SEDATIVE - HYPNOTICS.pptx SEDATIVE - HYPNOTICS.pptx

ppt on sedative hypnotics

1. SEDATIVE - HYPNOTICS Dr.Anubhuti Khare Asst. Prof. Dept. of Pharmacology

2. DEFINITIONS Sedative A drug that reduces excitement & calms the patient, without inducing sleep. Decreased responsiveness to stimulation. I n therapeutic doses - anxiolytic agents In larger doses - hypnosis (trans like state)   Hypnotic A drug which induces/maintains sleep resembling natural sleep In lower doses- sedative I n higher doses- General anaesthesia

3. DOSE DEPENDENT EFFECT

4. STAGES OF SLEEP ss

5. CLASSIFICATION

6. Barbiturates

7. Benzodiazepines

8. Benzodiazepines a/c to Duration of Action

9. Mechanism of action

10. SITE OF ACTION Barbiturates- in CNS effect is almost global - produce dose dependent effects Benzodiazepines- -midbrain ascending reticular formation (maintains wakefulness) -limbic system (thought and mental functions) -Medulla (Muscle relaxation) - cerebellum (ataxia)

11. Dose-response curves for two hypothetical sedative-hypnotics

12. BARBITURATES PHARMACOKINETICS Well absorbed from the g.i . tract, widely distributed in the body; rate of entry into CNS dependent on lipid solubility; cross placenta and are secreted in milk Three processes are involved in termination of action: (a) Redistribution : highly lipid soluble ( thiopentone ) (t½ 9 hours) (b) Metabolism :intermediate lipid-solubility (short-acting barbiturates) are primarily metabolized in liver by oxidation, dealkylation and conjugation. t½ 12–40 hours (c) Excretion : low lipid-solubility (long acting agents) are significantly excreted unchanged in urine. t½ phenobarbitone 80–120 hours. Alkalinization of urine increases ionization and excretion Barbiturates induce several hepatic microsomal enzymes and increase the rate of their own metabolism as well as that of many other drugs.

13. PHARMACOLOGICAL ACTIONS CNS sedation → sleep → anaesthesia → coma Hypnotic dose shortens the time taken to fall asleep and increases sleep duration REM and stage 3, 4 sleep are decreased Sedative dose (smaller dose of long acting barbiturate) given at daytime produce drowsiness , reduction in anxiety & excitability Barbiturates have anticonvulsant property : phenobarbitone have higher anticonvulsant : sedative ratio

14. Other actions At relatively high doses, barbiturates depress respiration, lower BP, decrease cardiac contractility & heart rate, but reflex tachycardia can occur due to fall in BP. Muscle tone, bowel motility & urine output are also reduced. Toxic dose cause respiratory failure & cardiovascular collapse.

15. THERAPEUTIC USES As sedative hypnotic- superseded by BZDs As anaesthetic - thiopentone / methohexitone iv as inducing agent As anticonvulsant- phenobarbitone To treat hyperbilirubinemia of neonates as they increase the activity of glucuronyl transferase enzyme by enzymatic induction

16. ADVERSE EFFECTS Hangover after hypnotic dose. Mental confusion, impaired performance and traffic accidents may occur Abuse liability; Psychological as well as physical dependence occurs; Withdrawal symptoms - excitement, hallucinations, delirium, convulsions; death Both cellular and pharmacokinetic (due to enzyme induction) tolerance develops on repeated use Various drug interactions due to enzyme induction . Reduce effectiveness— warfarin , steroids (including contraceptives), tolbutamide , griseofulvin , chloramphenicol , theophylline .

17. Idiosyncrasy- in occasional patient excitement; Precipitation of porphyria in susceptible individuals Additive action with other CNS depressants —alcohol, antihistamines, opioids , etc. Acute barbiturate poisoning- Mostly suicidal, sometimes accidental. Manifestations are due to excessive CNS depression— patient is flabby and comatose with shallow and failing respiration, fall in BP and cardiovascular collapse, renal shut down, pulmonary complications, bullous eruptions

18. BENZODIAZEPINES PHARMACOKINETICS marked pharmacokinetic differences Oral absorption of some is rapid while that of others is slow. Absorption from i.m . sites is irregular except for lorazepam Plasma protein binding also varies markedly (flurazepam 10% to diazepam 99%) More lipid soluble members have a two phase plasma concentration decay curve; relatively short duration of action & long elimination t½

19. Benzodiazepines are metabolized (phase I) in liver into metabolites, some of which may be active. The biological effect half-life of these drugs may be much longer than the plasma t½ of the administered compound eg.midazolam , diazepam,flurazepam , alprazolam , chlordiazepoxide . The phase I metabolites and certain BZDs themselves are conjugated with glucuronic acid & excreted in urine. BZDs cross placenta and are secreted in milk

20. PHARMACOLOGICAL ACTIONS CNS actions- In contrast to barbiturates, they are not general depressants, but exert relatively selective action: Antianxiety : With chronic administration relief of anxiety is maintained, but drowsiness wanes off due to development of tolerance Sleep : hasten onset of sleep, reduce intermittent awakening and increase total sleep time. Stage 2 is increased while stage 3 & 4 is shortened, REM phase also shortened but no. of REM cycles increase( Nitrazepam increase REM sleep). Some degree of tolerance develops to the sleep promoting action of BZDs after repeated nightly use

21. Muscle relaxant : produce centrally mediated skeletal muscle relaxation without impairing voluntary activity ( Clonazepam and diazepam) Anticonvulsant : Clonazepam , diazepam, nitrazepam , lorazepam & flurazepam (prominent anticonvulsant activity). Diazepam and lorazepam are highly effective for short-term use in status- epilepticus . Development of tolerance to the anticonvulsant action. i.v . diazepam (but not others) causes analgesia . In contrast to barbiturates, BZDs do not produce hyperalgesia . Other actions : Diazepam decreases nocturnal gastric secretion and prevents stress ulcers. Short-lasting coronary dilatation is produced by i.v . diazepam.

22. THERAPEUTIC USES 1) As hypnotic Transient insomnia- Triazolam , temazepam Short-term insomnia- Temazepam , flurazepam , estazolam Chronic insomnia- sleep hygeine measures, psychotherapy, flurazepam , nitrazepam Anxiety – alprazolam , lorazepam , oxazepam , diazepam, chlordiazepoxide 3) Anticonvulsant - diazepam, lorazepam , clonazepam : status epilepticus ; clonazepam - petit mal seizures; diazepam- febrile convulsions, tetanic spasms

23. 4) Centrally acting muscle relaxant- diazepam 5) Preanaesthetic medication , i.v . anaesthesia , conscious sedation- diazepam, lorazepam , midazolam 6) Before ECT, electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies, in obstetrics and many minor procedures—diazepam 7) Alcohol withdrawal in dependent subjects- diazepam, oxazepam , chlordiazepoxide 8) Along with analgesics, NSAIDs, spasmolytics , antiulcer and as adjuvants to treat ‘gas’ or nonspecific dyspeptic symptoms

24. ADVERSE EFFECTS BZDs are relatively safe drugs. Hypnotic doses -dizziness, vertigo, ataxia, disorientation, amnesia, prolongation of reaction time—impairment of psychomotor skills (should not drive). BZDs can aggravate sleep apnoea . Paradoxical stimulation , irritability and sweating may occur in an occasional patient, especially with flurazepam . Tolerance to the sedative effects develops gradually, with little tendency to increase the dose. Dependence producing liability of BZDs is low. Administration during labour may cause flaccidity and respiratory depression in the neonate.

25. NON-BENZODIAZEPINE HYPNOTICS act selectively on α1 subunit containing BZD receptors and produce hypnotic amnesic action Zopiclone (t½ 5–6 hours) does not alter REM sleep and tends to prolong stages 3 and 4. used to wean off insomniacs taking regular BZD medication & indicated for short term (< 2 weeks) treatment of insomnia. Eszopiclone (t½ 6 hours) Prolongs stage 2 t/t of short term as well as chronic insomnia

26. Zolpidem (t½ 2 hr) advantages are: relative lack of effect on sleep stages (REM suppression is slight); minimal residual day time sedation or fading of hypnotic action on repeated nightly use; no/little rebound insomnia on discontinuation; near absence of tolerance and low abuse potential combined with safety in overdose like BZDs indicated for short-term (1–2 weeks) use in sleep onset insomnia as well as for intermittent awakenings Because the plasma t½ is short, next day sedation is minimal Zaleplon (t½ 1 hour) shortest acting effective only in sleep-onset insomnia; does not prolong total sleep time or reduce the number of awakenings. Because of brevity of action, it can be taken late at night (> 4 hour before waking time) without causing morning sedation. Surprisingly, despite very short action, no daytime anxiety or rebound insomnia has been observed

27. BENZODIAZEPINE ANTAGONIST Flumazenil BZD analogue which has little intrinsic activity (practically no effect on normal subjects) abolishes the hypnogenic , psychomotor, cognitive and EEG effects of BZDs Injected i.v , action starts in seconds & lasts for 1-2hrs. Elimination t½ is 1 hr, due to rapid metabolism. Uses 1. To reverse BZD anaesthesia (0.3-1mg i.v ) Patients wakeup, get oriented and regain motor control within 1 min 2. BZD overdose (0.2 mg/min; max. 5mg) Patients intoxicated with a BZD alone respond within 5 min (reversal of respiratory depression is incomplete) Blocks the hypnotic effect of zolpidem -like non-BZDs as well Adverse effects Safe and well tolerated. Agitation, discomfort, tearfulness, anxiety, coldness and withdrawal seizures are occasional

28. OTHER HYPNOTICS TRICLOFOS Old CNS depressant; obsolete; sometimes used to sedate children in distress & rarely to induce sleep in adults Melatonin principal hormone of the pineal gland secreted at night Synchronize sleep wakefulness cycle Works on MT1 & MT2 type of melatonin receptors in the brain Used in the treatment of jet-lag, shift workers and elderly insomniacs

29. Ramelteon MT1 & MT2 melatonin receptor agonist Administered in a dose of 8 mg ½ hour before going to bed, it is shown to hasten sleep onset as well as increase sleep duration, without causing next morning sedation or impairment No rebound phenomenon, dependence seen so far Extensive first pass metabolism in liver; elimination t½ is 1–3 hours Suvorexant First member of novel class –’dual orexin receptor antagonists’ (DORAs) Acts on OX1R & OX2R orexin receptors Hasten sleep onset, help sleep maintenance & increase total sleep time; next day residual effects are nil with low dose(10mg) Low potential for amnesia, ataxia, addiction or dependence, or rebound phenomenon- chronic insomnia t ½ is 12hrs Safety concerns: day time somnolence, impaired driving, unconscious night time behaviours (sleep talking,sleep walking, etc.), narcolepsy like symptoms, suicidal ideation