SedativeHypnotic Drugs By Bohlooli S Ph D School

Sedative-Hypnotic Drugs By Bohlooli S, Ph. D School of Medicine, Ardabil University of Medical Sciences

Dose-response curves for two hypothetical sedative-hypnotics

BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS o CHEMICAL CLASSIFICATION o Pharmacokinetics o Pharmacodynamics

CHEMICAL CLASSIFICATION: o Benzodiazepines n 1, 4 -benzodiazepines n carboxamide group in the 7 -membered heterocyclic ring structure n A substituent in the 7 position, such as a halogen or a nitro group o Barbiturates and other older drugs o Several drugs with novel chemical structures o Other classes of drugs n antipsychotics , antidepressants , antihistaminics

Chemical structures of benzodiazepines

Chemical structures of barbiturates and other sedative-hypnotics

Chemical structures of newer hypnotics

Pharmacokinetics o ABSORPTION AND DISTRIBUTION o BIOTRANSFORMATION n Benzodiazepines n Barbiturates n Newer hypnotics o EXCRETION o FACTORS AFFECTING BIODISPOSITION

Biotransformation of benzodiazepines

Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans Drug Peak Blood Level (hours) Elimination Half-Life 1 (hours) Comments Alprazolam 1 -2 12 -15 Rapid oral absorption Chlordiazepoxide 2 -4 15 -40 Active metabolites; erratic bioavailability from IM injection 1 -2 (nordiazepam) 50 -100 Prodrug; hydrolyzed to active form in stomach 1 -2 20 -80 Active metabolites; erratic bioavailability from IM injection Eszopiclone 1 6 Flurazepam 1 -2 40 -100 Active metabolites with long half-lives Lorazepam 1 -6 10 -20 No active metabolites Oxazepam 2 -4 10 -20 No active metabolites Temazepam 2 -3 10 -40 Slow oral absorption Triazolam 1 2 -3 Rapid onset; short duration of action Zaleplon <1 1 -2 Metabolized via aldehyde dehydrogenase Zolpidem 1 -3 1. 5 -3. 5 Clorazepate Diazepam 1 Includes half-lives of major metabolites. Minor active metabolites No active metabolites

Pharmacodynamics o RAMELTEON o BUSPIRONE o MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR o NEUROPHARMACOLOGY o BENZODIAZEPINE BINDING SITE LIGANDS o ORGAN LEVEL EFFECTS

RAMELTEON o Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleepwake cycle o Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep o Is an agonist at MT 1 and MT 2 melatonin receptors located in the suprachiasmatic nuclei of the brain. o Adverse effects of ramelteon include dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin.

BUSPIRONE o Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. o As a partial agonist at brain 5 -HT 1 A receptors, o No rebound anxiety or withdrawal signs on abrupt discontinuance. o The anxiolytic effects of buspirone may take more than a week to become established o The drug is used in generalized anxiety states but is less effective in panic disorders. o The major metabolite is 1 -(2 -pyrimidyl)-piperazine (1 PP), which has alpha-2 -adrenoceptor-blocking actions

MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR

MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR o Assembled from five subunits o Oolypeptide classes (a, b, g, d, e, p, r, etc). n six different a, four b, and three g o Two a 1 and two b 2 subunits and one g 2 subunit o Zolpidem, zaleplon, and eszopiclone bind more selectively: n interact only with GABAA-receptor isoforms that contain a 1 subunits

NEUROPHARMACOLOGY o GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter o The benzodiazepines do not substitute for GABA n an increase in the frequency of channel-opening events o Barbiturates also facilitate the actions of GABA n to increase the duration of the GABA-gated chloride channel openings n may also be GABA-mimetic n depress the actions of excitatory neurotransmitters

BENZODIAZEPINE BINDING SITE LIGANDS o Agonists n benzodiazepines o Antagonists n benzodiazepine derivative flumazenil o Inverse agonists n the b-carbolines

ORGAN LEVEL EFFECTS o o o Sedation Hypnosis Anesthesia Anticonvulsant effects Muscle relaxation o Effects on respiration and cardiovascular function

Sedation o Calming effects o Depressant effects on psychomotor and cognitive functions o Dose-dependent anterograde amnesic effects

Hypnosis o Benzodiazepines n the latency of sleep onset is decreased (time to fall asleep) n the duration of stage 2 NREM sleep is increased n the duration of REM sleep is decreased n the duration of stage 4 NREM slow-wave sleep is decreased o Zolpidem n decreases REM sleep but has minimal effect on slowwave sleep o Zaleplon n decreases the latency of sleep onset with little effect on total sleep time o Eszopiclone n increases total sleep time, mainly via increases in stage 2 NREM sleep

Anesthesia o Barbiturates n thiopental and methohexital o Benzodiazepines: n diazepam, lorazepam, and midazolam n a persistent postanesthetic respiratory depression n reversible with flumazenil

Anticonvulsant effects o Benzodiazepines: n clonazepam, nitrazepam, lorazepam, and diazepam o Barbiturates: n phenobarbital and metharbital o Zolpidem, zaleplon, and eszopiclone n lack anticonvulsant activity

Muscle relaxation o Members of the carbamate n meprobamate o Benzodiazepine groups n Diazepam

Effects on respiration and cardiovascular function o Patients with pulmonary disease n significant respiratory depression o In hypovolemic states, heart failure, and other diseases n cause cardiovascular depression

Tolerance; Psychologic & Physiologic Dependence o Tolerance n partial cross-tolerance n Mechanism o An increase in the rate of drug metabolism o down-regulation of brain benzodiazepine receptors o Dependence n relief of anxiety, euphoria, disinhibition, and promotion of sleep lead to misuse

Physiologic Dependence o States of n Increased anxiety n Insomnia n central nervous system excitability o The severity of withdrawal symptoms depends on: n the magnitude of the dose n relate in part to half-life o Triazolam: daytime anxiety

BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL o Competitive antagonists o Blocks many of the actions of n n Benzodiazepines Zolpidem Zaleplon eszopiclone o Reversing the CNS depressant effects o Hasten recovery o Flumazenil acts rapidly but has a short halflife o May cause a severe precipitated abstinence syndrome

CLINICAL PHARMACOLOGY OF SEDATIVE-HYPNOTICS o TREATMENT OF ANXIETY STATES o TREATMENT OF SLEEP PROBLEMS o OTHERAPEUTIC USES

TREATMENT OF ANXIETY STATES o Secodary Anxiety States n Secondary to organic disease n Secondary to situational states n as premedication o o o Generalized anxiety disorder(GAD) Panic disorders Agoraphobia Acute anxiety states Panic attacks

TREATMENT OF SLEEP PROBLEMS o Sleep of fairly rapid onset o Sufficient duration o With minimal "hangover" effects n Drowsiness n Dysphoria n Mental or motor depression

Dosages of drugs used commonly for sedation and hypnosis Sedation Drug Hypnosis Dosage Drug Dosage (at Bedtime) Alprazolam (Xanax) 0. 25 -0. 5 mg 2 -3 times daily Chloral hydrate 500 -1000 mg Buspirone (Bu. Spar) 5 -10 mg 2 -3 times daily Estazolam (Pro. Som) 0. 5 -2 mg Chlordiazepoxide (Librium) 10 -20 mg 2 -3 times daily Eszopiclone (Lunesta) 1 -3 mg Clorazepate (Tranxene) 5 -7. 5 mg twice daily Lorazepam (Ativan) 2 -4 mg Diazepam (Valium) 5 mg twice daily Quazepam (Doral) 7. 5 -15 mg Halazepam (Paxipam) 20 -40 mg 3 -4 times daily Secobarbital 100 -200 mg Lorazepam (Ativan) 1 -2 mg once or twice daily Temazepam (Restoril) 7. 5 -30 mg Oxazepam 15 -30 mg 3 -4 times daily Triazolam (Halcion) 0. 125 -0. 5 mg Phenobarbital 15 -30 mg 2 -3 times daily Zaleplon (Sonata) 5 -20 mg Zolpidem (Ambien) 5 -10 mg

Clinical uses of sedative-hypnotics For relief of anxiety For insomnia For sedation and amnesia before and during medical and surgical procedures For treatment of epilepsy and seizure states As a component of balanced anesthesia (intravenous administration) For control of ethanol or other sedative-hypnotic withdrawal states For muscle relaxation in specific neuromuscular disorders As diagnostic aids or for treatment in psychiatry

CLINICAL TOXICOLOGY OF SEDATIVE-HYPNOTICS o Direct Toxic Actions n dose-related depression of the central nervous system n Hypersensitivity reactions n teratogenicity o Alterations in Drug Response n Tolerance n Cross-tolerance o Drug Interactions n With other central nervous system depressant drugs n hepatic drug-metabolizing enzyme systems