1、第三次課的內(nèi)容,1、腎上腺素能神經(jīng)系統(tǒng) （2）腎上腺素受體拮抗藥 2、鎮(zhèn)靜催眠藥,Adrenergic Receptor Antagonists,antagonists of NE at either a or b receptors. - competitive antagonists (reversible), blocking endogenous norepinephrine - irreversible antagonists Antagonist characteristics: receptor occupancy (binding affinity) no receptor a

2、ctivation (no efficacy) nonselective and selective drugs available for both the a or b receptors.,Adrenoceptor antagonists （1） receptor antagonists 12 receptor antagonists: short-acting: phentolamine（酚妥拉明） long-acting: phenoxybenzamine（酚芐明） 1 receptor antagonists: prazosin（哌唑嗪） 2 receptor antagonist

3、s: yohimbine（育亨賓）,Drug actions and classification,Adrenoceptor antagonists （2） receptor antagonists 12 receptor antagonists: propranolol （普萘洛爾） 1 receptor antagonists: atenolol（阿替洛爾） 2 receptor antagonists: butoxamine（布他沙明） （3）, receptor antagonists labetalol（拉貝洛爾）,Drug actions and classification,Ep

4、inephrine reversal （adrenaline reversal）,competitive, nonselective (1, 2 receptor antagonists),Phentolamine （酚妥拉明）,Pharmacological effects (1) Vasodilatation Blocking 1 receptor: vasodilation in both arteriolar resistance vessels and veins (2) Cardiac Stimulation Reflex；blocking 2 receptor NE releas

5、e (3) Cholinergic and histamine-like effects Contraction of GI smooth muscles, Gastric acid secretion ,Clinical uses (1) Hypertension from pheochromocytoma (short term use). pre- and post-operation of pheochromocytoma Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases Acrocyanosis

6、, Raynauds disease (3) Local vasoconstrictor extravasation Major Adverse effects Postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions,Phentolamine,Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla that produce

7、s excess epinephrine. Hypertension Inhibiting platelet aggregation, receptor antagonists,受體阻斷劑的藥理學(xué)特性,Clinical uses (1) Arrhythmia：supraventricular, sympathetic activity (2) Hypertension (3) Angina pectoris and myocardial infarction (4) Chronic heart failure (5) Others: hyperthyroidism, migraine head

8、ache, glaucoma（timolol，噻嗎洛爾）., receptor antagonists,Adverse effects (1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia (2) Worsening of asthma: contraindicated in bronchial asthmatic patients (3) Withdrawal syndrome：up-regulation of the receptors (4) Worsenin

9、g of peripheral vascular constriction (5) Others：central depression, hypoglycemia, etc., receptor antagonists,1, 2 receptor blocking no intrinsic activity first-elimination after oral administration, individual variation of bioavailability,Propranolol （普萘洛爾）,Timolol （噻嗎洛爾）,For treatment of glaucoma

10、(wide-angle),1receptor antagonists, no intrinsic activity atenolol : longer t1/2, once daily usually used for treatment of hypertension,Atenolol （阿替洛爾） Metoprolol（美托洛爾）, receptor antagonists, receptor blocking, usually used for treatment of hypertension,Labetalol （拉貝洛爾）,1. Hypotension,-To preserve a

11、dequate blood perfusion to heart, brain or kidneys in cases of hemorrhage, overdose of antihypertensive drugs or spinal cord injuries. -Short duration of treatment: NE, phenylephrine, methoxamine, ephedrine (a1 AR agonists).,2. Shock,3. Cardiogenic Shock,-Inadequate perfusion to tissues as a consequ

12、ence of hypovolemia, cardiac failure, or altered vascular resistance. -Usually associated with hypotension. -Use of a1-adrenergic agonists to increase peripheral vascular resistance, and b1-adrenergic agonists to improve cardiac function.,-Massive myocardial infarction. -Stimulation of cardiac b1-ad

13、renergic receptors is needed: isoproterenol, norepinephrine, epinephrine, dobutamine, dopamine.,Therapeutic Uses of a1 (b) AR Agonists,4. Local Vascular Effects,-Reduction of regional blood flow in surgery (nose, throat, larynx) to improve visualization by limiting hemorrhage. -Epinephrine retards t

14、he absorption of local anesthetics and increases the duration of anesthesia (vasoconstrictor effect of epinephrine),6. Allergic Reactions,5. Nasal Decongestion,-a1-Adrenergic agonists are used as nasal decongestants. -These drugs decrease the volume of the nasal mucosa and therefore reduce the resis

15、tance to airflow. -Oxymetazoline, phenylephrine and ephedrine are commonly used.,-Epinephrine (s.c.) is used in acute hypersensitivity reactions. -Activation of b-adrenergic receptors on mast cells suppresses the release of histamine and leukotrienes.,Therapeutic Uses of a1 (b) AR Agonists,1. Asthma

16、,-Asthma is a condition of overreactive airways. Asthma attacks can make it very difficult to breath because of excess bronchoconstriction. -b2 AR agonists such as albuterol, metaproterenol and terbutaline are used. -The drugs are administered by inhalation and are absorbed slowly, limiting their sy

17、stemic side effects, and b2 selectivity reduces cardiac stimulation.,2. Premature Labor,-When labor occurs prematurely (before 37 weeks), it is a risk to the fetus. - b2 AR agonists relax the smooth muscle of the uterus and help prevent premature delivery. The goal is to reach at least 37 weeks when

18、 the fetal lungs have matured.,Therapeutic Uses of b2 AR Agonists,1. Pheochromocytoma,2. Hypertension,3. Heart Failure,-While not commonly used anymore, a1 blockers can be use to treat hypertension. -Somewhat more common is the use of b blockers. These work centrally (the most important effect the m

19、echanism is not completely understood) and peripherally (decrease heart rate some).,-After a myocardial infarction, the SNS will be activated to increase the cardiac output from the remaining good heart tissue. This is good in the short-term, but long-term changes lead to cardiac hypertrophy and fai

20、lure. -Ironically, b blockers reduce the incidence of sudden death from heart failure.,Therapeutic Uses of a1 not remarkably affect on REM used for insomnia（失眠） and preanesthetic medication,A. Benzodiazepines,Diazepam 地西泮（安定）,(3) Antiepileptic and anticonvulsant effects Convulsion due various causes

21、; status epilepticus (i.v.) (4) Centrally acting muscle relaxant effect Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases. (5) Others Amnesia (短暫性記憶缺失

22、, i.v.） Respiratory and CVS effects,A. Benzodiazepines,ACh,NE,DA,5-HT,2. Mechanisms of actions,A schematic drawing showing key components of the ascending reticular activating system (ARAS) 網(wǎng)狀結(jié)構(gòu)上行激活系統(tǒng),(1) Sites of action: mainly acts on limbic system and midbrain reticular formation.,2. Mechanisms o

23、f actions (2) Interaction with GABAA receptor Benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for -aminobutyric acid (GABA). The binding of benzodiazepines enhances the affinity of GABA receptor for this neurotransmitte

24、r, resulting in a more frequent opening of adjacent chloride channels. - coagonist This in turn results in enhanced hyperpolarization（超極化）and further inhibition of neuronal firing.,A. Benzodiazepines,2. Mechanisms of actions (2) Interaction with GABAA receptor,2. Mechanisms of actions (2) Interactio

25、n with GABAA receptor,Co-agonist,Centrally acting muscle relaxant effect: increasing presynaptic inhibition in the spinal cord,3. Adverse effects (1) Central depression Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Ataxia (共濟(jì)失調(diào)); cognitive impairment An

26、tagonized by BZ receptor antagonist flumazenil（氟馬西尼）,A. Benzodiazepines,3. Adverse effects (2) Tolerance Dependence Withdrawal syndrome: central excitation,A. Benzodiazepines,(3) Others local pain, respiratory and CVS reactions (i.v.) teratogenic effects（致畸效應(yīng)） (4) Contraindications Myasthenia gravis

27、 Infants 6 months Pregnancy and lactation mothers Elderly, heart/lung/liver/kidney dysfunction,A. Benzodiazepines,藥物安全性,A. Benzodiazepines,阿普唑侖,丁螺環(huán)酯,氯氮卓,A. Benzodiazepines,Other benzodiazepines According to the metabolisms,三唑侖,奧沙西泮,B. Benzodiazepines,Phenobarbital 苯巴比妥,1. ADME Inducing hepatic enzym

28、es Alkalining urine: excretion 硫噴妥鈉脂溶性極高，故易通過BBB，易發(fā)生再分布； 苯巴比妥脂溶性低，不易在肝臟代謝； 脂溶性高，血漿蛋白結(jié)合率高。,B. Barbiturates,2. Pharmacological effects and clinical uses Sedative-hypnotic effects 可縮短REM，反跳明顯； (2) Preanesthetic medication (3) Antiepileptic and anticonvulsant effects,B. Barbiturates,3. Adverse effects (

29、1) Central depression: including after effect (hangover “宿醉”) (2) Tolerance and dependence: long-term uses (3) Acute poisoning supporting therapies alkalizing urine hemodialysis,B. Barbiturates,Chloral hydrate 水合氯醛 Sedative-hypnotic effects Anticonvulsant effect: usually used in children Hydroxyzine

30、 羥嗪（安泰樂） Meprobamate 甲丙氨酯（眠爾通） Buspirone 丁螺環(huán)酮，抗焦慮，但無鎮(zhèn)靜作用，可能與5-HT有關(guān) Methaqualone 安眠酮,C. Others,Antihistamines 抗組胺藥 Ethanol 乙醇 Melatonin 褪黑素,C. Others,1962年8月5日夢(mèng)露在洛杉磯布萊登木寓所的臥室內(nèi)被發(fā)現(xiàn)已經(jīng)去世，終年36歲,In her circulation system: 8 % chloral hydrate (3% toxic level and 10% lethal level) 4.5 % Nembutal (pentobarbit

31、al ) (death level 1.5-4%) In her stomach and duodenum: No drug crystal found!,Central stimulants,Psychomotor stimulants Respiratory center stimulants,Psychomotor stimulants (mainly acting on cerebral cortex) Xanthines: caffeine 咖啡因 Related drugs Respiratory center stimulants Direct stimulation Indirect stimulation (reflex),A Psychomotor stimulants,1. Pharmacological effects (1) Central stimulation (2) CVS effects: cardiac stimulation, dilatation of vessels (