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镇静催眠药 sedative-hypnotic drugs Pharmacological department , school of basic medicine , Peking union medical college 叶菜英 镇静催眠药 sedative-hypnotic drugs Definition : Drugs which can selectively inhibit CNS and cause sedation and hypnosis . 镇静催眠药 sedative-hypnotic drugs Inhibit CNS in a dose-dependent manner Low dose : relief patients’ irritability, sedation Suitable increment : Induce sleep. sleep → deepen and extend the role of hypnosis . Large dose： deepen Central inhibition → anticonvulsant anesthesia. poisoning dose → central inhibition death. The physiological significance of sleep Apperception and sleep are to maintain physiological function of the body . People must study and work in the wake - a clear head , high efficiency The body must have sufficient sleep - to relief the body from fatigue , get rest The physiological significance of sleep Promote the development of brain function Maintain energy of brain function Consolidation of memory and ensure the best brain functions Promote the growth of the body, resist aging Enhance the body's immune function 镇静催眠药sedative-hypnotic drugs categories 苯二氮卓类 Benzodiazepines ： 安定Diazepam，硝基安定等 巴比妥类 Barbiturates: 异戊巴比妥amobarbital等 其他类：水合氯醛chloral hydrate等 鎮静、催眠和抗焦虑药 苯二氮卓类 benzodiazepines 地西泮（安定） 奥沙西泮 三唑仑 Diazepam Oxazepam Triazolam 苯二氮卓类 Benzodiazepines Advantages：Efficacy, safe, fewer side effects categorise Long-acting：（T1/220hr） Middle-acting：（T1/26-20hr） Short-acting：（T1/26hr） 苯二氮卓类 benzodiazepines Long-acting：（T1/220hr） 安定 Diazepam、 氯氮卓chlordiazepoxide （利眠灵） 氟胺安定flurazepam (氟安定） 苯二氮卓类 benzodiazepines Middle-acting：（T1/26-20hr） 硝基安定（硝西泮） 去甲羟基安定（舒宁） Short-acting：（T1/26hr） 甲基三唑氯安定Trizolam（三唑仑) 苯二氮卓类 Benzodiazepines Physiological process Oral, injection absorption→ binding to plasma protein → distribution in the brain, blood-rich organizations →metabolised by liver enzyme , and metabolin can bind to glucuronic acid directly → eliminated from the kidney Some enter hepatoenteral circulation→ effects last → accumulation 几种苯二氮卓类药代动力学比较 药名 生物利 血 浆 蛋 分布 口服 T1/2 蓄积 代谢 活性代谢物 用度 白 结 合 容积 吸收 率 安定 100 98 1.1 快 20- 易产生 氧化 去甲安定、去 100 甲羟基安定 利眠 100 97 0.3 快 7-28 易产生 氧化 去甲氯氮卓、 灵 去甲羟安定 氟胺 100 97 2.2 快 20- 易产生 氧化 N- 脱 烷 基 氟 安定 100 安定 硝基 78 87 1.9 慢 15-20 不易 氧化 去甲安定 安定 去甲 88 90 1.0 慢 5-18 不易 结合 去甲安定 羟基 安定 甲基 55 90 1.1 慢 1.5-5 无 氧化 α-羟三唑安定 三唑 氯安 定 苯二氮卓类Benzodiazepines Pharmacokinetic characteristics： 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. 苯二氮卓类Benzodiazepines Pharmacokinetic characteristics Long-acting：slow elimination ，long t1/2 ， repeated administration → accumulation The majority of drugs are oxygenized in the body (such as diazapam) ——affected by many factors , Such as drinking , liver disease → t1 / 2 extended 苯二氮卓类 Benzodiazepines Pharmacological actions Anti-anxiety and anticonvalsant Sedation and hypnosis CNS inhibition Central muscle relaxant Lapsus memoriae Abstinent symptom 苯二氮卓类Benzodiazepines Pharmacological actions and clinical applications Anti-anxiety and anticonvulsant effect Advantages : high selectivity , wide safety margin , slow elimination , lasting effects ,low dependence and light withdrawal symptoms. Clinical applications : anxiety with obsessive- compulsive disorder , gastrointestinal neurosis ,heart neurosis . Strychnine and other drugs cause seizures. 苯二氮卓类Benzodiazepines Pharmacological actions and clinical applications Sedation and hypnosis : Clinical applications： Narcotic administration —— calm Treat insomnia —— difficult to fall asleep , wake up easily and early. 苯二氮卓类Benzodiazepines Pharmacological actions and clinical applications Central inhibition：strengthen the inhibition of central inhibitors （ such as ethanol , barbiturates）. Central muscle relaxant: Clinical applications: muscle cramps , cerebral vascular accident , spinal cord injuries and lumbar muscle strain 苯二氮卓类Benzodiazepines Lapsus memoriae ：damage in recent memory (reversible) Withdrawal symptoms ： psychological and physiological dependence after long- term use . Sudden withdrawal symptoms ： nervous , trembling , appetite lose and sleep disorders. 鎮静、催眠和抗焦虑药 苯二氮卓类 GABA—中枢抑制递质（2α、2β、γ2组成） GABA与R结合与Cl-通道相偶联→Cl-升高→突触后膜超 极化→中枢抑制 BZ与GABA-R分布相似，存在功能联系， 组成GABA.R.BZ-R.cl-复合物 苯二氮卓类Benzodiazepines 【Mechanism of action】 At present , it is thpught that the central role of BZ is possibly closely related to the drug effects on the γ-aminobutyric acid (GABA) receptor in different parts of the brain . The receptor is a comples macromolecule ,which is a ligand-gated Cl- channel . GABA is central suppressive neurotransmitter which is related to sedation , hypnosis , anticonvulsant and emotional stability . 苯二氮卓类Benzodiazepines 【Mechanism of action】 GABA neuron ending release GABA ，agitate GABAA receptors on postsynaptic membrane . GABAA receptor is constructed by two αsubunits and two βsubunits . GABA binds to GABAA receptorβsubunit and open Cl channel ，resulting in Cl－inflow , postsynaptic neurons potential decline and membrane hyperpolarization . The cell is hard to be excited . When GABA exhausted ，the role of the drugs disappear，indicating that the role depends on GABA but not the receptor。 苯二氮卓类Benzodiazepines 【Mechanism of action】 On the GABA neuron ending there are specific points with high affinity to BDZ . The binding point exists in the cortex , mid brain ,cornu ammonis , spinal cord and so on , consistent with the distribution of GABAA receptors . Recent years studies indicate the binding of BZ to GABAA receptor αsubunit can not open Cl- channel directly . But it can enhance the binding of GABA to GABAA receptor βsubunit , which can increase the frequency of the Cl- channel openness . 苯二氮卓类Benzodiazepines 【Mechanism of action】 In short，the binding of BZ with GABAA receptorαsubunit can enhance the binding GABA with GABAA receptors , increase the neurotransmitter function of GABA and synaptic inhibition effect ；It can also function by increasing the frequency of C1－ channel openness . It is generally believed that GABAA receptors in amygdala and cornu ammonis play a role in anti- anxiety of BZ ，while the sedation and hypnosis effect is related to receptors in the brain stem. 苯二氮卓类Benzodiazepines Adverse effects： Therapeutic dose ：drowsiness ，dizziness , fatigue , Memory decline . Large dose ：ataxia overdose →intoxation →coma , respiratory depression death Long term use ：tolerance ，addiction Ethanol strengthen toxicity Through the placenta : teratogenicity role 巴比妥类 Barbiturates [化学结构] ╱NH2 HOOC╲ ╱NH—OC╲ ╱H O═ C CH2→O═C (2) (5)C ╲NH2 HOOC╱ ╲NH—OC╱ ╲H Barbituric acid is a condensed by urea and malonate . Barbituric acid does not have hypnotic effect itself，C5 is substituted by different groups . C5-two H substituted ——barbiturates C5-benzene ring——anticonvulsant ，phenobarbital C5-side chain has branches——amobarbital C2-O substituted by S——thiopental 鎮静、催眠和抗焦虑药 巴比妥类 巴比妥类 barbiturates 长效：苯巴比妥 (phenobarbital） 作用维持6~8 h 中效：异戊巴比妥（amobarbital） 3~6 h 短效：司可巴比妥（secobarbital) 2~3 h 超短效：硫喷妥（thiopental） 0.5 h 巴比妥类barbiturates [Physiological process] Oral and intramuscular injection absorption→distribution all over the body , body fluid →brain High liposolubility（metabolised by liver drug enzyme ） → eliminated in urine （ short maintenance time） Low liposolubility→ eliminated in original form （long maintenance time） 巴比妥类作用快慢与消除比较 Main drugs liposolubility effect time eliminated way Phenol low slow some destroyed in liver， barbital some eliminated from kidney amobarbital slightly low slightly faster destroyed in liver secobarbital higher faster destroyed in liver thiopental highest fastest Store fat，destroyed in liver 巴比妥类barbiturates [Characteristics of pharmacological action] Barbiturates generally inhibit the CNS . It has sedative , hypnotic , anticonvulsant , antiepileptic and anaesthetic effect at different doses from low to large , respectively . Inhibit cardiovascular system at large dose . 10 times of hypnosis dose can cause respiratory paralysis and death . Poor safety，easy to cause dependence . The application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia . 巴比妥类barbiturates [Pharmacological actions and clinical application] Sedation & hypnosis Low dose —— sedation middle dose—— hypnosis , shorten time to fall asleep , extend sleeping time Long term use —— rebound phenomenon , dependence , addiction. 巴比妥类barbiturates [Pharmacological actions and clinical application] Anticonvulsant and antiepilepsia strong action for tetanus , children with high fever , eclampsia , meningitis , encephalitis and convulsion caused by central stimulants . Preanesthetic medication and anesthesia Thiopental : intravenous anesthesia ， induction of anesthesia . Phenolbarbitol ：anesthetic medication 巴比妥类barbiturates [Pharmacological actions and clinical application] Enhance the function of central depressant Barbiturates of sedative dose combined with antipyretic analgesic drugs can augment the analgesic effect of the latter . 巴比妥类barbiturates [Mechanism of action] The centrol role is related to the activation of GABAA receptors . Barbiturates can function as GABA in the absence of GABA , which can increase the permeability of Cl－ channel , leading to the cell membrane hyperpolarization . Different from BZ drugs which increase Cl－channel opening frequence ， barbiturates mainly extend the Cl－channel opening time . In addition ，barbiturates can weaken or block the excited reaction resulted from depolarization caused by the glumatic acids and inhibit the CNS . 巴比妥类barbiturates [Adverse effects] After effect :dizziness , drowsiness , fine uncoordinate movement Allergic response : nettle rash , angioneuroedema , erythema mlutiforme Tolerance Dependence Acute intoxication :significant inhibit respiration center . 巴比妥类barbiturates [Notes] The drug is a inducer of liver drug-metabolizing enzymes and promote metabolism of other drugs . The main cause of death of barbiturates is deep respiratory inhibition . In pregnant and lactant period , the thyroid function is low . Patients who have fever , anaemia , hypotension , hemorrhagic shock , heart , liver , kidney dysfunction and old people with mental disease should take the drug with caution . Patients with respiratory inhibition caused by bronchial asthma and head injury , severe liver dysfunction , uncontrolled diabetes and who is allergic are forbidden to take . 巴比妥类barbiturates [Acute intoxation treatment] Intoxation : deep coma , high respiratory inhibition , blood pressure drop , body temperature drop , shock and renal failure. Breath maintenance , circulation , O2 , trachea cannula , artificial breathing , transfusion , central stimulants. Gastric lavage ， alky drugs such as sodium bicarbonate , strong emictory , dialysis . 其他类Other sedative-hypnotic drugs 水合氯醛 chloral hydrate Hypnosis —— refractory insomnia Anti-convulsion —— tetanus , eclampsia . convulsion of epilepsia gravior Toxic dose —— inhibit respirate and blood pressure , large dose can cause anesthesia . Take 10% solution orally or per rectum generally in order to reduce stimulate . 水合氯醛 chloral hydrate 【Adverse effects】 Gastrointestinal reaction : strong stimulation of gastric mucous membrane causes nausea , vomit and epigastric discomfort . Large dose can inhibit myocardial contraction and shorten the cardiac muscle refractory peroid . Overdose cause damage to heart , liver and kidney . So patients with liver or kidney disease are forbidden to take . Allergic reactions occur occasionally , such as erythema, urticaria, dermatitis, and so on. 鎮静、催眠和抗焦虑药 The central effect of ethanol in blood Thanks!
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