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Sedative-Hypnotics Sedative: a drug that subdues excitement and calms the individual without inducing sleep Hypnotic: a drug that induces /maintain sleep similar to normal sleep Dose dependent CNS depression Dose Response Relationships Coma Barbiturates Medullary depression Benzodiazepines CNS Effects Anesthesia Hypnosis Sedation, disinhibition, anxiolysis Increasing dose 1.Barbiturates Long acting : Phenobarbital Short acting: Pentobarbital Secobarbital Ultra Short acting: Thiopentone 2.Benzodiazepines (BZDs) Hypnotic • Diazepam • Flurazepam • Midazolam Anticonvulsant • Diazepam • Clonazepam Antianxiety • Diazepam • Alprazolam • Chlordiazepoxide 3.Nonbenzodiazepine hypnotics • Zopiclone • Zolpidem MOA GABA A receptor: Pentameric membrane protein containing an ion channel selective for chloride ions β2 Extracellular part Transmembrane part α1 β2 α1 2 Cl- Benzodiazepine Barbiturates GABA -GABA receptor complex β2 α1 β2 BZ1 2 α1 Act on GABA-BZD receptor Cl channel complex Prolong duration of GABA-mediated chloride channel openings CNS depression Inhibitory effects on glutamate receptors MOA of Barbiturates MOA of BZDs Bind to BZ1() receptor, on GABABZD receptor Cl channel complex increased frequency of GABAmediated chloride channel openings CNS depression MOA of Zolpidem and Zaleplon Selective 1 Agonists – Stimulation of specific (1) benzodiazepine receptors – Bind to GABAA receptors isoforms that contain α1 subunits Following agents facilitate or mimic the action of GABA • alcohol; alphaxolone, etomidate, and propofol (intravenous anesthetics) • volatile anesthetics (eg, halothane) • several anticonvulsants (eg, gabapentin,vigabatrin) • ivermectin (an anthelmintic agent) • Drugs block the channel directly (picrotoxin) or • interfere with GABA binding bicuculline -convulsions Pharmacokinetics Absorption and distribution CNS entry depend on lipid solubility Thiopentone- high lipid soluble Rapid entry – used for induction of general anesthesia Rapid redistribution from brain to highly perfused tissues Table 13-3. Metabolism of benzodiazepines Metabolism of BZDs Long-acting metabolites 3-Hydroxy compounds Glucuronide conjugates -Hydroxy metabolites Chlordiazepoxide • Microsomal stimulation: multiple Desmethylchlordiazepoxide drug interactions, Clorazepate Diazepam porphyria Halazepam Prazepam N-Hydroxyethylflurazepam Lorazepam Demoxepam Temazepam Nordazepam Oxazepam N-desalkylflurazepam 3-Hydroxy derivatives 2-Oxo-quazepam Flurazepam Quazepam Estazolam Alprazolam Midazolam Triazolam -Hydroxy derivatives Zolpidem and Zaleplon rapid metabolism by liver enzymes Short duration of action half-life 2.5 hr (zolpidem) and 1 hr (zaleplon) Metabolism of Barbiturates undergo oxidation in liver Excretion BZD excreted via kidney Phenobarbital -elimination is increased by alkalanizing the urine Actions CNS: Dose dependent effects Sedation(anxiolysis) sleep(hypnosis) anaesthesia coma Pentobarbital – Sedation (50-100 mg) – Hypnosis (100-200 mg) – Anesthesia (300-400 mg) – Death (>600 mg) Steep dose response curve Not safe Barbiturates BZDs Flat dose response curve Safer CNS Actions 1. Sedative dose (smaller dose) • Drowsiness • Reduction in anxiety • Impair motor coordination • Impair learning and memory 2.Effect on sleep pattern • Shortens time taken for onset of sleep(sleep latency) • Sleep duration • REM sleep is decreased • On discontinuation (barbiturates) rebound in REM sleep hangover (irritability, dizziness, mood upset) CNS Actions • Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep • Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. • The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns. Selective 1 Agonists • Pharmacologic characteristics (2) – Rapid onset: 10-20 min – Short duration: half-life 2.5 (zolpidem) and 1 zaleplon) hr – Less amnesia; reduced anticonvulsant and muscle relaxant effects – Less selective antianxiety effect – Pregnancy category B (zolpidem), C (zaleplon) – May preserve normal sleep architecture – Reversible with flumazenil CNS Actions 3. Anaesthesia high doses • Depress the CNS - general anaesthesia Thiopental, methohexital- inducing anaesthesia Diazepam i.v anaesthesia, along with other agents CNS Actions cont.. 4. Anticonvulsant clonazepam, nitrazepam, diazepam Phenobarbital 5. Skeletal muscle relaxation BZDs inhibit Polysynaptic reflexes Other Actions Effect on RS High doses- respiratory depression Effect on CVS High doses- fall in BP Tolerance repeated use- a decrease in responsiveness Psychological dependence compulsive use of the drug to relieve anxiety Physiologic dependence altered physiological state leading to withdrawal syndrome when drug is discontinued Clinical Uses • The perceived desirable properties of relief of anxiety, euphoria, disinhibition, and promotion of sleep have led to the compulsive misuse of virtually all sedativehypnotics. • For this reason, most sedative-hypnotic drugs are classified as Schedule III or Schedule IV drugs for prescribing purposes. Clinical Uses Insomnia • barbiturates not preferred • Estazolam, flurazepam, triazolam • Zolpidem and zaleplon Less cognitive impairment Anxiety • Alprazolam and clonazepam more efficacy – Buspirone • No sedation/ cognitive impairment • Slow onset time (1-3 weeks) • 5-HT1A receptor partial agonist Uses cont… Epilepsy Phenobarbitone- Generalized tonic clonic seizures BZDs -Status epilepticus Tetanus Febrile convulsions Induction of GA • Thiopentone Uses cont… Acute muscle spasms-BZDs As a muscle relaxant Before ECT, cardiac catheterization, endoscopies- BZDs reduce anxiety, muscle relaxant Alcohol withdrawal- BZDs • Acute and chronic anxiety relief: Therapeuticlorazepam uses alprazolam, diazepam, • Perioperative sedation: diazepam, lorazepam, midazolam, triazolam • Acute insomnia: temazepam, triazolam • Alcohol withdrawal: diazepam, lorazepam • Muscle relaxation: diazepam • Seizures: clonazepam, clorazepate, diazepam, lorazepam, midazolam • Panic disorders and depression: alprazolam Benzodiazepines Toxicity • Psychomotor dysfunction Hangover BZDs metabolites which have long half life • Dependence • Overdosage Acute barbiturate poisoining Shallow respiration, fall in BP, coma, renal failure Gastric lavage Oxygen supportive measures Forced alkaline diuresis: i.v sodium bicarbonate Hemodialysis No specific antidote Treatment of barbiturate poisoning BZDs overdosage • Is not as fatal as barbiturates Specific antidote Flumazenil- BZD antagonist ,with a high affinity for the benzodiazepine binding site on the GABAA receptor flumazenil acts rapidly but has a short half-life (0.7–1.3 hours) 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.