Class sedatives and hypnotics 2
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This document summarizes information on sedative and hypnotic drugs. It discusses the mechanisms and effects of benzodiazepines, barbiturates, and other drugs such as zolpidem, zaleplon, zopiclone, melatonin, and buspirone. It provides details on the pharmacokinetics, therapeutic uses, and side effects of these classes of drugs. The document also covers topics like tolerance, dependence and withdrawal symptoms, overdose treatment, and newer non-benzodiazepine hypnotics.
Class sedatives and hypnotics 2
- 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.
- 2. An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. Sedation refers to decreased responsiveness to any level of stimulation and is associated with some decrease in motar activity and ideation A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state passive and highly suggestible
- 4. ACCORDING TO DURATION OF ACTION : ULTRA SHORT ACTING (3-5 HOURS). TRIAZOLAM, MIDAZOLAM SHORH ACTING (6-24 HOURS). ALPRAZOLAM, NITRAZEPAM LORAZEPAM ESTAZOLAM OXAZEPAM TEMAZEPAM LONG ACTING: ( 24-72 HOURS) CHLORAZEPATE CHLORDIAZEPOXIDE DIAZEPAM FLURAZEPAM. QUAZEPAM PRAZEPAM
- 5. Newer agents(non-benzodiazepines) ZOLPIDEM, ZALEPLON, ZOPICLONE, ESZOPICLONE Barbiturates PHENOBARBITONE, MEPHOBARBITONE, SECOBARBITONE, THIOBARBITONE, PENTOBARBITONE, THIOPENTONE, HEXOBARBITONE Miscellaneous PARALDEHYDE, CHLORAL HYDRATE, GLUTETHEMIDE, MELATONIN, RAMELTEON, MEPROBAMATE,
- 7. GABA –Gamma Amino Butyric Acid is a major inhibitory neurotransmitter in CNS Benzodiazepines potentiate GABA ergic inhibition at all levels of neuroxis—spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex and cerebral cortex Pentameric structure 5 subunits Macromolecular complex of ion channel
- 8. (1) Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental: anesthesia (2) Short-acting barbiturates: have a duration of action of about 2h. The principal use of Secobarbital : sleep- inducing hypnotics.
- 9. Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel, and prolong the duration of the opening of GABA- activated chloride channels. At high doses, barbiturates can inhibit the release of the Ca2+-dependent neurotransmitter They exhibit a GABA mimetic action Depress action of excitatory glutamate neurotransmitter by binding to AMPA receptor
- 10. High lipid solubility allows rapid transport across the blood-brain barrier and results in a short onset. Removal from the brain occurs via redistribution to the other tissues results in short duration of action. Barbiturates and their metabolites excretion via the renal route. Alkalization of the urine expedites the excretion of barbiturates. Treatment of acute over dosage: Sodium bicarbonate and dialysis
- 11. Solution of sodium alkaline Cannot be given by IM/SC route necrosis and pain Oral and IV Weakly acidic drugs Metabolism-phase1- oxidation Phase 2-glucuronyl conjugation
- 12. Sedative-hypnotic agents Be used in the emergency treatment of convulsions as in status epilepticus. Anesthetic (or be given before anesthetic) Combination with antipyretic-analgesic Treatment of hyperbilirubinemia and kernicterus in the neonate Neonatal jaundice Preanaesthetic medication
- 13. After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation drug automatism Tolerance: decreased responsiveness to a drug following repeated exposure because of down- regulation of receptors and induction of hepatic drug- metabolising enzymes.
- 14. Have a narrow therapeutic-to-toxic dosage range. Suppress REM sleep. Tolerance develops relatively quickly. Have a high potential for physical dependence and abuse drug automatism Respiratory depression and hypotension Potent inducers of hepatic drug-metabolising enzymes. hyperalgesia
- 15. Dependence: including psychologic and physiologic dependence. Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions. Depressant effect on respiration: can cross the placental barrier during pregnancy and secrete to breast milk. Others: Skin eruptions and porphyria Drug interaction-barbiturates metabolize OCPS anticoagulants, theophylline, tolbutamide
- 16. An overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure. Treatment (1) supporting respiration and circulation. (2) alkalinizing the urine and promoting diuresis. (3) Hemodialysis or peritoneal dialysis.
- 17. Benzodiazepines bind specifically to a regulatory site on the receptor, distinct from the GABA binding site, and enhanced receptor affinity for GABA. The GABAA-receptors is a ligand-gated ion channel consisting of a pentameric assembly of subunits.
- 18. Benzodiazepines act very selectively on GABAA- receptors, which mediate the fast inhibitory synaptic response produced by activity in GABA-ergic neurons. The effect of benzodiazepines is to enhance the response to GABA, by facilitating the opening of GABA- activated chloride channels (an increase in the frequency of channel opening, but no change in the conductance or mean open time).
- 19. Reasons for their extensive clinical use: 1) great margin of safety; 2) little effect on REM sleep; 3) little hepatic microsomal drug-metabolizing enzymes 4) slight physiologic and psychological dependence and withdrawal syndrome 5) less adverse effects such as residual drowsiness and incoordination movement.
- 20. 1. Reduction of anxiety and aggression : affects the hippocampus and nucleus amygdalae 2. Sedation and induction of sleep: The latency of sleep onset is decreased; The duration of stage 2 NREM sleep is increased; The duration of slow-wave sleep is decreased.
- 21. 3. Anticonvulsant and antiseizure They are highly effective against chemically induced convulsions caused by leptazol, bicuculline and similar drugs but less so against electrically induced convulsions. They can enhance GABA-mediated synaptic systems and inhibit excitatory transmission. PHARMACOLOGICAL EFFECTS
- 22. 4. Muscle relaxation relax contracted muscle in joint disease or muscle spasm. 5. Anticonvulsant effect: especially diazepam, lorazepam, clorazepate, clonazepam, nitrazepam. 6. Other effects lead to temporary amnesia decrease the dosage of anesthetic depress respiratory and cardiovascular function. PHARMACOLOGICAL EFFECTS
- 23. Well absorbed when given orally; They bind strongly to plasma protein, and their high lipid solubility cause many of them to accumulate gradually in body fat. All Benzodiazepines are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucuronide conjugation and excreted in the urine.
- 24. Dose reduction in Liver disease Old people. Synergistic effect with other CNS depressants Drug interaction Concurrent with sodium valproate can provoke psychotic symptoms Rifampicin (decreases half life) Cimetidine, isoniazid, OCPs (increases half life) Contraindication Alcohol and other CNS depressants, antihistamines
- 26. TRIAZOLAM used only for sedation in severe insomnias It also has amnesic, anxiolytic anticonvulsant, muscle relaxant properties Oral-44% sublingual-53% OXAZEPAM- Used to relieve anxiety with alcohol withdrawal Oral bioavailability is 95% Used in treatment of insomnias It is a metabolite of Diazepam, Prazepam It is amnesic, anxiolytic anticonvulsant, hypnotic Used in Post traumatic stress disorder Used in pre-menstrual syndrome 10-15mg
- 27. MIDAZOLAM Treatment of acute seizures, insomnias Anxiolytic, hypnotic, anticonvulsant Induction and maintenance of anaesthesia Intranasal, buccal route Used for endoscopy
- 28. Anxiety disorders: alprazolam General anxiety disorders Panic attack - major depressive disorders Sleep disorders (Insomnia). Estazolam, Lorazepam, temazepam: Flurazepam, Quazepam Long acting drugs can cause hangover.
- 29. 3.To control withdrawal symptoms of alcohols diazepam- chlordiazepoxide. 4.Treatment of epilepsy Diazepam – Lorazepam: Status epilepticus Clonazepam-Clorazepate: absence , myoclonic seizures. 5.Muscle relaxation: in spastic states (Diazepam)
- 30. In anesthesia 1. Preanesthetic medication diazepam 2. Induction of balanced anesthesia(Midazolam) 3. Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery).
- 31. Acute toxicity: Benzodiazepines in acute overdose are considerably less dangerous than other sedative- hypnotic drugs. Cause prolonged sleep, without serious depression of respiration or cardiovascular system The availability of an effective antagonist, flumazenil can avert toxicity reactions
- 32. Side-effects during therapeutic use: drowsiness, confusion, amnesia, impaired coordination. Main disadvantages are interaction with alcohol, long- lasting hangover and the development of dependence. Tolerance and dependence: induction of hepatic drug-metabolising enzymes; a change at the receptor level
- 33. 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. Has short duration of action T 1 /2 = 1 hour Absorbed orally, need to be used repeatedly IV
- 34. Zopiclone is a cyclopyrrolone in structure. Acts at the GABAA-benzodiazepine receptor It has a fairly fast (about 1 h) onset of action which lasts for 6–8 h, making it an effective drug both for initial and maintenance insomnia. Its duration of action is prolonged in the elderly and in hepatic insufficiency. The dose is 3.75–7.5 mg orally
- 35. Zolpidem It is an immidazopyridine in structure Fast onset (30–60 min) and short duration of action Sleep latency is shortened Sleep duration is prolonged Relative lack of effect on sleep stages (REM suppression) Zolpidem is nearly completely metabolised in liver Dose-10-20mg
- 36. Zaleplon Shortest acting newer non-BZD that inhibits BZD receptors containing alfa1 subunit Rapidly absorbed Oral bioavailability is 30% Due to first pass metabolism T1/2-1hr Dose-5-10mg HS
- 37. N-acetyl -5 methoxy tryptamine is principal hormone of pineal gland High dose-80mg can induce sleep Low dose-2-10mg donot depress CNS It has improved sleep quality in elderly insomnias Melatonin supplements may retard aging It is tried in cluster headache Meloset-3mg
- 38. Buspirone, Ipsapirone, Gepirone These drugs act through non-GABAergic system Selective activation of inhibitory presynaptic 5HT1A Receptor, they suppress 5HT neurotransmission through neuronal system BUSPIRONE Minimal abuse liability and no withdrawal reactions No rebound anxiety, insomnia Buspirone causes less impairment of psychomotar skills
- 39. Buspirone does not potentiate the CNS depressant effect of ethanol (non-sedating anxiolytic drug) It has no muscle relaxant, anticonvulsant or hypnotic action It can cause tachycardia nervousness, GIT distress and parasthesias
- 40. PROPRANOLOL Propranolol helps to suppress such performance anxiety by breaking vicious cycle Beta –blockers decreases palpitation, tremors, GIT upset hypertension and blood lactic acid levels 20mg TDS may have associated CVS effects makes it unlikely to be used as potential anxiolytic agent