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Sedative hypnotic drugs


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Sedative hypnotic drugs

  1. 1. Sedative-Hypnotic Drugs sedative-Hypnotic Drugs 1
  2. 2.  Slide producers:  Emad yazdanpanah  Mohammad moeini sedative-Hypnotic Drugs 2
  3. 3.  Sedation (with concomitant relif of anxiety) Encourage sleep sedative-Hypnotic Drugs 3
  4. 4.  This drug classification based on clinical uses rather than on similarities in chemical structure. sedative-Hypnotic Drugs 4
  5. 5.  Sedative: These agents should reduce anxiety Exert a calming effect CNS depression should be the minimum consistant sedative-Hypnotic Drugs 5
  6. 6.  Hypnotic: These should produce drowsiness Maintance sleep CNS depression is more(by increasing the dose) sedative-Hypnotic Drugs 6
  7. 7. Comparison(figure22-1)A:barbiturates &alcoholsB: benzodiazopines sedative-Hypnotic Drugs 7
  8. 8.  Benzodiazepines Barbiturates Glutethmide & Meprobamat Alcohole zolpidem,zaleplon,eszopiclone(s-enantiomer of zopiclone) Ramelteon Buspirone sedative-Hypnotic Drugs 8
  9. 9. sedative-Hypnotic Drugs 9
  10. 10. sedative-Hypnotic Drugs 10
  11. 11. sedative-Hypnotic Drugs 11
  12. 12.  Benzodiazepines: 1,4-benzodiazepines Carboxamide group in 7-membered ring Halogen or a Nitro group in the 7 position (triazolam & alprazolam have triazole ring at the 1,2 position) sedative-Hypnotic Drugs 12
  13. 13. It dependes on lipophilicity All sedative-hypnotics absorbtion is good.Examples: Triazolam absorbtion is rapid Diazepam & clorazepate is rapid than other BZ Barbiturates,older sedative-hypnotic & newer hypnotics are absorbed rapidly into the blood sedative-Hypnotic Drugs 13
  14. 14.  Cross placental barrier Depression of neonatal vital function Detectable in breast milk sedative-Hypnotic Drugs 14
  15. 15.  They should metabolize to more water soluble Microsomal enzyme is important (few are excreted from the body in unchanged form) sedative-Hypnotic Drugs 15
  16. 16.  The rate of metabolism depend on the indivdual drugs Most of theme undergo microsomal oxidation(phase 1),including N-dealkylation & aliphatic hydroxylation Metabolites are conjugated(phase 2) to form glucronides Most of metabolites are active(e.g desmethyldiazepam) sedative-Hypnotic Drugs 16
  17. 17. Chlordiazpoxide Diazepam Prazepam ClorazepateDesmethyl chlordiazpoxide Demoxapam Desmethyldiazepam Alprazolam & Triazolam Oxazepam alpha-hydroxy metabolites Hydroxymethyl- flurazepam LorazepamFlurazepam CONJUGATION CONJUGATION desmethyl- flurazepam URINARY EXCRETION URINARY EXCRETION sedative-Hypnotic Drugs 17
  18. 18.  Elimination of the paren drug may have little relation to the time course of pharmacologic effect Metabolism of benzodiazepines are effected by inducers & inhabitors sedative-Hypnotic Drugs 18
  19. 19.  Insignificant quantities are excreted unchanged(exception:phenobarbital) Oxidation is involved to form alcohols,ketones,acids which appear in the urine as glucronide conjugates Elimination rate is usually slow sedative-Hypnotic Drugs 19
  20. 20. I. Zolpidem: Metabolized to inactive metabolites CYP3A4 isozyme is involved Half-life: 1.5 - 3.5 hrII. Zaleplon: Metabolized to inactive metabolites Aldehyde oxidase & partly CYP3A4 is involved sedative-Hypnotic Drugs 20
  21. 21.  Cimetidine,inhabits aldehyde dehydrogenase & CYP3A4 plasma levelIII. Eszopiclone : Metabolized by especially CYP3A4 Half-life: 6hr Rifampin hepatic metabolism Ketokenazol hepatic metabolism sedative-Hypnotic Drugs 21
  22. 22. Drug peak blood Elimination Comment level(hr) half-life(hr)Alprazolam 1-2 12-15 rapid oral absorbtionChlordiazpoxide 2-4 15-40 active metabolites;erratic bioavailibility from IM injectionClorazepate 1-2 50-100 prodrug;hydrolyzed to active from in stomachDiazepam 1-2 20-80 active metabolites;erratic bioavailibility from IM injectionEszopiclone 1 6 minor active metabolitesFlurazepam 1-2 40-100 active metabolites with long half-lifeLorazepam 1-6 10-20 no active metabolitesOxazepam 2-4 10-20 no active metabolitesTemazepam 2-3 10-20 slow oral absorbtionTriazolam 1 2-3 rapid onset;short duration of actoinZaleplon <1 1-2 metabolized via aldehyde dehydrogenaseZolpidem 1-3 1.5-3.5 no active metabolites sedative-Hypnotic Drugs 22
  23. 23.  They are excreted via the kidney Changes in renal function do not have marked effects on the elimination Phenobarbital (20-30%) is excreted unchanged in the urine excretion of phenobarbital by alkalinization of the urine sedative-Hypnotic Drugs 23
  24. 24.  Benzodiazepines: Increase in the frequency of channel-opening events barbiturates: increase the duration of the GABAA-gated channel opening(facilitate the action of GABA & GABA mimetic) sedative-Hypnotic Drugs 24
  25. 25. Figure 22-6A model of the GABAA receptor-chloride ion channelmacromolecular complex (otherscould be proposed). Aheterooligomeric glycoprotein, thecomplex consists of five or moremembrane-spanning subunits.Multiple forms of a, b, and gsubunits are arranged in differentpentameric combinations so thatGABAA receptors exhibit molecularheterogeneity. GABA appears tointeract with a or b subunitstriggering chloride channelopening with resulting membranehyperpolarization. Binding ofbenzodiazepines to g subunits or toan area of the a unit influenced bythe g unit facilitates the process ofchannel opening but does notdirectly initiate chloride current.(Modified and reproduced, withpermission, from ZorumskiCF, Isenberg KE: Insights into thestructure and function of GABAreceptors: Ion channels andpsychiatry. Am J Psychiatry1991;148:162.) sedative-Hypnotic Drugs 25
  26. 26.  Benzodiazepines binding site:GABAa receptor Three types of ligand-benzodiazepines receptor interaction have been reported:1) Agonist2) Antagonist3) Inverse agonist sedative-Hypnotic Drugs 26
  27. 27.  Sedation Hypnosis Anesthesia Anticonvulsant effect Muscle relaxation Effects on respiratory & cardiovascular function sedative-Hypnotic Drugs 27
  28. 28. Table 22-2. clinical uses of sedative-hypnoticsFor relief of anxietyFor insomniaFor sedation and insomnia before and during medical and surgical procedureFor treatment of epilepsy and seizure statesAs a component of balanced anesthesia (IV)For control of ethanol or other sedative0hypnotic withdrawal statesFor muscle relaxation in spesific neuromuscular disordersAs diagnostic aids or for treatment in psychiatry sedative-Hypnotic Drugs 28
  29. 29.  Common feature of sedative-hypnotic drug Result from increasing the dose to promote sleep Partial cross-tolerance occures between them The mechanisms are not well understood Withdrawal symptoms occures according to the individual drug Treatment:using long half-life drugs(diazepam) sedative-Hypnotic Drugs 29
  30. 30.  Act as competetive antagonist Can not block ethanol,opioids,or general anesthetics` action Short half-life: 0.7- 1.3 hr Repeated administration of the antagonis is needed(???) Adverse effect: agitation,confusion,dizzines,and nausa sedative-Hypnotic Drugs 30
  31. 31.  For patiens who have difficulty in falling asleep Agonist of MT Oral administration Has active metabolite CYP1A2 is responsible for metabolism Adverse effect: dizziness,somnolence,fatigue,endocrine changes sedative-Hypnotic Drugs 31
  32. 32.  Selective anxiety effect Differs from other sedative-hypnotic(?) Is not effective for withdrawal syndrome Uses for general anxiety Oral administration Less psychomotor imairment PB may be elevated in patients receiving MAOinhabitors sedative-Hypnotic Drugs 32
  33. 33.  Short-term use of sedative-hypnotics for treating anxiety Premedication prior to surgery or some unpleasant medical procedure Panic & Agoraphobia(alprazolam Is the best) Treatment of sleep problems(zolpidem & zaleplon are common) sedative-Hypnotic Drugs 33
  34. 34. Sedation HypnosisDrug Dosage Drug Dosage(at bedtime)Alprazolam(xanax) 0.25-0.5 mg 2-3 times daily Chloral hydrate 500-1000 mgBuspirone(buspar) 5-10 mg 2-3 times daily Estazolam(prosom) 0.5-2 mgChlordiazpoxide(librium) 10-20 mg 2-3 times daily Eszopiclone(lunesta) 1-3 mgClorazepate(tranxene) 5-7.5 mg twice daily Lorazepam(ativan) 2-4 mgDiazepam(valium) 5 mg twice daily Quazepam(doral) 7.5-15 mgHalazepam(paxipam) 20-40 mg 3-4 times daily Secobarbital 100-200 mgLorazepam(ativan) 1-2 mg once or twice daily Temazepam(restoril) 7.5 -30 mgOxazepam 15-30 mg 3-4 times daily Triazolam(halcion) 0.125-0.5 mgPhenobabital 15-30 mg 2-3 times daily Zaleplon 5-20 mg Zolpidem(ambiem) 5-10 mg sedative-Hypnotic Drugs 34
  35. 35.  Result from dose-related depression of CNS Low doses:drowsiness,impaired judgment,diminished motor skills Benzodiazopines : Antrograde amnesia, impair ability to learn new information Criminal use: Date rape Alprazolam is more toxic in overdose than other benzodiazepines sedative-Hypnotic Drugs 35
  36. 36.  Severe toxicity: Respiratory depression Aspiration of gastric content(more with ethanol) Cardiovascular depression In such cases the treatment is:I. Patent airway with mechanical ventilationII. Maintance of plasma volumeIII. Renal out putIV. Cardiac funcionV. Dopamine preserves renal blood flowVI. Hemodialysis or Hemoperfusion sedative-Hypnotic Drugs 36
  37. 37.  With other CNS depressant drugs(additive effect) With inhabitors & inducers of microsomal enzymes sedative-Hypnotic Drugs 37
  38. 38. Preparation availableBenzodiazepines Midazolam(Versed)Alprazolam(Xanax) oral:2mg/ml syruporal:0.25,0.5,1,2 mg tablet,extended- parentral:1,5 mg/ml in 1,2,5,10 mlrelease tablet,and orally disintegrating vial for injectiontablets;1.0 mg/ml solution Chlordiazpoxide(Librium) Oxazepam oral:5,10,25 mg capsules oral:10,15,30 mg capsules parentral:100 mg powder for injectionChorazepat(Tranxene) Quazepam(Doral)oral:3.75,7.5,15 mg tablets & capsules oral:7.5,15 mg tabletsoral sustained-release:11.25,22.5 mg tabletsClonazepam(Clonopin) Temazepam(Restroil)oral:0.2,1,2 mg tablets;0.125,0.25,0.5,1,2 oral:7.5,15,22.5,30 mg capsulesmg orally disintegrating tablets Diazepam(Valium) Traizolam(Halicion) oral:2,5,10 mgtablets;1.5 mg/ml solution oral:0.125,0.25 mg tablets parentral:5 mg/ml for injectionEstaolam(Prosom) Benzodiazepines antagonistoral:1,2 mg tabletsFlurazepam(Dalmane) Flumazenil(Ramazicon)oral:15,30 mg capsules parentral:0.1 mg/ml for iv injectionLorazepam(Ativam)oral:o.5,1,2 mg tablets;2 mg/ml solutionparentral:2,4 mg/ml for injection sedative-Hypnotic Drugs 38
  39. 39. Preparation availableBarbiturates Chloral hydrate(Aqachloral supprettes)Amobarbital(Amytal) oral:500 mg capsules;250,500 mg/5mlparentral:powder in 250,500 mg vials to syrupreconstitute for injection rectal:324,648 mg suppositoriesMephobarbital(Mebaral) Eszopiclone(Lunetsa)oral:32,50,100 mg tablets oral:1,2,3 mg tabletsPentobarbital(Nembutal sodium) Hydrazine(Atarax,Vistaril)oral:50,100 mg capsules;4 mg/ml elixir oral:10,25,50,100 mg tablets;25,50,100rectal:30,60,120,200 mg suppositories mg capsules;10 mg/5ml suspentionparentral:50 mg/ml for injection parentral:25,50 mg/ml for injectionPhenobarbital(Luminal sodium) Meprobamate(Eqanil,Miltown)oral:15,16,30,60,90,100 mg tablets;16 mg oral:200,400 mg tabletscapsules;15,20 mg/5ml elixirparentral:30,60,65,130 mg/ml for injectionSecobarbital(Secotal) Paraldehydeoral:100 mg capsules oral,recta liquids:1g/ml Ramelteon(Rozeram) oral:8 mg tabletsMiscellaneous Drugs Zaleplon(sonata)Buspiron(BuSpar) oral:5,10 mg capsulesoral:5,7.5,10,15,30 mg tablets Zolpidem(Ambien,Ambien-CR) oral:5,10 mg tablets;6.25,12.5 mg extended-release tablets sedative-Hypnotic Drugs 39
  40. 40. sedative-Hypnotic Drugs 40