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- 3. SEDATIVES & HYPNOTICS SEDATIVES & HYPNOTICS Sedatives Sedatives D Drugs which decrease activity, reduce anxiety & rugs which decrease activity, reduce anxiety & exert calming effect with little or no effect on motor exert calming effect with little or no effect on motor or mental functions & produce minimum CNS or mental functions & produce minimum CNS depression. depression. Hypnotics Hypnotics Drugs which produce drowsiness, facilitate onset & Drugs which produce drowsiness, facilitate onset & maintenance of sleep which resemble natural sleep. maintenance of sleep which resemble natural sleep. A hypnotic produces marked CNS depression. A hypnotic produces marked CNS depression.
- 6. CLASSIFICATION CLASSIFICATION 1. 1. BENZODIAZEPINES BENZODIAZEPINES 2. NEWER HYPNOTICS 2. NEWER HYPNOTICS Zaleplon, Zolpidem, Eszopiclone Zaleplon, Zolpidem, Eszopiclone 3. BARBITURATES 3. BARBITURATES
- 7. 4. OLDER SEDATIVES/HYPNOTICS 4. OLDER SEDATIVES/HYPNOTICS Chloral hydrate, Meprobamate Chloral hydrate, Meprobamate Glutethimide , Alcohol Glutethimide , Alcohol 5. 5. 5- 5-HT HT1A 1A RECEPTOR AGONISTS RECEPTOR AGONISTS Buspirone Buspirone 6. MELATONIN RECEPTOR AGONIST 6. MELATONIN RECEPTOR AGONIST Ramelteon Ramelteon 7. OREXIN ANTAGONIST 7. OREXIN ANTAGONIST Suvorexant Suvorexant
- 8. OTHER GROUPS WITH SEDATIVE EFFECTS OTHER GROUPS WITH SEDATIVE EFFECTS ANTIDEPRESSANTS ANTIDEPRESSANTS • Venlafaxine Venlafaxine • Duloxetine Duloxetine • Trazodone Trazodone • SSRIs SSRIs ANTIHISTAMINES ANTIHISTAMINES Hydroxyzine, Promethazine, Diphenhydramine Hydroxyzine, Promethazine, Diphenhydramine ANTIPSYCHOTICS ANTIPSYCHOTICS
- 10. CLASSIFICATION CLASSIFICATION According to Duration of Action According to Duration of Action A- A- Short acting: (3-5 hours) Short acting: (3-5 hours) TRIAZOLAM, MIDAZOLAM TRIAZOLAM, MIDAZOLAM B- B- Intermediate: (6-24 hours) Intermediate: (6-24 hours) ALPRAZOLAM ALPRAZOLAM LORAZEPAM LORAZEPAM ESTAZOLAM ESTAZOLAM OXAZEPAM OXAZEPAM TEMAZEPAM TEMAZEPAM
- 11. Long acting: ( 24-72 hours) Long acting: ( 24-72 hours) CLORAZEPATE CLORAZEPATE CHLORDIAZEPOXIDE CHLORDIAZEPOXIDE CLONAZEPAM CLONAZEPAM DIAZEPAM DIAZEPAM FLURAZEPAM FLURAZEPAM QUAZEPAM QUAZEPAM
- 15. BENZODIAZEPINES: BENZODIAZEPINES: Pharmacokinetics Pharmacokinetics A Absorption: bsorption: well absorbed if given orally well absorbed if given orally , rate of absorption is , rate of absorption is different depending upon lipid solubility different depending upon lipid solubility All cross placental barrier, excreted in breast milk All cross placental barrier, excreted in breast milk B Binding: inding: strongly bound to plasma proteins strongly bound to plasma proteins D Distribution: istribution: large Vd: accumulation in body fat (high lipid solubility) large Vd: accumulation in body fat (high lipid solubility) M Metabolism etabolism: : (Hepatic) (Hepatic) Hydroxylation Hydroxylation & dealkylation (Phase I) & dealkylation (Phase I) conjugation with glucuronic acid conjugation with glucuronic acid (Phase II) (Phase II) Metabolites are excreted via kidney in urine Metabolites are excreted via kidney in urine
- 17. Site of Action Site of Action Site of action is the GABA Site of action is the GABAA A receptor receptor GABA GABAA A receptor has multiple isoforms receptor has multiple isoforms Predominant GABA Predominant GABAA A receptor isoform is receptor isoform is comprised of 5 subunits comprised of 5 subunits 2 2 α α1 1 subunits subunits 2 2 β β2 2 subunits subunits 1 1 γ γ2 2 subunit subunit
- 19. BZD binds to GABA BZD binds to GABAA A recepts. recepts. Enhance GABA effects without directly activating Enhance GABA effects without directly activating GABA recepts GABA recepts Enhancement in Enhancement in Cl Cl- - ion conductance by BZD result ion conductance by BZD result an increase in frequency of channel opening an increase in frequency of channel opening events. events. Cl Cl- - influx influx cell membrane hyperpolarization cell membrane hyperpolarization inhibition of propagation of action potential inhibition of propagation of action potential inhibitory effect on different sites of brain inhibitory effect on different sites of brain especially motor cortex & limbic system. especially motor cortex & limbic system.
- 21. PHARMACOLOGICAL EFFECTS PHARMACOLOGICAL EFFECTS OF BDZs OF BDZs
- 22. 1. Sedation 1. Sedation 2. Anterograde amnesia 2. Anterograde amnesia 3. Hypnosis 3. Hypnosis Induction of sleep Induction of sleep Latency of sleep onset is decreased Latency of sleep onset is decreased Duration of stage 2 NREM sleep is increased Duration of stage 2 NREM sleep is increased Duration of REM sleep is decreased Duration of REM sleep is decreased Duration of stage 4 NREM slow-wave sleep is Duration of stage 4 NREM slow-wave sleep is decreased decreased
- 23. 4- Anesthesia 4- Anesthesia As an adjunct to other general anesthetics are As an adjunct to other general anesthetics are used as a agent for induction of balanced used as a agent for induction of balanced anesthesia anesthesia (Diazepam, Midazolam, Lorazepam---I/V) (Diazepam, Midazolam, Lorazepam---I/V) Adjunct therapy during minor surgery Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery). (endoscopy, bronchoscopy, dental surgery).
- 24. 5- Anticonvulsant effect: 5- Anticonvulsant effect: diazepam, lorazepam, clorazepate, clonazepam, diazepam, lorazepam, clorazepate, clonazepam, nitrazepam. nitrazepam. They inhibit the development & spread of They inhibit the development & spread of epileptiform activity in CNS epileptiform activity in CNS 6- Central skeletal muscle relaxant effect 6- Central skeletal muscle relaxant effect e.g. e.g. Diazepam relaxes muscle by inhibiting Diazepam relaxes muscle by inhibiting polysynaptic reflexes. polysynaptic reflexes. At high doses may also depress transmission at the At high doses may also depress transmission at the skeletal neuromuscular junction skeletal neuromuscular junction
- 25. 7- CVS and respiratory system 7- CVS and respiratory system Minimal depressant effects in therapeutic doses & Minimal depressant effects in therapeutic doses & in normal patients. in normal patients. 8. Gastrointestinal Tract - Reduce anxiety related GIT disorders - Decrease nocturnal gastric secretion
- 26. THERAPEUTIC USES THERAPEUTIC USES To relieve anxiety & related states To relieve anxiety & related states To induce & maintain sleep To induce & maintain sleep For symptomatic treatment of convulsions/ For symptomatic treatment of convulsions/ Epilepsy Epilepsy Pre- anaesthetic medication Pre- anaesthetic medication To control ethanol & other CNS depressants To control ethanol & other CNS depressants withdrawal symptoms withdrawal symptoms To relieve Muscle spasm To relieve Muscle spasm
- 27. Use in anaesthesia . Control of convulsions induced by local anaesthetic. Use in short procedures not requiring much analgesia. e.g.Endoscopy, Cardioversion, Cardiac Catheterization, Obstetric procedures etc.
- 28. ADVERSE EFFECTS ADVERSE EFFECTS Tolerance Tolerance Dependence Dependence Impairment of motor & mental functions Impairment of motor & mental functions Drowsiness Drowsiness Light headedness Light headedness Lethargy Lethargy Anterograde amnesia Anterograde amnesia Behavioral disinhibition --- very high doses Behavioral disinhibition --- very high doses Hypersensitivity reaction------ skin rashes Hypersensitivity reaction------ skin rashes CVS & respiratory depression in higher doses CVS & respiratory depression in higher doses
- 29. FLUMAZENIL A competitive antagonist of benzodiazepine Also blocks action of zolpidem, zaleplon & eszopiclone Do not antagonize action of other sedative-hypnotics Available only for I/V administration - half-life is 1 hr Duration - 30 to 60 mins Primary indication: management of benzodiazepine overdose & reversal of its sedative effects
- 30. ZOLPIDEM & ZALEPLON ZALEPLON M.OA: binds selectively to BDZ receptors having α α1 1 subunit. subunit. Actions antagonized by flumazenil Use for short-term treatment of insomnia, decrease sleep latency, prolong total sleep time. decrease sleep latency, prolong total sleep time.
- 31. ZOLPIDEM & ZALEPLON ZALEPLON has no muscle relaxant effect has no muscle relaxant effect has no anticonvulsant effect has no anticonvulsant effect Minimal psychomotor dysfunction Minimal psychomotor dysfunction Minimal tolerance & dependence Minimal tolerance & dependence Minimal rebound insomnia Minimal rebound insomnia
- 32. BARBITURATES BARBITURATES Derivatives of Derivatives of barbituric acid barbituric acid
- 33. Types Types Barbituric Acid Barbituric Acid Amobarbital Phenobarbital Pentobarbital
- 34. CLASSIFICATION CLASSIFICATION Long Acting Barbiturates( 24-28 h) Long Acting Barbiturates( 24-28 h) Phenobarbital Phenobarbital Mephobarbital Mephobarbital Metharbital Metharbital Intermediate Acting Barbiturates (8-24hrs) Intermediate Acting Barbiturates (8-24hrs) Amobarbital Amobarbital
- 35. Short Acting Barbiturates (3-8hrs) Short Acting Barbiturates (3-8hrs) Pentobarbital Pentobarbital Secobarbital Secobarbital Ultra – Short Acting Barbiturate (25 minutes) Ultra – Short Acting Barbiturate (25 minutes) Thiopental Thiopental
- 36. Pharmacokinetics Pharmacokinetics • All barbiturates are weak acids All barbiturates are weak acids • Absorption - rapid & complete absorption after oral intake • Distribute throughout the body Distribute throughout the body • Thiobarbiturates are very lipid soluble (high rate of Thiobarbiturates are very lipid soluble (high rate of entry into CNS- very brief onset of action). entry into CNS- very brief onset of action).
- 37. Biotransformation - metabolize in the liver by oxidation, metabolites form glucoronide conjugates Potent inducers of hepatic enzymes – multiple drug Potent inducers of hepatic enzymes – multiple drug interactions (major reason for tolerance) interactions (major reason for tolerance) Excretion glucoronide conjugates excreted in urine elimination rate significantly increased by alkalinization of urine with (NaHCO3) (NaHCO3)
- 38. PHARMACODYNAMICS Barbiturates increase duration of opening of GABA- mediated Cl- ion channel. At high concentrations At high concentrations Barbiturates are GABA-mimetic, directly activating Barbiturates are GABA-mimetic, directly activating Cl Cl- - channels. channels. Inhibit action of glutamate on AMPA receptors Inhibit action of glutamate on AMPA receptors At higher conc. Inhibit function of voltage gated At higher conc. Inhibit function of voltage gated Na Na+ + channels. channels. Bariturates cause CNS depression ranging from mild Bariturates cause CNS depression ranging from mild sedation to general anesthesia in a dose- sedation to general anesthesia in a dose- dependent fashion. dependent fashion.
- 39. THERAPEUTIC USES THERAPEUTIC USES Sedative/Hypnotic agents(replaced by BDZs) Sedative/Hypnotic agents(replaced by BDZs) In status epilepticus (Phenobarbital sodium) In status epilepticus (Phenobarbital sodium) Induction of anesthesia (thiopental, methohexital). Induction of anesthesia (thiopental, methohexital). Treatment of hyperbilirubinemia & kernicterus in Treatment of hyperbilirubinemia & kernicterus in neonate (increase glucouronyl transferase & neonate (increase glucouronyl transferase & bilirubin binding proteins). bilirubin binding proteins).
- 40. Adverse effects: Adverse effects: 1. 1. Respiratory depression Respiratory depression 2. Hangover 2. Hangover 3. Tolerance 3. Tolerance 4. Withdrawal symptoms 4. Withdrawal symptoms 5. Precipitation of acute attack of porphyria. 5. Precipitation of acute attack of porphyria. 6. Many drug interactions. 6. Many drug interactions. 7. Allergic reaction: urticaria and skin rash. 7. Allergic reaction: urticaria and skin rash. Toxicity Toxicity Respiratory depression, Cardiovascular Respiratory depression, Cardiovascular collapse, coma & death. collapse, coma & death.
- 41. Advantages of BZD over barbiturates Advantages of BZD over barbiturates 1. Selective: minimal respiratory & CVS 1. Selective: minimal respiratory & CVS depression. depression. 2. High therapeutic index. 2. High therapeutic index. 3. Less hangover. 3. Less hangover. 4. Not enzyme inducer. 4. Not enzyme inducer. 5. Less dependence with minimal withdrawal 5. Less dependence with minimal withdrawal symptoms. symptoms. 6. Has specific antagonist 6. Has specific antagonist. .
- 42. BUSPIRONE Relieves anxiety without marked sedative or euphoric effects No hypnotic, anticonvulsant or muscle relaxant property Mechanism of action: does not interact directly with GABAergic does not interact directly with GABAergic systems systems Partial agonist at 5-HT1A receptors but it also has affinity for but it also has affinity for brain dopamine D brain dopamine D2 2 receptors. receptors. no tolerance, no dependence, no withdrawal symptoms no tolerance, no dependence, no withdrawal symptoms less psychomotor impairment than diazepam anxiolytic effects of buspirone may anxiolytic effects of buspirone may take take >1 >1week week to become to become established established less effective in panic disorders less effective in panic disorders
- 43. RAMELTEON RAMELTEON Pharmacodynamic: Pharmacodynamic: – Melatonin receptors Melatonin receptors circadian rhythms of sleep- circadian rhythms of sleep- wake cycle wake cycle – an agonist at MT an agonist at MT1 1 and MT and MT2 2 melatonin receptors melatonin receptors – no direct effects on GABAergic neurotransmission no direct effects on GABAergic neurotransmission . .
Editor's Notes
- #5: Graded dose-dependent depression of central nervous system function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of central nervous system depression. The linear slope for drug A (most non benzodiazepine drugs) is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve central nervous system depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.