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Sedative hypnotics
- 2. OUTLINES • Sleep • Hypnotic vs Sedative • Hypnotic Sedative Drugs • Benzodiazepine • Barbiturates • Miscellaneous Agents • Summary 2
- 3. SLEEP 3
- 4. Naturally recurring,periodic state of depression of consciousness,relatively inhibited sensory activity and inhibition of voluntary muscles.There is decreased ability to react to stimuli but person is arousable. Non-rapid eye movement(NREM) sleep: 70%-75% Stage 1,2 (Thinking when awakened) Stage 3,4:slow wave sleep, SWS(restoration ) Stage4-low metabolic rate & GH secretion highest,NIGHT TERRORS Rapid eye movement(REM) sleep-about 20-25%- dreams, tachycardia,relaxation of voluntary muscles,(dreaming when awakened),consolidation of learning,NIGHT MARES Normal sleep 4
- 5. Night terrors vs nightmares
- 7. INSOMNIA Primary-no medical,psychiatry or environmental attribution Secondary – attributable
- 9. SEDATIVE Drugs that have an inhibitory effect on the CNS to the degree that they reduce: – Nervousness – Excitability – Irritability without causing sleep (McKenry et al., 2003) An effective sedative agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. (Katzung et al., ed 11) 9
- 10. HYPNOTICS • Calm or soothe the CNS to the point that they cause sleep • 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. • A sedative can become a hypnotic if it is given in large enough doses dose dependent (Katzung; Goodman & Gilman) 10
- 11. Anxiolytic & Hypnotic drugs • Anxiety (adaptive response) – Intense ,excessive and persistent worry and fear about everyday situations. When bcm all consuming and interfere with daily living. – Among other fear responses include defensive behaviors, autonomic reflexes, arousal and alertness, corticoid secretion and negative emotions
- 13. Anxiolytics: reduce anxiety Sedatives: decrease activity, calming effect Hypnotics: induce sleep Some drugs have anxiolytic and sedative/hypnotic effects. 13
- 14. CLASSIFICATION 1.BZD-most important- Long acting short acting ultra short acting Diazepam temazepam trizolam Chlordiazepoxide lorazepam midazolam clonazepam alprazolam Clobazam nitrazepam Flurazepam 24-48hrs 12-24hrs <6hrs
- 15. Classification cont…. 2. NEWER AGENTS- a)Melatonin &congeners melatonin,ramelteon,tasimelteon b) ‘Z’ hypnotics/Non-BZDs Zolpidem,zopiclone,eszopiclone,zaleplon c) Orexin receptor antagonists Suvorexant,almorexant,filorexant
- 16. Classification contd. 3.BARBITURATES- Long acting short acting ultrashort acting Phenobarbital pentobarbital thiopental Mephobarbital secobarbital methohexitone amobarbital 4.MISCELLANEOUS- Paraldehyde,triclophos,hydroxyzine,promethazine
- 18. BZD vs BARBITUARATES • BZDs- mimics natural sleep • anaesthesia-/loss of consciousness • Enzyme induction,D I,metabolic tolerance • Abuse liability,tolerance,dependence • REM sleep affected (rebound REM) • Hangover • Hyperalgesia • Automatism&amnesia-poisoning • CVS &RS functions • ANTAGONIST-flumazenil(BZD) Inability to create new memories
- 19. BZDs –pharmacological actions • Sedation &hypnosis –induction&maintenance-NREM stage2 increased,stage4 &REM is decreased(less affected) • Anxiolytic-calming effect-alprazolam-antidepressant actn • Anaesthesia-dose dependent CNS depression-midazolam • Muscle relaxants-(-) spinal polysynaptic reflexes,NMJ neurotransmission • Anticonvulsants-increase seizure threshold, Status epilepticus, febrile seizures • Amnesia-anterograde • CVS &RS depression
- 20. Site of action BZD-depresses- LIMBIC SYSTEM > RAS (thoughts & mental functions) wakefulness ***ANXIOLYTIC WITH LESS Sedative effect Muscle relaxation- medullary action-(-) polysynaptic reflexes in spinal cord
- 21. Mechanism of action NA,5-HT Ach,histamine,dopamine RAS &LIMBIC SYSTEM GABA GLUTAMATE (inhibitory) (excitatory) GABA- SEDATION,AMNESIA,MUSCLE RELAXATION GLUTAMATE- ANXIETY,AROUSAL,INSOMNIA RESTLESSNESS
- 22. Site and Structure of Action • Site of action is the GABAA receptor Cl channel complex • GABA acts on – GABA A – Post synaptic-linked to Cl ion channels GABA B –GPCRs-decreased cAMP-pre & post synaptic inhibition –by inhibiting Ca channels &increasing K conductance • Structure of GABAA receptor – Comprised of 5 subunits • 2 α subunits (to which GABA binds) • 2 β subunits (to which barbiturates bind) • 1 γ subunit (to which benzodiazepines bind) 22
- 23. 23
- 24. BENZODIAZEPINES : Pharmacodynamic 24 ↑Frequency of channel opening GABA -facilitatory
- 25. MOA-GABAA RECEPTOR • BZD-GABA facilitatory-increase frequency of channel opening • Barbiturates-GABA-mimetic- increase duration of channel opening clˉ BZD Flumazenil Inverse agonist Channel modulator (barbiturates) Channel blockers picrotoxin GABA GABA binding site
- 26. MOA-BZDs BZDs Bind specific site on GABAA-BZD receptor Enhance receptor’s affinity for GABA (GABA facilitatory) ↑frequency of Cl channel opening ↑Cl¯ conductance Neuronal memb hyperpolarization ↓ Synaptic transmission CNS depression
- 27. USES- 1.ANXIETY NEUROSIS Alprazolam(anxiolytic+AD)- panic disorders Lorazepam- OCD,tension induced psychosomatic symptoms, Oxazepam- elderly,liverdysfunction,short lived anxiety Diazepam- acute panic-anxiety states asso with organic disease Chlordiazepoxide- chronic anxiety
- 28. 2.INSOMNIA- Transient insomnia short term ins. Long term ins -<7 d 1-3 wks >3 wks -Jet lag,shift,journey bereavement,occupational underlying disease -Triazolam, Temazepam temazepam,flurazepam flurazepam,nitrazepam
- 29. 3.PREANAESTHETIC MEDICATION& INDUCTION OF ANAESTHESIA- Lorazepam, midazolam, diazepam 4.SMR-diazepam Spasticity of central* origin 5.ANTICONVULSANTS- Diazepam,clonazepam Status epilepticus,myoclonic/petimal seizures,tetanic spasm
- 30. 6.Alcohol withdrawal- Diazepam,oxazepam,cholrdiazepoxide 7.Adjuvant in peptic ulcer disease
- 31. Adverse effects 1.Dose dependent- drowsiness,fatiue,disorientation,lethargy,psychomotor impairment. High margin of safety-50 times the TD is safe 2.tolerance- ‘mild self inducers’ 3.dependence- downregulation of GABA receptors
- 32. 33
- 33. Flunitrazepam- ‘date rape drug’ Tasteless, amnesic, sedative
- 34. 4.ELDERLY- increased forgetfulness & disorientation DRUG INTERACTIONS- • CNS depressants,alcohol,neuroleptics • Smoking decreases effect • Aminophylline antagonizes sedative effect • Enzyme inhibitors-increase action
- 35. NON BENZODIAZEPINE HYNOTICS/Z HYPNOTICS • Zopiclone,zaleplon,zolpidem,eszopiclone • Chemically different from benzodiazepines • Act on specific BZD receptors located on α subunit-agonist at modulatory site of GABAA rec.-facilitate the actions of GABA • BZ1-brain&cerebellum- antianxiety,sedative ,hypnotic • BZ2-cortex,hippocampus,spinal cord- muscle relaxation,anticonvulsant,amnesia • Flumazenil is competitive antagonist • Hypnotic amnesic but weak anti anxiety, anticonvulsant & muscle relaxant-short term use • Low abuse ,REM alteration/residual sedation/rebound insomnia
- 36. uses • t/t of insomnia • Zopiclone-Wean insomniacs taking regular BZD • Zolpidem- sleep latency ↓,intermittent awakenings↓ • Zaleplon- shortest acting ,no active metabolite ,sleep onset insomnia
- 37. Orexin receptor antagonists • Orexins-peptide neurotransmitters –control wakefulness • Receptors-OX 1 &OX2 • Suvorexant,almorexant,filorexant • Block binding of orexinA&B to rec.
- 38. Atypical anxiolytics • Buspirone,ipsapirone,gepirone • Act thru non-GABAergic systems • Partial agonist at brain 5-HT1A receptors(inhibitory) • Buspirone-delayed action(2wks)-nt used in acute anxiety • Low abuse liability,withdrawl,rebound anxiety. • No interaction with ethanol • Tachycardia,nervousness,GIT upset,paresthesias,pupillary constriction
- 39. Β-blockers,melatonin,ramelton • Propranolol- control Sympathetic overactivity symptoms • Melatonin-darkness promotes release---ACTS ON MT1 &MT2 rec. present in SCN-to induce &promote sleep &maintain circadian rhythm. • Ramelton-selective agonist at MT1 &MT2 • Triclofos-converted to trichloroethenal-short term m/m of insomnia &in children for sedation in recurrent colics • Hydroxyzine- antihistaminic,Antiemetic,sedative,anticholinergic&local anesthetic • Promethazine-antihistaminic with anticholinergic & antiemetic action.
- 40. Barbiturates • Barbiturates-GABA potentiating action--increase duration of channel opening • High conc.-increase cl conductance-GABA mimetic action clˉ BZD Flumazenil Inverse agonist Channel modulator (barbiturates) Channel blockers picrotoxin GABA GABA binding site
- 41. Barbiturates,,contd… • Alkaline-no i.m /sc adm. • Ultra short acting-used in GA-resdistribution • Microsomal enzyme induction-metabolic tolerance • Poisoning-alkalise the urine Pharmacological effects- Dose dependent CNS depression REM sleep affected- ‘I dint sleep well’ Drug automatism CVS-high dose- BP, HR, myocardium depression RS-high dose-depression Relax- GIT, bladder ,uterus, urine output ↓
- 42. BARBIT… Uses- • As sedative hypnotics-obsolete • Anesthesia-thiopental(i.v fast inducing agent) • Anticonvulsant-long acting agents • Hyperbilirubinemia in neonates A/E- • Metabolic tolerance • Abuse liability • Dependence • Psychomotor impairment • Respiratory depression, laryngeal edema, hypersensitivity
- 43. Barbiturates… Poisoning&overdose suicidal & accidental respiratory failure,cvs collapse,coma,renal failure t/t gastric lavage,artificial ventillation forced alkaline diuresis,supportive measures
- 44. THANX
Editor's Notes
- Sleep is subdivided into: rapid eye movement (REM) sleep, which is characterized by high-frequency electroencephalogram (EEG) recordings and muscle atonia non-REM (slow-wave) sleep, characterized by low frequency EEG recordings and body rest
- 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.
- Sedative-hypnotic drugs. In: Basic and clinical pharmacology, 8th edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:364–381. Benzodiazepines (BDZs) bind to the gamma sub-unit of the GABA-A receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. BDZs do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential A model of the GABAA receptor-chloride ion channel macromolecular complex. The complex consists of five or more membrane-spanning subunits. GABA appears to interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization. Binding of BZs to gamma subunits facilitates the process of channel opening
- The speed of Absorption and the extent of plasma binding are in equilibrium with liposolubility . More than 90 % bind → absorbed quickly, such as diazapam , etc. Liver metabolism : metabolised to a range of active substances by liver drug enzyme , t1 / 2 longer than the mother nuclide . Demethyldiazapam is metabolised to a wide range of active metabolins, t1/2 20-100 hr.