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Sedative and hypnotics part 1

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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 thought and mental function. HYPNOTICS : Drugs that initiate sleep. and maintain the normal  Site of action is on the midbrain and ascending RAS which maintain wakefulness.
  • 3. CLASSIFICATION OF DRUGS  Barbiturates.  Benzodiazepines ( BDZ ).  Non BDZ drugs  Zolpidem  Zaleplon  zopiclon
  • 4. BARBITURATES Classification: Long acting( 24-28 h): Phenobarbitone Intermediate (8-24h): Amylobarbitone Bayere dicoverer of barbiturates. Short-acting(3-8h): • • • Pentobarbitone Secobarbitone Amobarbital Ultrashort acting (25 minutes): Thiopentone, Methohexitone.
  • 5. MECHANISM OF ACTION  Facilitation of GABA action on the brain: Barbiturates bind at the β 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 actions ANAESTHETIC DOSES:  Interfere with Na+ & 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 into CNS- 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 and methohexitone. 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 lorazepam  Hypnotics : Triazolam Diazepam Alprazolam Lorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam  Preanesthetics : Diazepam - Midazolam Leo sternback
  • 14. MECHANISM OF ACTION Bzs bind to the α subunit of the GABA receptor. Bzs facilitation of GABA action on GABA receptors chloride channels opening membrane hyperpolarization action potential chloride influx to the cell cell inhibition of propagation of inhibitory effect on different sites of the brain especially 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 placental barrier 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 three physiologic 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 alcohols diazepam- 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 in long 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 but not other sedative /hypnotics.  Blocks psychomotor, cognitive and memory impairment of BZs.
  • 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 DRUGS Drug-A = Barbiturates , Drug-B = Benzodizepaines.
  • 26. WHY BENZODIZEPINES HAS SUPRESSED BARBITURATES ? BZS BARBITURATES  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 GABA mediated neuronal inhibition.  Its action is antagonized by flumazenil.  rapidly absorbed from GIT and metabolized to metabolites 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 combination with 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 drug ADVANTAGES : Less impairment of pyschomotor performance than BZs or zolpidem.

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