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SEDATIVE - HYPNOTICS.pptx SEDATIVE - HYPNOTICS.pptx
- 1. SEDATIVE - HYPNOTICS Dr.AnubhutiKhare Asst. Prof. Dept. of Pharmacology
- 2. DEFINITIONS • Sedative Adrug that reduces excitement & calms the patient, without inducing sleep. Decreased responsiveness to stimulation. In 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 In higher doses- General anaesthesia
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- 4. STAGES OF SLEEP •ss • From lying down to falling asleep • 1–2% of sleep time • α activity - eyes are closed and β activity - eyes are open Stage 0 (awake) •α activity is interspersed with θ waves •3–6% of sleep time Stage 1 (dozing) •θ waves with interspersed spindles, K complexes can be evoked on sensory stimulation •40–50% of sleep time Stage 2 (unequivocal sleep) •θ, δ and spindle activity, K complexes can be evoked with strong stimuli only. • 5–8% of sleep time Stage 3 (deep sleep transition) •δ activity predominates , K complexes cannot be evoked. •10–20% of sleep time Stage 4 (cerebral sleep) •waves of all frequency, K complexes cannot be elicited. •20–30% of sleep time REM sleep (paradoxical sleep)
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- 6. Barbiturates Long acting • Phenobarbitone Shortacting • Butobarbitone • Pentobarbitone Ultra-short acting • Thiopentone • Methohexitone
- 7. Benzodiazepines Hypnotic • Diazepam • Flurazepam •Nitrazepam • Alprazolam • Temazepam • Triazolam Antianxiety • Diazepam • Chlordiazepoxide • Oxazepam • Lorazepam • Alprazolam • Clonazepam Anticonvulsant • Diazepam • Lorazepam • Clonazepam • Clobazam
- 8. Benzodiazepines a/c toDuration of Action Short acting • Triazolam • Oxazepam • Midazolam Intermediate acting • Alprazolam • Estazolam • Temazepam • Lorazepam • Nitrazepam Long acting • Diazepam • Flurazepam • Clonazepam • Chlordiazepoxide
- 9. Newer Non-benzodiazepines • Zopiclone •Eszopiclone • Zolpidem • Zaleplon • Etizolam Other hypnotics • Triclofos • Melatonin • Ramelteon • Suvorexant
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- 11. 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)
- 12. Dose-response curves fortwo hypothetical sedative-hypnotics
- 13. BARBITURATES PHARMACOKINETICS • Well absorbedfrom 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.
- 14. 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
- 15. Other actions • Atrelatively 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.
- 16. THERAPEUTIC USES • Assedative 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
- 17. ADVERSE EFFECTS • Hangoverafter 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.
- 18. • Idiosyncrasy- inoccasional 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
- 19. BENZODIAZEPINES PHARMACOKINETICS • marked pharmacokineticdifferences • 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
- 20. • Benzodiazepines aremetabolized (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
- 21. 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
- 22. • 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.
- 23. THERAPEUTIC USES 1) Ashypnotic • Transient insomnia- Triazolam, temazepam • Short-term insomnia- Temazepam, flurazepam, estazolam • Chronic insomnia- sleep hygeine measures, psychotherapy, flurazepam, nitrazepam 2) Anxiety – alprazolam, lorazepam, oxazepam, diazepam, chlordiazepoxide 3) Anticonvulsant- diazepam, lorazepam, clonazepam: status epilepticus; clonazepam- petit mal seizures; diazepam- febrile convulsions, tetanic spasms
- 24. 4) Centrally actingmuscle 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
- 25. ADVERSE EFFECTS • BZDsare 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.
- 26. NON-BENZODIAZEPINE HYPNOTICS • actselectively 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
- 27. • Zolpidem (t½2 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
- 28. BENZODIAZEPINE ANTAGONIST Flumazenil • BZDanalogue 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
- 29. OTHER HYPNOTICS TRICLOFOS • OldCNS 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
- 30. 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