Sedative- Hypnotics drugs for MBBS 2022.pptx

Medical

1. SEDATIVE- HYPNOTICS

2. Learning Objectives - PH 1.19 Introduction Sleep cycle Historical Perspectives Classification: Sedative / Hypnotics Mechanism of action Barbiturates Benzodiazepines Miscellaneous Hypnotics & Anxiolytics Recent advances

3. Sedative : A drug that ↓ excitement & calms the subject, Without Inducing sleep. ↓ responsiveness to any level of stimulation & ↓ motor activity Hypnotics : A drug that induces and/or maintains sleep Similar to normal arousable sleep

4. Dose Dependent Action

5. stage 2,3,and 4 steady HR, BP, Resp. Rate, muscles are relaxed. about 90 min somnambulism and night terror Non REM sleep REM sleep (paradoxical sleep) marked, irregular eye movements; dreams and nightmares occur , H R. BP fluctuate; Resp.rate irregular, Muscles fully relaxed. About 20-30 % of sleep time is spent in REM HYPNO CYCLE Sleep - Reversible state of reduced consciousness lasts 20 min

6. Stages of Sleep Stage2 Non REM 67-75% REM sleep 25-33% Stage 1 2-5% Stage 3 & 4 Deep sleep 15-25%

7. Normal Sleep pattern Slow wave sleep

8. NREM 70-80% Of Total sleep time Slow wave sleep Stages of Sleep…

9. HYPNO CYCLE STAGE 0 awake (1-2%) STAGE I dozing (3-6%) α – eye closed, α , Ɵ waves β - eyes open STAGE II (40- 50% ) STAGE III (DEEP SLEEP ) Ɵ with spindles, ( 5-8%) Ɵ, δ , spindles & k. k complexes. STAGE IV (CEREBRAL SLEEP) (10-20%) δ ACTIVITY NO K complexes.

10. Normal  Relief from Anxiety _________  _________________ SEDATION (Drowsiness/decrease reaction time)  HYPNOSIS  Confusion, Delirium, Ataxia  Surgical Anesthesia  Depression of respiratory and vasomotor center in the brainstem COMA  DEATH

11. Insomnia Inability to fall asleep ( sleep latency ) Inability to stay asleep ( Frequent awakenings ) Shorter duration of sleep ( wake up too early ) Sleep interrupted by nightmares Constant feeling of fatigue ( poor quality of sleep )

12. Insomnia Total time spent in sleep is decreased sleep EEG patterns vary widely in insomnia decreased amount of slow wave sleep

13. Anxiety Unpleasant state of tension, apprehension, or uneasiness that arises from either a known or an unknown source Change in mood (fear and apprehension) Increased sympathetic nervous system activity Hypervigilance

14. History Alcohol, Opioids, herbals ⇒ sleep Bromide, Chloral hydrate, paraldehyde, urethane. 1903 - Barbital – Baeyr - DOWNERS 1912 - Phenobarbital 1960s - BZDs – Leo Sternback

15. SEDATIVE-HYPNOTIC DRUGS SEDATIVE-HYPNOTICS Benzodiazepines Barbiturates Miscellaneous agents Short Ultra action action Anxiolytics : Buspirone Intermediate Short Antidepressants action action Hypnotics : Long Long Z-drugs action action Antihistaminics Ramelteon

16. CLASSIFICATION 1) Barbiturates Long acting Phenobarbitone Short acting Butobarbitone, Pentobarbitone Ultra- short acting Thiopentone, Methohexitone 2) Benzodiazepines Hypnotic Diazepam, Flurazepam , Nitrazepam Alprazolam, Temazepam,Triazolam Antianxiety Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam Anticonvulsant Diazepam, Lorazepam, Clonazepam, Clobazam Zopiclone , Es zopiclone , Zolpidem, Zaleplon, Etizolam 3) Newer nonbenzodiazepine hypnotics

17. HYPNOTICS LONG ACTING INTERMEDIATE SHORT ACTING (>24hrs) (6-24 hrs) (< 6hrs) Flurazepam Estazolam Triazolam Diazepam Temazepam Midazolam Clonazepam Alprazolam Oxazepam Lorazepam Nitrazepam

18. 4. DRUGS WITH SIGNIFICANT SEDATIVE ACTION. ANTIHISTAMINES – Promethazine NEUROLEPTICS – Chlorpromazine ANTIDEPRESSANTS – Amitriptyline ANTICHOLINERIC – Hyoscine OPIOID – Morphine, Pethidine 5 . MELATONIN (R) AGONIST - Ramelteon,Tasimelteon 6. Ornexin Receptor antagonist - Suvorexant

19. Site of Action Midbrain ( RAS ) - Wakefulness Limbic system - Thought & mental functions Medulla - Muscle relaxation Cerebellum - Ataxia Effect : Limbic system > Midbrain RAS ⇓ Therapeutic dose ⇒ Anxiolytic > Sedative Higher dose ⇒ Depress RAS → Sedative & hypnotic effect

20. Dose-response curves for two hypothetical sedative-hypnotics Drug A – Barbitutates Steeper DRC Narrow margin of safety Drug B – Benzodiazepines Flatter dose response curve Greater margin of safety

21. SEDATIVE / HYPNOTICS GABAergic SYSTEM

22. GABA-A Receptor Pentameric ( abdgepr ) glycoprotein. It is a Cl - Channel. Binding of GABA causes the channel to open and Cl - to flow into the cell membrane hyperpolarization. GABA AGONISTS Barb  BZDs e Cl   d 

23. α γ α β GABA Bicuculline Diazepam Intra cellular side Flumazenil DMCM Barbiturate GABA A Receptor Barbiturate receptor BZD Receptor Cl -- Picrotoxin β GABA A Benzodiazepine receptor- chloride channel complex

24. Barbiturates / Benzodiazepines Bind to GABA A receptor at different allosteric sites Facilitates GABA action Barbiturates increase duration & Benzodiazepines increase frequency of opening of Cl - channel Membrane hyperpolarization CNS depression At higher dose Barbiturates can act as GABA mimetic Mechanism of Action

25. 1,4-Benzodiazepines Barbiturates

26. BIOTRANSFORMATION OF BZDs CHLORDIAZEPOXIDE DIAZEPAM PRAZEPAM CHLORAZEPATE DESMETHYL CHLORD DEMOXEPAM DESMETHYLDIAZEPAM MIDAZOAAM ALPRAZOLAM TRIAZOLAM OXAZEPAM OH ETHYL FLURAZEPAM α - OH METABOLITES FLURAZEPAM DES ALKYL LORAZEPAM FLURAZEPAM ESTAZOLAM URINARY EXCRETION CONJUGATION

27. Barbiturates - PK Absorption – good, wide distribution Plasma protein binding – varies Crosses placenta, secreted in milk Redistribution – highly lipid soluble drug. Metabolism - oxidation, Hydroxylation, deakylation & desulfuration 25% - excreted unchanged in urine

28. BENZODIAZEPINES 1. MOA Frequency of cl - Channel opening. Modulate GABA effect x Adenosine uptake x Ca2+ Currents. 2. HIGH THERAPEUTIC INDEX BARBITURATES Duration of channel opening. GABA facilitatory - low dose GABA mimetic – high dose X Ca2+ dep NT release X Glutamate thro ‘AMPA ‘R’ x Na+ channels NARROW THER. INDEX

29. 3. CNS General depressant General Depressant selective Anxiolytic , Dose dep. effects Hypnotic, SEDATION SLEEP Muscle relaxation ANAESTHESIA Anticonvulsant COMA SLEEP - sleep latency 100 – 200 mg Hypnotic dose awakenings REM. STAGE III &IV

30. stage II III & IV REM - NREM cycle - disrupted REM (LESS) Regular intake - Effect decreases Nightmares & body DRUG WITH DRAWL - movements. Rebound REM Night mares REFRESHING SLEEP HANGOVER ( ) Skeletal muscle relaxation Anticonvulsant action anticonvulsant– limited role Analgesic action- Diazepam Hyperalgesia.

31. 4. RS NORMAL – NO effect HIGEHER DOSES - Apnoea Respiration alveolar ventilation 5. CVS minimal effects Dose- BP, HR HYPNOTIC DOSE- Mild BP, HR Diazepam Midazolam Dose - BP LV work TPR (a) Ganglionic blockade C.O (b) Vasomotor center (c) cardiac contractility cerebral blood flow coronary blood flow

32. 6. OTHER SYSTEMS Bowel tone, motility Nocturnal Gastric sec. URINE FLOW stress ulcers BP ADH TOXICITY – oliguria . 7. MICROSOMAL ENZYME CYP450 - INDUCER - NOT altered DRUG LEVELS.

33. 8. Abuse liability- low EUPHORIA IN ADDICTS TOLERANCE – MILD Impair Learning SHORT MEMORY JUDGEMENT DEPENDENCE TOLERANCE PD WITHDRAWL PK Dependence Abuse liability With drawl Hallucinations Delirium convulsions & death Idiosyncrasy precipitate porphyria

34. 9. Treatment of poisoning 2 -3g short acting, 5- 10g – long acting BZD ANTAGONIST NO specific antagonist supportive measures. FLUMAZENIL gastric lavage Alkaline diuresis Hemodialysis, Hemoperfusion

35. ADVERSE EFFECTS - Barbiturates

36. ADVERSE EFFECTS - BZDs Light-headedness Fatigue Increased reaction time Motor incoordination Impairment of mental and motor functions Confusion Antero-grade amnesia Cognition appears to be affected less than motor performance. All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol.

37. THERAPEUTIC USES Hypnotic - insomnia Anxiolytic -- Panic attacks and phobias Anticonvulsant Muscle relaxant- central acting Preanaesthetic medication For alcohol withdrawl and abstinence Before short procedures.

38. CATEGORIES OF INSOMNIA Transient insomnia Short-term insomnia Long-term insomnia Lasts <3 days Caused by a brief environmental or situational stressor. ---Respond to attention to sleep hygiene rules. --- Hypnotics should be used at the lowest dose and for only 2-3 nights. 3 days to 3 weeks Caused by a personal stressor such as illness, grief, or job problems. ---Sleep hygiene education is the first step. ---Hypnotics may be used adjunctively for 7-10 nights. ---- Hypnotics are best used intermittently during this time, with the patient skipping a dose after 1-2 nights of good sleep. lasted for >3 weeks N o specific stressor may be identifiable. --- A more complete medical evaluation is necessary in these patients, but most do not need an all-night sleep study.

39. SLEEP HYGIENE

40. Contraindications Acute intermittent porphria . 2. Respiratory obstruction. 3. Liver & kidney diseases. 4. Shock. 5. Old people ( mental confusion). 6. Pregnancy. 7. Hypersensitivity to barbiturates.

41. Advantages of BZD over barbiturates 1. Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less hangover. 4. Not enzyme inducer. 5. Less dependence with minimal withdrawal symptoms. 6. Has specific antagonist .

42. ZOLPIDEM ZALEPLON sleep latency t 1/2 - 1 Hour duration of sleep, REM sleep latency BINDS with α 1 SABUNIT OF BZD ‘R’ t 1/2 - 2 HOURS Anticonvulsant action muscle relaxantion No tolerance, dependence - low 5-10 mg

43. MELATONIN CONGENERS RAMELTEON Synthetic tricyclic analog of MELATONIN . It was approved for the treatment of insomnia, specifically sleep onset difficulties. MECHANISM OF ACTION Melatonin levels in the suprachiastmatic nucleus rise and fall in a circadian fashion concentrations increasing in the evening as an individual prepares for sleep, and then reaching a plateau and ultimately decreasing as the night progresses.

44. MELATONIN CONGENERS Mechanism of Action Two GPCRs for melatonin, MT 1 and MT 2 , are found in the suprachiasmatic nucleus, each playing a different role in sleep. RAMELTEON binds to both MT 1 and MT 2 receptors with high affinity. Binding of Melatonin to MT 1 receptors promotes the onset of sleep . RAMELTEON is efficacious in combating both transient and chronic insomnia

45. Buspirone A weak agonist of 5-HT 1A receptors, Presynaptic inhibition of 5-HT synthesis antidepressant No sedation, little amnesia or confusion Very slow development of main effect: several weeks tid . Useful for GAD and anxiety in older people.

46. MCQs Q1. Sleep promoting effect of ramelteon is mediated by receptor: A. GABA A  receptor B. Opiate receptors C. GABA B  receptor D. Melatonin receptors MT 1  and MT 2 Ans - D

47. Q2. Which one of the following effects is NOT seen with barbiturates? A. Analgesic B. Anticonvulsant C. Induction and maintenance of anaesthesia D. Sedation Ans - A

48. Q3. An ideal hypnotic drug should NOT have: A. rapid onset of action B. sustained effect throughout the night C. without any residual effect in the following morning D. increase in sleep latency Ans - D

49. Q5. Beta carboline at benzodiazepine receptor act as: A. Agonist B. Inverse agonist C. Antagonist D. Partial agonist Ans - B

50. Q6. Benzodiazepine antagonist is: A. Naloxone B. Zolpidem C. Nalorphine D. Flumazenil Ans- D

51. Q7. Benzodiazepines act by: A. Activating GABA A  receptors directly B. Modulating the effects of GABA on GABA A  receptors  C. Antagonistic effect on GABA A  receptors  D. GABA mimetic effect Ans- B

52. Q8. Administration of barbiturate is contraindicated in: A. Kernicterus B. Anxiety C. Epilepsy D. Acute Intermittant porphyria Ans-D

53. Q9. Which is NOT true about Flumazenil? A. Acts on GABA A  receptor B. Specific antagonist of benzodiazepine C. Given intravenously D. May be used in barbiturate poisoning Ans- D

54. Q10. True statement about zolpidem: A. Relieve sleep onset insomnia B. Cause profound rebound insomnia C. Cause profound REM suppression D. Has strong anticonvulsant effect Ans- A