Sedative- Hypnotic drugs.pptx vvvggggggyyftyhy

Pharmacology

1. Sedative- Hypnotic drugs Dr. Maham Israr

2. Sedative / anxiolytic drugs The drugs which reduce anxiety and exert a calming effect Hypnotic drug Drug which produce drowsiness and encourage the onset and maintenance of a state of sleep.

3. Sedative-Hypnotic drugs Benzodiazepine Barbiturate Glutethimide rarely used now Meprobamate Chloral hydrate Alcohol Antipsychotics A ntidepressant drug Hypnotic drug Zolpidem , zaleplon , eszopiclone Ramelteon Suvorexant Certain antihistaminic agents Anxiolytic agent Buspirone

4. Classification A. BDZ compounds Short acting Half-Life < 6 hours Midazolam Triazolam Oxazepam Intermediate acting Half-Life 6 -24 hours Alprazolam Lorazepam Long acting Half-Life > 24 hours Diazepam Clorazepate Nitrazepam Clonazepam Flunitrazepam Parazepam

5. B. Barbiturates Ultra short acting Half-Life < 15 min Thiopental Na Short acting Half-Life 1-3 hours Pentobarbitone Hexobarbitone Intermediate acting Half-Life 4- 6 hours Amobarbitone Secobarbitone Butabarbitone Long acting Half-Life > 6 hours Phenobarbitone

6. C. Other drugs Hypnotics Zolpidem Z aleplon E szopiclone Ramelteon Sedatives Buspirone

7. Pharmacokinetic Route : Oral or I/V Lipid solubility : Sufficient Absorption from GIT : Well Plasma protein binding : Not significant Crosses placenta Secreted in breast milk Biotransformation BDZ compounds Phase Ⅰ : microsomal oxidation (N- dealkylation and aliphatic hydroxylation) Phase Ⅱ : Glucuronides Don’t induce enzymes

8. Directly conjugated without metabolism Estazolam Lorazepam Temazepam Triazolam Short acting, don't accumulate, safe in liver failure and in elderly

9. Barbiturates Phase Ⅰ : oxidation by hepatic enzymes to form alcohols, acids, and ketones Phase Ⅱ : Glucuronides Induce hepatic enzymes Newer hypnotics Zolpidem metabolized by hepatic CYP3A4. Zaleplon is metabolized by hepatic aldehyde oxidase and partly by the cytochrome P450 isoform CYP3A4.

10. Eszopiclone is metabolized by hepatic cytochromes P450 (especially CYP3A4) The orexin receptor antagonist suvorexant is also a substrate of CYP3A4 Excretion Renal

11. GABA Receptor Heterogeneity α1 subunits in GABA sedation, amnesia, and ataxic effects α2 and α3 subunits are involved in their anxiolytic and muscle-relaxing actions α5 memory impairment

12. GAB Benzodiazepines Barbiturates Newer hypnotics ( eg , zolpidem ) Alcohol I ntravenous anesthetics ( etomidate , propofol ) Halothane V igabatrin Tiagabine Picrotoxin Bicuculline Flumazenil β- carbolines GAB Baclofen  

13. MOA BDZ Increase in the frequency Cl channel-opening events Hyperpolarization CNS depression

14. MOA Barbiturates GABA- ergic inhibition increase in the duration GABA- mimetic directly activates GABA channel Inhibit Glutamate, Aspartate Barbiturates also exert nonsynaptic membrane effects I nduce full surgical anesthesia M ore pronounced central depressant effects

15. Organ Level Effects Sedation Calming effect with reduction of anxiety Euphoria Impaired judgment Disinhibition of punishment suppressed behaviour Loss of self control Dose dependent anterograde amnesia

16. 2. Hypnosis the latency of sleep onset is decreased 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. 3. Anesthesia Stage III of general anesthesia Barbiturates thiopental and methohexital BDZ diazepam, lorazepam , and midazolam

17. 4. Anti-convulsion Inhibit the development and spread of epileptiform electrical activity in CNS clonazepam, nitrazepam , lorazepam , midazolam, clobazam , clorazepate , and diazepam 5. Muscle relaxation inhibitory effects on polysynaptic reflexes and internuncial transmission at high doses may also depress transmission at the skeletal neuromuscular junction

18. 6. Cardio-respiratory system Depression of the medullary respiratory center and cvs collapse at toxic dose and in patients with pulmonary dysfunction and hear failure.

19. Clinical uses of Sedative-hypnotic

20. TREATMENT OF ANXIETY STATES A cute anxiety states R apid control of panic attacks P anic disorders and agoraphobia Alprazolam CLINICAL PHARMACOLOGY OF SEDATIVE-HYPNOTICS

21. TREATMENT OF SLEEP PROBLEMS Abrupt discontinuance of many drugs in this class can lead to rebound insomnia Benzodiazepines cause a dose-dependent decrease in both REM and slow-wave sleep The newer hypnotics are less likely to change sleep patterns.

22. Premedication prior to anesthesia Withdrawal from physiologic dependence on ethanol or other sedative-hypnotics phenobarbital To suppress the symptoms of delirium tremens Parenteral lorazepam R elaxant effects in skeletal muscle spasticity of central origin diazepam

23. I nitial management of mania control of drug-induced hyperexcitability states ( eg , phencyclidine intoxication) Drugs used in the management of seizure disorders and as intravenous agents in anesthesia

24. Indications of barbiturates Induction of GA Congenital hyperbilirubinaemia In epilepsies ( phenobarbitone ) Emergency treatment in convulsions Narcoanalysis and Narcotherapy Sedation and hypnosis Ethanol withdrawal states

25. Adverse effects of BDZ a. w ithin therapeutic dose Hangover effect Somnolence Lethargy Drowsiness Impaired judgment Diminished motor skill Anterograde amnesia

26. In larger doses Cardiac failure Resp centre depression May cause total memory loss, in long term use Rhambdomyolysis Serious aggressive behaviour Other Rebound insomnia Addiction (Psychological and physical) Abnormal sleepiness of breastfed baby Development of tolerance BDZ Downregulation of GABA receptor Pharmacodynamic tolerance Barbiturate Induce hepatic drug metabolizing enzyme Pharmacokinetic tolerance

27. Contraindication Cardiac failure Pulmonary insufficiency COPD Symptomatic sleep apnea Acute intermittent porphyria , variegate porphyria, hereditary porphyria barbiturate

28. CNS depression when administered with other drugs, alcoholic beverages, opioid analgesics, anticonvulsants, Phenothiazines , antihistamines , antihypertensive agents , and antidepressant drugs of the tricyclic class. Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems. Drug interaction

29. NEWER HYPNOTICS Zopiclone Eszopiclone Zaleplon Zolpidem ꞷ subtype of GABA MOA Bind selectively to a subgroup of GAB receptors , acting like benzodiazepines to enhance membrane hyperpolarization. Effects Rapid onset of hypnosis with few amnestic effects or day after psychomotor depression or somnolence  

30. Clinical Applications Sleep disorders, especially those characterized by difficulty in falling asleep Pharmacokinetics, Toxicities , Interactions Oral activity • short half-lives • CYP substrates • Toxicity: Extensions of CNS depressant effects • dependence liability • Interactions: Additive CNS depression with ethanol and many other drugs

31. MELATONIN RECEPTOR AGONISTS MOA Ramelteon Activates MT1 and MT2 receptors in suprachiasmatic nuclei in the CNS Effects Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms Clinical Applications Sleep onset insomnia Pharmacokinetics, Toxicities, Interactions • not a controlled substance, Oral activity • forms active metabolite via CYP1A2 • Toxicity: Dizziness • fatigue • endocrine changes • Interactions: Fluvoxamine inhibits metabolism Tasimelteon : Orally active MT1 and MT2 agonist, recently approved for non-24-hour sleep disorder

32. OREXIN ANTAGONIST MOA Suvorexant Blocks binding of orexins , neuropeptides that promote wakefulness Effects Promotes sleep onset and duration Clinical Applications Sleep disorders, especially those characterized by difficulty in falling asleep Pharmacokinetics, Toxicities, Interactions CYP450 metabolism is inhibited by fluconazole , verapamil, and grapefruit juice, next-day somnolence and driving impairment

33. 5-HT-RECEPTOR AGONIST Buspirone , ( Ipsapirone , Gepirone , Tandospirone ) MOA Partial agonist at 5-HT receptors but affinity for D2 receptors also possible Effects Slow onset (1–2 weeks) of anxiolytic effects • minimal psychomotor impairment, no additive CNS depression with sedative-hypnotic drugs. Minimal abuse liability. No withdrawl Clinical application Generalized anxiety states Pharmacokinetics, Toxicities, Interactions Oral activity • forms active metabolite • short half-life • Toxicity: Tachycardia • paresthesias • gastrointestinal distress. Dose dependent pupil constriction Raises BP with MAO • Interaction : CYP3A4 inducers and inhibitors

34. Drugs used in insomnia Drugs used in hypersomnia Methylphenidate Modafinil Anti-depressants Citalopram Fluoxetine Paroxetine Sertraline

35. Drugs used in GAD SSRI Citalopram , Escitalopram , Fluoxetine TCA imipramine Propranolol Social anxiety disorder Gapapentin , pregabalin Panic attack Alprazolam

36. BENZODIAZEPINE ANTAGONIST Flumazenil Antagonist at Benzodiazepine binding sites on the GAB receptor Blocks actions of benzodiazepines and zolpidem but not other sedative-hypnotic drugs Management of benzodiazepine overdose IV, short half-life • Toxicity: Agitation, confusion • possible withdrawal symptoms in benzodiazepine dependence.  

37. Mx of benzodiazepine poisoning Urgent hospitalization ABCD Mx In case of cardio-respiratory depression : Artificial respiration If patient is conscious, vomiting should be induced Gastric lavage : By activated charcoal 50mg in 400ml distilled water within 4 hours IV fluid 5 % DA 2000cc and 5% DNS 1000cc IV @ 3O drops / min Acidosis : NaHCo3 IV Antidote : flumazenil IV

38. Mx of barbiturate poisoning C/F Impaired consciousness Low Bp Pupil is usually dilated Face is congested, cyanotic Muscles are flaccid Reflexes are diminished Cardio-respiratory depression Barbiturate blisters

39. Urgent hospitalization ABCD Mx In case of cardio-respiratory depression : Artificial respiration If patient is conscious, vomiting should be induced Gastric lavage : By activated charcoal 50mg in 400ml distilled water within 4 hours IV fluid 5 % DA 2000cc and 5% DNS 1000cc IV @ 3O drops / min Acidosis : NaHCo3 IV If no improvement : Inj bemegride General care