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1、HYPNOTIC DRUGSBENZODIAZEPINESBARBITURATES OTHER AGENTSObjectives Describe the pharmacological effects,clinical application and adverse reactions of benzodiazepines.Explain the mechanism of action for benzodiazepines,know the antagonist of benzodiazepine receptor flumazenil.Compared with benzodiazepi
2、nes,the characteristics of hypnotic effects of barbiturates Understand the effects of other sedative hypnotics such as chloral hydrate.AACTIONS BMECHANISM OF ACTIONCTHERAPEUTIC USESDPHARMACOKINETICSEDEPENDENCEFADVERSE EFFCTSBenzodiazepine Reduction of anxietySedative and hypnotic AnterogradeamnesiaA
3、nticonvulsant Muscle relaxantReduction of anxiety Low doses Inhibiting limbic system by enhance the function of GABA（-aminobutyric acid）SLEEP Promote the development Maintain brain function Consolidate memory Delaying aging Enhance immune functionMuscle tissue rests and restores physical fatigueNerv
4、ous system development,memory,recovery of brain fatigue Commonly used sedative-hypnotics inhibit fast-wave sleep in different degrees,affecting memory and learning.In one-night sleep,the two sleep phases alternate 45 timesSlow wave sleepFast wave sleepSedative and hypnoticLow dose:sedationHigher dos
5、es produce hypnotic effectsReduce induction time to fall sleep,extend sleep duration,reduce WASO.AnticonvulsantsAntiepilepticMuscle relaxantsReduce spasticity at high doseSpinal cordIncrease the Frequency ofchloride channel opening-small hyperpolarization-movethepostsynapticpotential away from its f
6、iringthresholdAnxiety Aerophobia Therapeuticuses Panic disorder Generalized anxiety disorder Social anxiety disorder Performance anxiety PTSD Obsessive compulsive disorder Specific phobia Depression and schizophreniaAntianxiety effects less tolerance then hypnotic effectsShort term useLonger acting
7、agents:Clonaze-pam,diazepam,lorazepamReserved for continued severe anxietyNot used for normal stress of everyday lifeMuscular disorderSkeletal muscle spasmsTreating spasticity Muscle strain Degenerative disorders:MLS,cerebral palsy Amnesia Shorter acting agents Premedication for endoscopy Conscious
8、sedation Midazolam induction of anesthesia EpilepsyGrand mal and status epilepticusWithdrawal related seizure(alcohol withdrawal)AntiseizureClonazepam Diazepam(first choice)and lorazepamChlordiazepoxide Clorazepate Diazepam,oxazepamSleep disorderFlurazepam:long-actingContinued use,maintain its effec
9、tiveness up to 4 weeks,half life 85hrsTemazepam:frequent wakening,peak sedative 1-3hrs Triazolam:short duration,used for patient have difficulties in going to sleepTolerance frequent,use intermittentlyTherapeutic index high,little influence on respiration,does not cause anesthetic effectSmallinfluen
10、ce on REM sleep,less nightmare occurred after discontinuationDependence,withdrawal symptoms lessoccurrenceLittleeffect on CYP450Lipophilic,rapidly and completely absorbed,distributed throughout the body Duration of action determine the therapeutic effects Cross placental barrier and secret in to bre
11、ast milk,metabolized in liver and excreted in urineEWithdrawal symptom:Confusion,anxiety,agitation,restlessness,insomnia,tension,rarely seizure Long half-lives:occur slowlyShort half-lives:abrupt and severeF.Drowsiness and confusion most common side effectsAtaxia:high dosesCognitive impairmentTriazo
12、lam:rapid tolerance early morning insomnia daytime anxiety amnesia Patients with liver diseaseAVOID:ACUTE NARROW ANGLED GLUCOMAALCHOL AND BENZODIAZEPINES ARE THE DANGEROUS COUPLESpecial Reverse the effects of BZIV onlyShort durationCause seizure and withdrawal Barbiturates Introduction ToleranceDrug
13、 metabolizing enzymesPhysical dependenceComa in toxic doses Depression of CNSRespiratory depression sedationhypnosisanesthesiacomadeathDoseEffectanalgesicSuppress the hypoxicChemoreceptor response to CO2OVERDOSAGEDEATHCYTOCHROME P450Action of the many drugs dependent on CYP450 andconcentration Prolo
14、ngthedurationofchloride channel opening-small hyperpolarization-movethepostsynapticpotential away from its firingthresholdBlock glutamate receptorAnesthetic concentration block high-frequency of Na channels Anesthesia/Anticonvulsant/Anxiety Ultrashort-acting barbiturates:thiopental Phenobarbital:ton
15、ic-clonic seizure,status epilepticus Phenobarbital:Recurrent febrile seizures(young children)drug of choice Metabolized in liver and excreted in urineCross placentaECNSPrecaution Poisoning Physical dependenceDrug hangoverSluggishness,synergize with ethanolTiredness Impaired ability to function normally Contraindicated in acute Intermittent porphyria Severe withdrawal Symptom can cause deathNo specific antagonist available Alkalinization Summary Benzodiazepines Antianxiety,sedative and hypnotic,anticonvulsants,muscle relaxant Barbiturates CNS depression,respiration depression,CYP450 induction