SEDATIVE HYPNOTICS and Anti-Anxiety Drugss

Sedative hypnotics
Classification
Mechanism of action
Uses of Benzodiazepines and Non Benzodiazepines

1. SEDATIVE HYPNOTICS

2. INTRODUCTION Sedation- decreased alertness & reduced level of responsiveness to any stimuli without inducing sleep. Hypnosis- resembles natural sleep which can be aroused by strong stimuli.

3. CLASSIFICATION Benzodiazepines Non-Benzodiazepine Hypnotics. Barbiturates. Miscellaneous.

4. BARBITURATES Long acting Phenobarbitone , Mephobarbitol . Short Acting Phentobarbitone , butobarbitone . Utra short acting Thiopentone & Methohexitone

5. BARBITURATES GABA benzodiazepine receptor chloride channel complex. Increases the duration of opening of chloride channel induced by GABA. Binds to a different site than BZD. At high concentration, GABA mimetic action. Inhibit Ca dependent release of neurotransmitters. Through AMPA, depresses glutamate induced depolarization.

6. Pharmacological Actions CNS Sedation Sleep Anaesthesia Coma REM decreased, sleep cycle disrupted. Rebound increase in REM & nightmares . Drowsiness, reduction in anxiety, anti- convulsant . Depression of reticular activating system(inability to maintain wakefullness ).

7. Actions Contd.. Respiration - depressed in higher doses. CVS - toxic doses, fall in BP(ganglion & vasomotor center block). Skeletal muscle - Anesthetic doses depress the excitability at NM junction. Smooth muscles - tone &motility reduced. Kidney - reduces urinary flow by reducing BP.

8. Pharmacokinetics Rate of absorption- lipid solubility. Redistribution- Thiopentone . Metabolised by phase I (hepatic microsomal enzymes) & Phase II ( glucuornyl conjugation). Excretion- Alkalinization increases elimination. Induces microsomal enzymes ( glucuronyl transferase ) & increases the rate of its own metabolism as well as others.

9. USES Epilepsy. Anaesthesia . Hypnotics & Anxiolytics . (supersedes by BZD) Congenital non hemolytic jaundice & kernicterus . (induces glucuronyl transferase enzyme, increased conjugation and excretion of bilirubin ).

10. Adverse Effects Hangover, Tolerance & dependence. Idiosyncratic excitement. Hypersensitivity. Abuse liability. Drug automatism. Drug interactions.

11. Acute Barbiturate Poisoning Flabby, comatose, shallow failing respiration, low BP, renal shut down, bullous eruptions. Lethal dose 2-3g(short acting) & 5-10gm( phenobarbitone ). TREATMENT Gastric lavage , charcoal. Supportive measures. Alkaline diuresis . Hemodialysis . NO SPECIFIC ANTIDOTE.

12. Barbiturates interactions Induce metabolism of Warfarin , Steroids(contraceptives), Tolbutamide , griseofulvin , Chloramphenicol , Theophylline . Additive with Alcohol, antihistamine, Opioids . Sodium valproate increases the plasma conc of phenobarbitone . Phenobarbitone inhibits as well as induces phenytoin & imipramine metabolism. Phenobarbitone decreases absorption of griseofulvin .

13. Benzodiazepines High therapeutic index. Do not affect respiratory or cardiovascular functions. Less effect on sleep architecture. No enzyme induction. Lower abuse liability. Flumazenil – Specific antagonist available.

14. BENZODIAZEPINES Short Acting Triazolam , Oxazepam , Midazolam . Intermediate Acting Alprazolam , Estazolam , Temazepam , Lorazepam , Nitrazepam . Long Acting Diazepam, Flurazepam , Clonazepam , Chlordiazepoxide .

15. BENZODIAZEPINES Anxiolytic , hypnotic, muscle relaxant, Depressant action on limbic system. Muscle relaxation by medullary action(inhibits polysynaptic reflexes in spinal cord). Anxiolytic action with less sedative effects.

16. GABA receptor

17. β α β GABA Diazepam Flumazenil carboline Barbiturate intracellular Cl picrotoxin

18. GABA Cl BZD Flumazenil β carboline Channel modulators Channel blockers

19. PK IM irregular except lorazepam . Plasma protein binding. Slow elimination- Flurazepam . Slow elimination with marked redistribution- Diazepam & nitrazepam , Rapid elimination- Alprazolam , Temazepam . Ultrarapid elimination- Triazolam & midazolam .

20. Adverse Effects Dizziness, vertigo, amnesia, disorientation. Tolerance to sedative effects gradually disappears. Pregnancy- increased birth defects.

21. Drug interactions Synergise with alcohol & CNS depressants. Displacement reactions rare. CYP3A4 interactions.

22. USES HYPNOTIC Chronic insommnia Short term insommnia Transient insommnia . As anxiolytic . Anticonvulsant. Centrally acting muscle relaxant. Preanaesthetic medication. Before ECT, cardiac catheterization, minor procedures. Alcohol withdrawal.

23. Flumazenil Competitive antagonist at BZD site. High first pass metabolism, given IV. Action lasts for 1-2 hrs. USES To reverse BZD anaesthesia . BZD overdose(.2mg iv to a maximum of 5 mg).

24. Benzodiazepines Vs Barbiturates Provides anaesthesia but patient easily aroused. High therapeutic index. Not enzyme inducers, hence drug interactions less. Very low abuse liability. Does not affect REM sleep. No hyperalgesia . Amnesia with no automatism. Can be used as daytime anxiolytic -sedative in sub hypnotic doses. Does not affect CVS or respiratory functions. Specific antagonist available( Flumazenil ).

25. NON BENZODIAZEPINES Not BZD, binds to GABA A receptors ( α 1 ), facilitate GABA binding. No anticonvulsant, antianxiety or muscle relaxant property. Lower risk of dependence & tolerance. Rapid & short acting with no hangover. Actions blocked by Flumazenil .

26. Non Benzodiazepines Zolpidem (2-3hrs) 10-20mg. Zopiclone (6-8hrs) 7.5mg. Eszopiclone (6hrs)1-3mg. Zaleplon (3-4hrs)10-20mg.

27. ZOLPIDEM Good hypnotic. Does not suppress deep sleep. Short acting(2hrs). Doses reduced in hepatic dysfunction. ADVERSE EFFECTS Dizziness & Diarrhoea

28. ZALEPLON Rapidly absorbed on empty stomach. Fast onset, sleep pattern not affected Enzyme inhibitors prolong action. Avoided in pregnancy. ADVANTAGES No hangover No withdrawal symptoms. No tolerance or abuse potential. No side effects on therapeutic doses.

29. Contd …….. Zopiclone Eszopiclone S- enantiomer of zopiclone . Prolongs sleep time, mild tolerance after 4-6 mths . ADVERSE EFFECTS Dryness of mouth, metallic taste, impaired psychomotor performance. USES Treatment of insommnia . New drugs, side effects not established.

30. Miscellaneous Melatonin & Ramelteon . Hormone from pineal gland involved in skin colouration . Acts on melatonin receptors MT 1 & MT 2 in the suprachiasmatic nucleus. Promotes sleep & maintains normal sleep cycle. Used in Jet lag. Ramelteon .

31. Ramelteon Agonist at MT1 & MT2 receptor. Approved for insommnia . Fatigue, dizziness & somnolence.

32. Anti anxiety drugs Benzodiazepines. Buspirone . β adrenergic blockers. SSRI/ SNRI/ Gabapentin .

33. Buspirone 5HT 1A agonist ( presynaptic receptors). No sedation. No action BZD receptor. Takes 2 weeks for action. High first pass metabolism (BA = <5%). SE: dizziness, nausea, headache, lightheadedness.

34. β adrenergic blockers

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