镇静催眠药山东大学药理学英文课件

Chapter 17 Sedative-Hypnotic Drugs Definition Sedation:An effective sedative agent should reduce anxiety and exert an effect with little or no effect on motor or mental functions. Definition Hypnosis: 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. Hypnotic effects can be achieved with most sedative drugs simply by increasing the dose. Phases of Sleep Phases of Sleep REM(rapid eye movement sleep), 25% of the total sleep, about lasts30 min dream NREM(non-rapid eye movement sleep), about 75% of total sleep, about 90 min In man, the physiological sleep consists of 4-5 cycles of alternative REM and NREM sleep NREM NREM Stage 1 dozing and drowsiness Stage 2 major fraction, 50% of sleep Stage 3 deep sleep transition slow wove sleep Stage 4 “cerebral” sleep somnambulism and nightmare Specificity Graded dose-dependent depression of CNS function Type A sedation hypnosis anesthesia coma paralysis failure Type B sedation hypnosis anesthesia? Specificity 2.Tolerance metabolic tolerance (enzyme inducer) pharmacodynamic tolerance(down- regulation) 3. Dependence Psychological dependence Physiological dependence Classification Benzodiazepines(BZ) Barbiturates Other Section 1 Benzodiazepines The most widely used Sedative-Hypnotics. They are more effective and safer than barbiturates. Approximately 20 benzodiezepines are currently available. Chemical Structure of BZ 1,4-benzodiazepines Classifications of BZs Drug T1/2(h) Short-acting Triazolam 24 Intermediate lorazepam 614 Oxazepam 610 clonazepam Long Diazepam 3060 Flurazepam 50100 chlordiazepoxide Pharmacological Effects and Uses 1.Anti-anxiety anxiety: nervous, anxious, excite at the lowest effective doses used for relieving of anxiety states, including restlessness,worry,stress that accompanies some forms of depression and schizophrenia. selectively inhibits neuronal circuits in the limbic system of the brain. amnesia(短暂性记忆缺失) 2. Sedation used prior to general anesthesis to relieve the stress of patients. amnesia(短暂性记忆缺失) used for patients undergoing tracheoscopy and electric defibrillation before the treatment or examination. Pharmacological Effects and Uses 2.Hypnosis reduces both sleep-induction time and the number of awakenings, and increases the duration of sleep. prolong stage 2 sleep, shorten stage 4 sleep, little influence on REM little rebound Uses: insomnia 3. Anticonvulsant effect and antiepileptic effect Inhibit the development and spread of epileptiform activity in the CNS and are useful in the treatment of convulsion and status epilepticus. diazepam:continuous seizure first choice 4. Central muscle relaxation Relax the spasticity of skeletal mucle, probably by increasing presynaptic inhibition in the spinal cord. Useful in the treatment of skeletal mucle spasms such as occur in mucle stain,and in treating spasticity from degenerative disorders,such as multiple sclerosis and cerebral palsy. 5.Others Respiration cardiovascular function Mechanisms of action Increase the efficiency of -aminobutyric acid (GABAergic) inhibition enhance R affinity for GABA increase the frequency of Cl- channel opening do not substitute for GABA Pharmacokinetics Absorption the oral absorption well, Cmax about 1 hour: rapid triazolam Distribution high plasma protein binding lipid solubility plays a major role placental barrier/breast milk Pharmacokinetics Dutation of actions half-lives important clinically Pharmacokinetics Fate A. Biotransformation metabolized by the liver to compounds that are also active. B. Excretion excreted by kidey as glucuronides or oxidized metabolites Advantages of BZs Higher therapeutic index, no anesthesia in large dose The duration of slow-wave sleep little influences on REM 3. Do not induce hepatic enzyme 4. Light dependence 5. Low after effect Adverse Reactions CNS depression: 1.drowsiness, fatigue, dizziness; 2.ataxia; 3.coma ; inhibition of respiration Inhibition of cardiovascular function Tolerance and Dependence Benzodiazepine Antagonist Flumazenil（氟马西尼） The only antagonist available Use for diagnosis and therapy of BZ overdose First-pass elimination A short half life, so requiring repeated administration Section 2 Barbiturates Pharmacokinetics Absorbed easily following po, im Duration of action of babiturates depends on degree of lipid solubility. Thiopental: redistribution Pharmacokinetics C.Biotransformation and excretion Metabolites lack activity Drugs with high lipophilicity: liver metabolism Drugs with low lipophilicity: kidney excretion Alkalinization of urine promotes excretion of babiturates. Phenobarbital intoxication: alkalinization of the urine Mechanisms GABAergic inhibition(duration of Cl- channel opening) GABA mimetic(high dose) Inhibit exicitatory neurotransmitter Pharmacological Effects and Uses Sedation and hypnosis Anticonvulsant effects Anesthesia and administration pre- anesthesia thiopental（硫喷妥钠） Enhance the effects of other CNS depressants Adverse Drug Reactions After effect Tolerance and dependence Inhibition of respiration function Hepatic enzyme induction Adverse Drug Reactions Poisoning An overdose can result in coma, severe respiratory depression. supporting respiration and circulation,purging the stomach Alkalization of the urine often aids in the elimination of phenobarbital. Section 3 Chloral hydrate （水合氯醛） lHypnosis lNo influence on REM lAnticonvulsant effects lIrritation to mucous membrane lInhibit cardiac contractility Buspirone Uses:relief of anxiety Mechanism: a partial agonist at brain 5-HT1A-R Advantages: no sedative-hypnotic effects no psychomotor impairment no tolerance and dependence Melatonin （褪黑素） Clinical uses of sedative- hypnotics. For relief of anxiety For ins