave sleep, to a state in which the brain becomes electrically and metabolically activated. REM occurs in bursts, and is accompanied by increase in cerebral blood flow, generalized muscle atonia, vivid dreaming, and fluctuations in respiratory and cardiac rate. MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR : MOLECULAR PHARMACOLOGY OF THE GABA A RECEPTOR The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopiclone, and many other drugs bind to molecular components of the GABA A receptor in neuronal membranes in the central nervous system. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA . The GABA A receptor has a pentameric structure assembled from five subunits (each with four transmembrane-spanning domains) selected from multiple polypeptide classes (alpha, beta,gamma etc). Multiple subunits of several of these classes have been characterized. PowerPoint Presentation: A major isoform of the GABA A receptor that is found in many regions of the brain consists of two alpha 1 and two beta 2 subunits and one gamma 2 subunit. In this isoform, the binding sites for GABA are located between adjacent alpha 1 and beta 2 subunits, and the binding pocket for benzodiazepines (the BZ site of the GABA A receptor) is between an alpha 1 and the gamma 2 subunit. CLASSIFICATON: CLASSIFICATON BARBITURATES Long acting: Phenobarbitone, mephobarbitone Short acting : Butobarbitone, secobarbitone, pentobarbitone. Ultra short acting : Thiopentone, methohexitone, hexobarbitone. BENZODIAZEPINES Hypnotics: Diazepam, flurazepam, nitrazepam, flunitrazepam, temazepam, triazolam,midazolam. NEWER NONBENZODIAZEPINE HYPNOTICS Zopiclone, zolpidem, zaleplon OTHERS Ramelteon BARBITURATES MECH. OF ACTION: BARBITURATES MECH. OF ACTION Barbiturates facilitate the actions of GABA at multiple sites in the central nervous system, but in contrast to benzodiazepines they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than benzodiazepines. BENZODIAZEPINES MECH. OF ACTION: BENZODIAZEPINES MECH. OF ACTION Benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines appear to increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substitute for GABA but appear to enhance GABA's effects allosterically without directly activating GABA A receptors or opening the associated chloride channels. The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events. CLINICAL PHARMACOLOGY OF SEDATIVE HYPNOTICS: CLINICAL PHARMACOLOGY OF SEDATIVE HYPNOTICS TREATMENT OF ANXIETY STATES The benzodiazepines are widely used for the management of acute anxiety states and for rapid control of panic attacks. They are also used in the long-term management of panic disorders. alprazolam is particularly effective in the treatment of panic disorders . PowerPoint Presentation: 2 ) TREATMENT OF SLEEP PROBLEMS Benzodiazepines can cause a dose-dependent decrease in both REM and slow-wave sleep .all of the sedative-hypnotics induce sleep if high enough doses are given. (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM sleep is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased. The newer hypnotics all decrease the latency to persistent sleep. OTHER THERAPEUTIC USES : OTHER THERAPEUTIC USES For sedative and possible amnestic effects during medical or surgical procedures such as endoscopy and bronchoscopy as well as for premedication prior to anesthesia. Long-acting drugs such as chlordiazepoxide and diazepam and, to a lesser extent, phenobarbital are administered in progressively decreasing doses to patients during withdrawal from physiologic dependence on ethanol or other sedative-hypnotics. Psychiatric uses of benzodiazepines other than treatment of anxiety states include the initial management of mania. PHARMACOKINETICS: PHARMACOKINETICS ABSORPTION AND DISTRIBUTION The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. PowerPoint Presentation: BIOTRANSFORMATION Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N - dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in the urine as glucuronide conjugates. PowerPoint Presentation: EXCRETION The water-soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. ADVERSE EFFECTS AND DRUG INTERACTIONS: ADVERSE EFFECTS AND DRUG INTERACTIONS BARBITURATES: ADVERSE EFFECTS: Hangover is common , mental confusion, impaired performance, hypersensitivity may occur like swelling of eyelids, lips etc. On repeated use , tolerance develops. Psychological as well as physical dependence occurs and barbiturates have considerable abuse liability. PowerPoint Presentation: DRUG INTERACTIONS: Barbiturates show additive action with other CNS depressants like alcohols, opioids. Phenobarbitone competitively inhibits as well as induces phenytoin and imipramine metabolism. Barbiturates induce the metabolism of many drugs and reduce their effectiveness. PowerPoint Presentation: BENZODIAZEPINES : ADVERSE EFFECTS: Side effects include dizziness , vertigo, ataxia , amnesia etc. DRUG INTERACTIONS: BZDs synergise with alcohol and other CNS depressants. Use with sod. Valproate has provoked psychotic symptoms. PowerPoint Presentation: BENZODIAZEPINE ANTAGONISTS : FLUMAZENIL Flumazenil is one of several 1,4-benzodiazepine derivatives with a high affinity for the benzodiazepine binding site on the GABA A receptor that act as competitive antagonists. It blocks many of the actions of benzodiazepines, zolpidem, zaleplon, and eszopiclone, but does not antagonize the central nervous system effects of other sedative-hypnotics, ethanol, opioids, or general anesthetics. Flumazenil is approved for use in reversing the central nervous system depressant effects of benzodiazepine overdose and to hasten recovery following use of these drugs in anesthetic and diagnostic procedures. PowerPoint Presentation: When given intravenously, flumazenil acts rapidly but has a short half-life due to rapid hepatic clearance. Because all benzodiazepines have a longer duration of action than flumazenil, sedation commonly recurs, requiring repeated administration of the antagonist. PowerPoint Presentation: Alprazolam (generic, Xanax) Oral: 0.25, 0.5, 1, 2 mg tablets Chlordiazepoxide (generic, Librium) Oral: 5, 10, 25 mg capsules Parenteral: 100 mg powder for injection Clorazepate (generic, Tranxene) Oral: 3.75, 7.5, 15 mg tablets and capsules Oral sustained-release: 11.25, 22.5 mg tablets Clonazepam (generic, Klonopin) Oral: 0.5, 1, 2 mg tablets Diazepam (generic, Valium) Oral: 2, 5, 10 mg tablets; 1, 5 mg/ mL solutions Parenteral: 5 mg/ mL for injection PREPARATIONS AVAILABLE BENZODIAZEPINES THANKS: THANKS You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.