sedative and hypnotics part 1

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SEDATIVE AND HYPNOTICS L.Nagakrishna. Pharmacology.

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  • 1.L.Nagakrishna. Pharmacology.

2. DEFINITION SEDATIVE : Drugs that clam the patient and reduce anxiety without inducing normal sleep. Site of action is on the limbic system which regulates thoughtand mental function.HYPNOTICS : Drugs that initiate sleep.and maintain the normal Site of action is on the midbrain and ascending RAS whichmaintain wakefulness. 3. CLASSIFICATION OF DRUGS Barbiturates.Benzodiazepines ( BDZ ).Non BDZ drugs ZolpidemZaleplonzopiclon 4. BARBITURATES Classification: Long acting( 24-28 h): Phenobarbitone Intermediate (8-24h): Amylobarbitone Bayere dicoverer of barbiturates.Short-acting(3-8h): Pentobarbitone Secobarbitone AmobarbitalUltrashort acting (25 minutes): Thiopentone, Methohexitone. 5. MECHANISM OF ACTION Facilitation of GABA action on the brain: Barbiturates bind atthe sub unit of GABA-A receptor and increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. 6. Cont.. SUB-ANAESTHETIC DOSES: depress excitatory neurotransmitter actionsANAESTHETIC DOSES: Interfere withNa+ & K+ transport across cell membranes (reticular activating system inhibition). 7. PHARMACOKINETICS All barbiturates are weak acids lipid soluble absorbed orally. distribute throughout the body Thiopentone is highly lipid soluble (high rate of entry intoCNS- quick onset of action). 8. PHARMACOKINETICS Redistribute in the body from the brain to skeletal muscles-adipose tissues. metabolized in the liver to inactive metabolites Excreted in the urine. Alkalinization increases excretion (NaHCO3) Cross the placenta ( pregnancy). 9. PHARMACOLOGICAL ACTIONS CENTRAL NERVOUS SYSTEM: In a dose-dependent fashion. Sedative Hypnotic Anesthesia in large dose Anticonvulsant action Coma and death. RESPIRATORY SYSTEM: suppress hypoxic and chemoreceptor response to CO2 Large doses leads to respiratory depression & death. 10. PHARMACOLOGICAL ACTIONS CVS: Healthy patient: at low doses, they have insignificant effects. Hypovolemicstates, CHF: normal doses may cause cardiovascular collapse. Large dose circulatory collapse due to medullary vasomotor depression. SKELETAL MUSCLE: Anesthetic dose reduce muscle contraction by depressing excitability of neuromuscular junction 11. USES ANTICONVULSANT: Phenobarbitone. INDUCTION OF ANESTHESIA: thiopentone andmethohexitone. HYPNOTIC: pentobarbital HYPERBILIRUBINEMIA AND KERNICTERUS : pentobarbital 12. ADVERSE EFFECTS Respiratory depression. Hangover: residual sedation after awakening. Tolerance Withdrawal symptoms Precipitation of acute attack of porphyria. Many drug interactions. Allergic reaction: urticaria and skin rash.Toxicity : Respiratory depression, Cardiovascular collapse, coma and death. 13. BENZODIZEPINES Sedative (Anxiolytics) : Alprazolam Chlordiazepoxide oxazepam Diazepam lorazepamHypnotics : Triazolam Diazepam Alprazolam Lorazepam Estazolam Temazepam Flurazepam Nitrazepam QuazepamPreanesthetics : Diazepam - MidazolamLeo sternback 14. MECHANISM OF ACTION Bzs bind to the subunit of the GABA receptor.Bzsfacilitation of GABA action on GABA receptorschloride channels opening membrane hyperpolarizationaction potentialchloride influx to the cellcellinhibition of propagation ofinhibitory effect on different sites of the brainespecially motor cortex, and limbic system. 15. PHARMACOKINETICS most of them are well absorbed orally. Bzs are lipid soluble and widely distributed Redistribution from CNS to skeletal muscles, adipose tissue. Cross placentalbarrier during pregnancy and are excreted in milk (Fetal & neonatal depression). Highly bound to plasma protein. 16. PHARMACOKINETICS All Bzs are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucouronide conjugation and excreted in the urine. Many of Phase I metabolites are active : Incresae elimination half life of the parent compound , cumulative effect with multiple doses.EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam. 17. Therapeutic uses ANXIETY DISORDERS : alprazolam, lorazepam, oxazepam, diazepam and chlordiazepoxide. Alprazolam has anxiolytic-antidepressant effect. Diazepam is preferred in acute panic-anxiety. Chlordiazepoxide is preferred in chronic anxiety states. 18. Therapeutic uses INSOMNIA : in ability to sleep. Triazolam, lorazepam is effective in treating individuals who have difficulty in going sleep. Flurazepam, temazepam & nitrazepam is useful for insonia caused by inability to stay asleep. Normal sleep consists of distinct stages,based on threephysiologic measures: the electroencephalogram, the electromyogram, and the electronystagmogram. Non-rapid eye movement(NREM) sleep: 70%-75%. Rapid eye movement(REM) sleep. 19. Therapeutic uses To control withdrawal symptoms of alcoholsdiazepam- chlordiazepoxide. Treatment of epilepsy Diazepam Lorazepam: Status epilepticus Clonazepam-Clorazepate: absence , myoclonic seizures. Muscle relaxation: in spastic states (Diazepam) . 20. Therapeutic uses In anesthesia :Preanesthetic medication diazepam Induction of balanced anesthesia (Midazolam) 21. ADVERSE EFFECTS Ataxia (motor incoordination), cognitive impairment. Hangover Sleep tendency, drowsiness, confusion especially inlong acting drugs. Tolerance Physical and Psychological dependence withdrawal symptoms Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion. 22. FLUMAZENIL A selective competitive antagonist of BZD receptors (Bz1). Blocks action of benzodiazepines, zaleplon and zolpidem butnot other sedative /hypnotics. Blocks psychomotor, cognitive and memory impairment ofBZs. 23. PHARMACOKINETICS Has short duration of action T 1 /2 = 1 hour. Absorbed orally . Undergoes extensive first pass metabolism. NO active metabolites. Should be used IV . Repeated doses are necessary. 24. THERAPEUTIC USES Acute BZD toxicity (comatose patients). Reversal of BZD sedation after endoscopy, dentistry.SIDE EFFECTS Nausea Dizziness Precipitate withdrawal symptoms. 25. DOSE RESPONSE CURVE OF DRUGSDrug-A = Barbiturates , Drug-B = Benzodizepaines. 26. WHY BENZODIZEPINES HAS SUPRESSED BARBITURATES ? BZSBARBITURATES They do not produce anesthesia in Produce loss of consciousness and high doses & patient can be aroused. These are not enzyme inducers, Very low abuse liability. Lesser distortion of normal hypnogram. Bzs have no hyperalgesia. Bzs can be used as day time anxiolytic. Do not effect respiratory or cvs function. There is a specific antagonistFlumazenil. have low margin of safety enzyme inducers. High abuse liability. Marked suppression of REM sleep. Hyperalgesic action. Unacceptable drowsiness is seen. Causes respiratory and depression & hypotension. No specific antagonist. 27. ZOLPIDEM acts on benzodiazepine receptors (BZ 1) & facilitate GABAmediated neuronal inhibition. Its action is antagonized by flumazenil. rapidly absorbed from GIT and metabolized tometabolites via liver CYT P450. Short duration of action ( 2- 4 h).inactive 28. Only hypnotic effect Its efficacy is similar to benzodiazepines. Minor effect on sleep pattern, but high doses suppress REM. Respiratory depression occur at high doses in combinationwith other CNS depressant as ethanol. 29. has no muscle relaxant effect. has no anticonvulsant effect. Minimal psychomotor dysfunction Minimal tolerance & dependence. Minimal rebound insomnia. 30. THERAPEUTIC USES AND ADVERSE EFFECTS a hypnotic drug for short term treatment of insomnia Dose should be reduced in hepatic or old patients.Adverse Effects GIT upset Drowsiness Dizziness 31. ZALEPLON Rapid absorption rapid onset of action Short duration of action (1 hr) Metabolized by liver microsomal enzymes metabolism is inhibited by cimetidine. 32. Only hypnotic effect decreases sleep latency Little effect on sleep pattern Potentiates action of other CNS depressants (alcohol). Dose reduction as before. Used as hypnotic drugADVANTAGES : Less impairment of pyschomotor performance than BZs or zolpidem.