Sedative- Hypnotics wonderful presentation.pptx

this is wonderful ppt describing sedatives and hypnotics

1. Sedative-Hypnotics Dr. Arun Jakhar - MBBS,MD (KGMU) Senior Resident Department of Pharmacology UPUMS, Saifai

2. Sedative: subdues excitement calms the subject without inducing sleep drowsiness may be produced decreased responsiveness to stimulation decrease in alertness, ideation and motor activity

3. Hypnotic: induces and/or maintains sleep similar to normal arousable sleep not to be confused with ‘hypnosis’ meaning a trans-like state subject becomes passive and highly suggestible

4. Stages of CNS Depression

5. Stages Characteristics Duration Wave 0 (Awake) lying down to falling asleep 1-2% α - eyes closed β - eyes open 1 (Dozing) neck muscles relax 3-6% α , θ 2 (unequivocal sleep) easily arousable 40-50% Sleep Spindles K - complexes 3 (deep sleep transition) not easily arousable 5-8% θ δ 4 (cerebral sleep) eyes are practically fixed difficult to arouse night terror 10-20% δ REM (paradoxical sleep) Marked eye movements dreams and nightmares Irregular – BP, HR and Respiration Muscles fully relaxed Erection in males 20-30% All wave forms

6. BARBITURATES popular upto 1960s but are not used now to promote sleep or to calm patients are substituted derivatives of barbituric acid ( malonyl urea) b arbituric acid as such is not a hypnotic but compounds with alkyl or aryl substitution on C5 have this property Replacement of O with S at C2 yields thiobarbiturates which are more lipid-soluble and more potent

7. PHARMACOLOGICAL ACTIONS: depressants for all excitable cells more for the CNS CNS: Barbiturates produce dose-dependent effects: sedation → sleep → anaesthesia → coma

8. Hypnotic dose: shortens the time taken to fall asleep increases sleep duration n ight awakenings are reduced REM and stage 3, 4 sleep are decreased REM-NREM sleep cycle is disrupted

9. effects become progressively less if taken every night rebound increase in REM sleep and nightmares when drug discontinued after a few nights of use it takes several nights for normal pattern to be restored h ang over (headache, dizziness, distortions of mood, irritability and lethargy) may occur in the morning after a nightly dose

10. Sedative dose: smaller dose of a longer acting barbiturate given at daytime can produce drowsiness, reduction in anxiety and excitability however, barbiturates do not have selective anti anxiety action they can impair learning, short-term memory and judgement euphoria may be experienced by addicts

11. 2. Other actions: at relatively higher doses depress respiration lower BP decrease cardiac contractility and heart rate but reflex tachycardia can occur due to fall in BP muscle tone, bowel motility and urine output are also reduced toxic does cause respiratory failure and cardiovascular collapse

12. MECHANISM OF ACTION: Increase duration of chloride channel opening At high concentrations : directly increase Cl¯ conductance (GABA-mimetic action) inhibit Ca2+ dependent release of neurotransmitters depress glutamate induced neuronal depolarization through AMPA receptors (a type of excitatory amino acid receptors) depress voltage sensitive Na+ and K+ channels

13. GABA(A)-benzodiazepine receptor-chloride channel complex

14. PHARMACOKINETICS: well absorbed from the g.i. tract widely distributed in the body rate of entry into CNS is dependent on lipid solubility Highly-lipid soluble thiopentone has practically instantaneous entry while less lipid-soluble ones ( pentobarbitone ) take longer phenobarbitone enters very slowly cross placenta secreted in milk produce effects on the foetus and suckling infant

15. termination of action of barbiturates: redistribution, metabolism and excretion induce several hepatic microsomal enzymes (CYP3A4/5, CYP2D6, CYP2C8/9, CYP2B6, UGTs) increase rate of their own metabolism as well as that of many other drugs

16. USES: phenobarbitone ----epilepsy thiopentone / methohexitone ---anaesthesia ADVERSE EFFECTS: hangover mental confusion impaired performance and traffic accidents tolerance and dependence

17. Acute barbiturate poisoning: Mostly suicidal some times accidental infrequently encountered now Manifestations: patient is flabby and comatose shallow and failing respiration fall in BP and cardiovascular collapse renal shut down pulmonary complications

18. Treatment of Acute barbiturate poisoning: Gastric lavage- ---activated Supportive measures : patent airway, assisted respiration, oxygen, maintenance of blood volume by fluid infusion and use of vasopressors—dopamine may be preferred for its renal vasodilating action Alkaline diuresis Haemodialysis and haemoperfusion

19. BENZODIAZEPINES (BZDs) selective CNS depressants have a high therapeutic index h ypnotic doses do not affect respiration or cardiovascular functions cause less distortion of sleep architec ture ; rebound phenomena on discontinuation do not alter disposition of other drugs by microsomal enzyme induction have lower abuse liability than barbiturates specific BZD antagonist flumazenil is available

20. USES: Antianxiety Hypnotic Muscle relaxant Anticonvulsant Alcohol withdrawal( Chlordiazepoxide )

21. MECHANISM OF ACTION: act preferentially on midbrain ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions) Muscle relaxation---- primary medullary site of action and ataxia is due to action on cerebellum

22. GABA(A)-benzodiazepine receptor-chloride channel complex

23. ADVERSE EFFECTS: hypnotic doses----dizziness, vertigo, ataxia, disorientation, amnesia, prolongation of reaction time—impairment of psychomotor skills ( should not drive ) Sleep walking, sleep driving and other abnormal sleep behaviours with no memory of these events has been recognized as a possible hazard Hangover----less common Weakness, blurring of vision, dry mouth and urinary incontinence are sometimes complained Older individuals--more susceptible to psychomotor side effects Like any hypnotic, BZDs can aggravate sleep apnoea

24. NON-BENZODIAZEPINE HYPNOTICS chemically different from BZDs but act as agonists on a specific subset of BZD receptors action is competitively antagonized by flumazenil which can be used to treat their overdose toxicity act selectively on α1 subunit containing BZD receptors produce hypnotic-amnesic action With weak antianxiety, muscle relaxant and anticonvulsant effects have lower abuse potential than hypnotic BZDs shorter duration of action----preferred over BZDs

25. Zopiclone Eszopiclone Zolpidem Zaleplon

26. Types of Insomnia Chronic insomnia (> 3 weeks) Short-term insomnia (3–21 days) Transient insomnia (1–3 days)

27. BENZODIAZEPINE ANTAGONIST FLUMAZENIL: competes with BZD agonists as well as inverse agonists reverses their depressant or stimulant effects respectively absorbed orally, but it is not used orally Injected i.v. ----- action starts in seconds and lasts for 1–2 hours elimination t½ is 1 hr , due to rapid metabolism Uses: To reverse BZD anaesthesia BZD overdose

28. Other Hypnotics Triclofos : old CNS depressant fast-acting hypnotic acts in 30 min, action lasts 6–8 hours though obsolete some times used to sedate children in distress and rarely to induce sleep in adults

29. Melatonin: principal hormone of the pineal gland secreted at night important role in sleep-wakefulness cycle receptor MT1 and MT2 in the brain Both are GPCRs high doses (80 mg) of melatonin administered orally can induce sleep low doses (2–10 mg) do not depress the CNS, but probably increase the propensity of falling asleep Uses: jet-lag, shift workers and elderly insomniacs

30. Ramelteon : MT1 , MT2 melatonin receptor agonist 8 mg ½ hour before going to bed hasten sleep onset as well as increase sleep duration without causing next morning sedation or impairment

31. Suvorexant : first member of a novel class of insomnia drugs— ’dual orexin receptor antagonists’ (DORAs) Orexins are neuropeptides found in lateral hypothalamus which promote wakefulness by acting on OX1R and OX2R orexin levels are high during day time and low at night, and that narcolepsy (episodes of sudden sleep) is associated with loss of orexin neurones , support this role of orexin