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

2. Dose-response curves for two hypothetical sedative-hypnotics

3. BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS  CHEMICAL CLASSIFICATION  Pharmacokinetics  Pharmacodynamics

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

5. Chemical structures of benzodiazepines

6. Chemical structures of barbiturates and other sedative-hypnotics

7. Chemical structures of newer hypnotics

8. Pharmacokinetics  ABSORPTION AND DISTRIBUTION  BIOTRANSFORMATION Benzodiazepines Barbiturates Newer hypnotics  EXCRETION  FACTORS AFFECTING BIODISPOSITION

9. Biotransformation of benzodiazepines

10. DrugPeak Blood Level (hours) Elimination Half-Life 1 (hours) Comments Alprazolam1-212-15Rapid oral absorption Chlordiazepoxide2-415-40Active metabolites; erratic bioavailability from IM injection Clorazepate1-2 (nordiazepam)50-100Prodrug; hydrolyzed to active form in stomach Diazepam1-220-80Active metabolites; erratic bioavailability from IM injection Eszopiclone16Minor active metabolites Flurazepam1-240-100Active metabolites with long half-lives Lorazepam1-610-20No active metabolites Oxazepam2-410-20No active metabolites Temazepam2-310-40Slow oral absorption Triazolam12-3Rapid onset; short duration of action Zaleplon<11-2Metabolized via aldehyde dehydrogenase Zolpidem1-31.5-3.5No active metabolites 1 Includes half-lives of major metabolites. Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans

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

12. RAMELTEON  Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep- wake cycle  Ramelteon, a novel hypnotic drug prescribed specifically for patients who have difficulty in falling asleep  Is an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain.  Adverse effects of ramelteon include dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin.

13. BUSPIRONE  Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects.  As a partial agonist at brain 5-HT1A receptors,  No rebound anxiety or withdrawal signs on abrupt discontinuance.  The anxiolytic effects of buspirone may take more than a week to become established  The drug is used in generalized anxiety states but is less effective in panic disorders.  The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has alpha-2-adrenoceptor-blocking actions

14. MOLECULAR PHARMACOLOGY OF THE GABAA RECEPTOR

15.  Assembled from five subunits  Oolypeptide classes ( etc  six different , four , and three   Two 1 and two 2 subunits and one 2 subunit  Zolpidem, zaleplon, and eszopiclone bind more selectively: interact only with GABA A -receptor isoforms that contain 1 subunits

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

17. BENZODIAZEPINE BINDING SITE LIGANDS  Agonists benzodiazepines  Antagonists benzodiazepine derivative flumazenil  Inverse agonists the -carbolines

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

19. Sedation  Calming effects  Depressant effects on psychomotor and cognitive functions  Dose-dependent anterograde amnesic effects

20. Hypnosis  Benzodiazepines the latency of sleep onset is decreased (time to fall asleep) the duration of stage 2 NREM sleep is increased the duration of REM sleep is decreased the duration of stage 4 NREM slow-wave sleep is decreased  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  Eszopiclone increases total sleep time, mainly via increases in stage 2 NREM sleep

21. Anesthesia  Barbiturates thiopental and methohexital  Benzodiazepines: diazepam, lorazepam, and midazolam a persistent postanesthetic respiratory depression reversible with flumazenil

22. Anticonvulsant effects  Benzodiazepines: clonazepam, nitrazepam, lorazepam, and diazepam  Barbiturates: phenobarbital and metharbital  Zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity

23. Muscle relaxation  Members of the carbamate meprobamate  Benzodiazepine groups Diazepam

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

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

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

27. BENZODIAZEPINE ANTAGONISTS: FLUMAZENIL  Competitive antagonists  Blocks many of the actions of Benzodiazepines Zolpidem Zaleplon eszopiclone  Reversing the CNS depressant effects  Hasten recovery  Flumazenil acts rapidly but has a short half- life  May cause a severe precipitated abstinence syndrome

28. CLINICAL PHARMACOLOGY OF SEDATIVE-HYPNOTICS  TREATMENT OF ANXIETY STATES  TREATMENT OF SLEEP PROBLEMS  OTHER THERAPEUTIC USES

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

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

31. SedationHypnosis DrugDosageDrugDosage (at Bedtime) Alprazolam (Xanax)0.25-0.5 mg 2-3 times daily Chloral hydrate500-1000 mg Buspirone (BuSpar)5-10 mg 2-3 times dailyEstazolam (ProSom)0.5-2 mg Chlordiazepoxide (Librium) 10-20 mg 2-3 times dailyEszopiclone (Lunesta) 1-3 mg Clorazepate (Tranxene) 5-7.5 mg twice dailyLorazepam (Ativan)2-4 mg Diazepam (Valium)5 mg twice dailyQuazepam (Doral)7.5-15 mg Halazepam (Paxipam) 20-40 mg 3-4 times dailySecobarbital100-200 mg Lorazepam (Ativan)1-2 mg once or twice daily Temazepam (Restoril)7.5-30 mg Oxazepam15-30 mg 3-4 times dailyTriazolam (Halcion)0.125-0.5 mg Phenobarbital15-30 mg 2-3 times dailyZaleplon (Sonata)5-20 mg Zolpidem (Ambien)5-10 mg Dosages of drugs used commonly for sedation and hypnosis

32. 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 uses of sedative-hypnotics

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