基础医学各论III课件：16_神经系统药理6 2014-11-11

1、神经系统药理6 一、麻醉性镇痛药 二、解热镇痛抗炎药,一、麻醉性镇痛药,General Considerations,Pain (疼痛)： 躯体痛快痛，慢痛 内脏痛 情绪反应 Analgesia (镇痛)： 选择性抑制疼痛感觉， 不影响意识和其他感觉,Pain Classification,Headache (migraine),Acute,Chronic,Pain,Nociceptive,Mixed,Neuropathic,Visceral,Diabetic neuropathy (DN) Post-herpetic neuralgia (PHN) Radiculopathy 神经根痛(RA

2、DIC),Cancer pain Low back pain,Osteoarthritis Rheumatoid arthritis Fibromyalgia纤维肌痛,IBS Pancreatitis Bladder pain Noncardiac chest pain Abdominal pain syndrome,Injury Postoperative Flare,An adverse or unpleasant reaction plus the reactions evoked by it,Pain generation and reactions,The perception of

3、 somatic pain,Drugs for the Relief of Pain,Drugs for the Relief of Pain,Classification of analgesics： Opioid analgesics (centrally acting) opiates synthetic agents Antipyretic, analgesic, and anti-inflammatory drugs (peripherally acting) aspirin, indomethacin Other drugs (for special types of pain)

4、carbamazepine, atropine, nitroglycerin, etc.,General Considerations,Opium,A. Opioid Analgesics,Morphine 吗啡,Morphine 吗 啡,Heroin 海洛因,A. Opioid Analgesics,Morphine: Morphus, the Greek god of dreams,1. Pharmacological effects (1) Mechanisms of actions Acting on central opioid receptors receptors recepto

5、rs receptors,A. Opioid Analgesics,ATP,cAMP,Opioid Receptors and Endogenous Ligands,Endorphin (内啡肽),Enkephalin (脑啡肽),Dynorphin (强啡肽),K+,a,b,g,a,b,g,=,Opioids and opioid receptor ligands,Mechanisms of morphine actions,Peripheral mechanisms of morphine actions,Central mechanisms of morphine actions: Pa

6、in inhibitory system,(2) Central nervous system effects A. Analgesia：maximal analgesic efficacy； relieving unpleasant sensation; euphonia (欣快) and potential of dependence; sedation B. Depression of respiration: reducing the sensitivity of respiratory center to CO2 C. Depression of cough reflex D. Ot

7、her central effects: miosis（瞳孔缩小）, emesis（呕吐）,A. Opioid Analgesics,(3) Cardiovascular effects A. Postural hypotension： Releasing histamine; depressing CVS centers B. Increase of intracranial pressures： Respiratory depression brain CO2 increase vasodilatation in the brain,A. Opioid Analgesics,(4) Eff

8、ects on smooth muscles A. GI tract： Constipation (便秘): increasing resting tone of smooth muscles and sphincters, decreasing propulsive peristalsis and secretions; Biliary tract：Oddis sphincter contraction, increasing the pressure in the biliary tract B. Respiratory tract：bronchoconstriction C. Urina

9、ry tract：increasing vesical sphincter tone urinary retention D. Uterus： decreasing uterus smooth muscle tone,A. Opioid Analgesics,(5) Other effects A. Immune depression B. Endocrine effects, increase,A. Opioid Analgesics,2. Clinical uses (1) Analgesia the pain of high intensity and the pain of termi

10、nal illness Cautions: a) obscure the symptoms and the progress of the disease; b) dependence or addiction; not used for long-term if no clear indications c) biliary colic: combined with atropine,A. Opioid Analgesics,(2) Cardiac asthma (acute left ventricular failure) As an adjuvant treatment A. Vaso

11、dilatation: afterload B. Sedation: anxiety C. Respiratory depression: breathing slowly and deeply (3) Diarrhea Mixture containing opiate,A. Opioid Analgesics,3. Adverse effects (1) Side effects (2) Tolerance and dependence psychological and physic dependence: addiction withdrawal syndromes or abstin

12、ance syndromes (戒断症状),A. Opioid Analgesics,药物依赖性与药物成瘾相关的概念 1、药物依赖性 是药物与机体相互作用所造成的一种精神状态，有时也包括身体状态，它表现出一种强迫要连续或定期使用该药的行为和其他反应，为的是要去感受它的精神效应，或是为了避免由于停药所引起的不舒适。 包括：精神依赖性和生理依赖性 （ psychological and physic dependence ）,（1）精神依赖性（psychological dependence，psychic dependence） 精神依赖性是指使人产生一种对药物欣快感的渴求，这种精神上不能自制的

13、强烈欲望驱使滥用者周期性或连续地用药。 又被称为情感动机依赖性,（2）身体依赖性（physical dependence） 指大多数具有依赖性特征的药物经过反复使用所造成的一种适应状态，用药者一旦停药，将发生一系列生理功能紊乱，称戒断综合征（withdrawal syndrome）。 精神依赖性与身体依赖性的主要不同点是前者在停药后不出现严重的戒断症状。,2、药物成瘾（drug addiction） 指强迫性、失去控制的用药行为，是药物的精神依赖性和生理依赖性共同造成的结果。 一些具有生理依赖性的药物，如某些抗癫痫药、抗高血压药、受体阻断药、糖皮质激素等，突然停药可引起停药综合征，但不属于药物

14、成瘾。,3、药物滥用（drug abuse） 指与医疗目的无关的反复使用能成瘾的药物，用药者采用自身给药的方式，是药物成瘾的后果。成瘾药物 表11-1，美国精神病学会对物质依赖和物质滥用的评判标准 应与药物误用（misuse）区别，如不合理应用抗菌药、激素等。,(3) Acute intoxication coma, respiratory depression, hypotension, pinpoint pupils reversed by naloxone, an opioid receptor antagonist (4) Contraindications labor and lac

15、tation; bronchial asthma and cor pulmonal(肺心病); increased intracranial pressures; severe hepatic damage,A. Opioid Analgesics,Pinpoint pupils,Morphine toxicity can be reversed by opioid receptor antagonist (naloxone),Analgesia; central antitussive,Codeine 可待因,A. Opioid Analgesics,Pethidine(哌替啶) 1. Ph

16、armacological effects Similar to morphine but ineffective for cough and diarrhea, and its metabolite normeperidine has central stimulant effects. 2. Clinical uses analgesia; cardiac asthma; preanesthetic medication or artificial hibernation; 3. Adverse effects similar to morphine, convulsion (overdo

17、se),B. Synthetic Analgesics,Fentanyl （芬太尼） high efficacy combined with droperidol (氟哌利多): 1:50 neuroleptanalgesia 神经安定镇痛术 Methadone （美沙酮） orally effective long-acting also used for displacement in heroin or morphine detoxication,B. Synthetic Analgesics,Pentazocine （喷他佐辛, 镇痛新） receptor agonist / rece

18、ptor partial agonist; low-narcotic analgesic drug psychotomimetic effects: anxiety, nightmare, hallucinations Tramadol （曲马朵） Relatively weak efficacy and dependence,Rotundine （l-tetrahydropalmatine, 罗通定） dl-Tetrahydropalmatine （延胡索乙素） chronic pain; sedative effects; no addiction,C. Other Analgesics,

19、B. Synthetic Analgesics,Summary of opioid receptor ligands,Naloxone （纳洛酮） Naltrexone （纳曲酮） Antidotes for acute intoxication of opioids Treatment of shock and other diseases,Opioid receptor antagonists,附：癌痛的镇痛治疗,三级镇痛阶梯治疗： 轻度：解热抗炎镇痛药 中度：加用或改用弱阿片药, 辅助治疗药 重度：强阿片药，加非阿片及辅助治疗药 应用原则： 尽可能口服用药 按时规则用药，剂量个体化 辅助

20、措施,WHO Analgesic Ladder,二、解热镇痛抗炎药,Peripheral mechanisms of pain,Drugs for the Relief of Pain,Non-steroidal anti-inflammatory drugs (NSAIDs) are just that - drugs that act to relieve inflammation, but are not structurally related to the corticosteroids,Cyclooxygenases: COX 1, COX 2,- PGs, mostly by C

21、OX-1, are constitutively expressed in almost all tissues; COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms - Under normal physiologic conditions, PGs play an essential homeostatic role in cytoprotection of gastric mucosa, hemostas

22、is(止血), renal physiology, gestation(怀孕), and parturition(分娩) Only COX-1 in platelets converts arachidonic acid to TXA2 COX-1 predominant in gastric mucosa is a source of cytoprotective PGs - The production of PGs (inducible COX-2 activity COX-1) at sites of inflammation propagate pain, fever,COX-1 c

23、ompared to COX-2,NSAID Therapy,NSAID inhibition of PGs production alleviates most of the pathologic effects associated with inflammation, but it also interferes with the physiologic role of these molecules Consequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse

24、 effects, particularly those caused by erosion of gastric mucosal protection, GI bleeding,Pharmacodynamic Effects of NSAIDs,Positive analgesic - refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache); - produce a mild degree of analgesia which is

25、 much less than the analgesia produced by opioid analgesics such as morphine anti-inflammatory - these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disorders antipyretic - reduce fever; lower elevated body temperature by their action on the hypothala

26、mus; normal body temperature is not reduced Anti-platelet - inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects,Analgesic : compared with Opioids,Anti-inflammatory: compared with glucocorticoid,antipyretic : compared with chlorpromazine,NSAIDs,Chlorpromazine(氯丙嗪),Effects,

27、Clinical usage,Side effects,GI reactions，no addiction,Lower the abnormal high temperature to normal. Used for various fever.,artificial hibernation(人工冬眠), Hypothermic anesthesia,Extrapyramidal effects (锥体外系反应),Inhibit PGs synthesis and enhance thermolysis,Inhibit thermotaxic center in hypothalamus,

28、induce the body temperature change according to that of environment.,Pharmacodynamic Effects of NSAIDs,Negative Gastric irritant Decreased renal perfusion Bleeding CNS effects,NSAID-associated dyspepsia(消化不良) occurs in up to 50% of patients who use these drugs no relationship, however, between NSAID

29、-associated dyspeptic symptoms and the presence of erosions or ulceration up to 100% of patients taking nonselective NSAIDs，subepithelial hemorrhage, 50% have erosions (small, shallow breaks in the GI mucosa) 20% have ulceration (injury extending through the muscular mucosa) unless the ulcer results

30、 in symptoms or becomes complicated (e.g., causes bleeding or perforation), it is not clinically relevant. Only 1 - 3% of patients develop serious GI side effects while taking NSAIDs.,Gastrointestinal Adverse Effects associated with NSAIDs,For patients presenting to hospital with upper gastrointesti

31、nal (UGI) bleeding - a significant percent were using NSAIDs,Note: Over-the-counter (OTC) use of NSAIDs was more prevalent than was prescribed NSAID usage.,NSAIDs - Gastric Irritant Effects: Molecular Mechanisms,PGs reduce H+ secretion and increase mucous production. Consequently, NSAIDs cause some

32、degree of gastric upset due to inhibition of PG synthesis.,- Misoprostol. a synthetic prostaglandin analogue, can also decrease the risk of NSAID-induced ulceration and complications.,- PPIs can reduce the risk of peptic ulcer formation.,NSAIDs and Platelet Function,Physiology: TXA2 is mainly produc

33、ed in platelets: upon platelet activation; promotes platelet aggregation, vasoconstriction, and vascular proliferation platelets do not have a nucleus and cannot synthesize new COX molecules to replace those that have been irreversibly inactivated. Pharmacology: - apart from aspirin (irreversible CO

34、X inhibition), all NSAIDs inhibit COX competitively, and inhibitory effects on platelet aggregation depend on the pharmacokinetic profiles of the agents. After administration of a single dose of aspirin, platelet aggregation is impaired for up to 4 days, until new platelets enter the circulation in

35、sufficient numbers. - as thrombotic events can occur at any time and for a prolonged period after rupture of a vulnerable plaque, sustained inhibition of platelet activity is needed in order to provide cardioprotection.,small doses (4080 mg/d): inhibiting TXA2 synthesis, preventing thrombosis. large

36、r doses: inhibiting PGI2 synthesis, promoting thrombosis. PGI2: vasodilation and platelet depolymerization (血小板解聚). Most of these drugs will potentiate the action of oral anticoagulants such as coumadin, by their effects on platelet aggregation.,NSAIDs Effects on Renal Function,In healthy hydrated i

37、ndividuals, renal PGs do not play a major role in sodium and water homeostasis Under certain conditions of localized circulatory stress associated with elevated levels of angiotensin II and catecholamines resulting in decreased renal perfusion, renal blood flow is dependent upon prostaglandin synthe

38、sis NSAID-induced inhibition of PG synthesis can result in significant decreases in renal blood flow and GFR, leading to acute renal failure in kidney function-compromised individuals Patients at most risk include those with congestive heart failure, volume depletion, chronic renal disease, liver di

39、sease and those patients receiving diuretics,Salicylates(水杨酸类) aspirin(阿司匹林),History - Salicylates,Salicylates were first discovered when the observation was made that chewing willow bark could relieve pain Hippocrates (希波克拉底): Willow bark as a pain killer during childbirth Stone (1700) Extract of w

40、illow bark to reduce fever Piria (1838) Isolation of salicin(水杨苷) from willow bark Kolbe (1853) Synthesis of salicylate from salicin Von Gerhardt at Beyer Pharmaceutical Co. synthesized acetyl SA (ASA) in 1850 Hoffman, at Beyer gave ASA to his rheumatoid father Beyer started sales of Aspirin in1899

41、Acetylsalicylic acid (aspirin) was introduced as a pain reliever in 1899, at that time it was used in doses of 650 mg every 4 hours,History - Salicylates,Aspirin-Mechanism of Action: Covalent Binding to COX,ASA covalently and irreversibly modifies both COX-1 and COX-2 by acetylating serine-530 in th

42、e active site Acetylation results in a steric block, preventing arachidonic acid from binding,Note: Acetylation of COX-2 retains the COX activity although the reaction produces a different product, 15-R-HETE,Aspirin Metabolism Pathways,acetylsalicylic acid (ASA),ASA: t1/2 20 min,salicylate t1/2 3-5

43、hrs,irreversible acetylation of COX,- Salicylate elimination is 1st order at low and moderate doses; - When total body salicylate 600mg (3.5g/d), elimination is zero order,Uses of Aspirin,Dose-Dependent Effects: Low: 300mg blocks platelet aggregation Intermediate: 300-2400mg/day antipyretic and anal

44、gesic effects High: 2400-4000mg/day anti-inflammatory effects,Salicylism(水杨酸中毒),耳鸣,中枢性过度换气,代谢性酸中毒,脱水,低凝血酶原血症,Side effects of aspirin,Gastrointestinal symptoms CNS toxicity / Salicylate reaction Anaphylaxis (asthma) Metabolic acidosis, respiratory alkalosis Hepatic damage / Reyes syndrome Renal damag

45、e Hematologic effects,NSAIDs: Classification by Plasma Elimination Half Lives,Short Half Life ( 10 hours): slower onset of effect and slower clearance Naproxen (萘普生，14 2 hrs) Sulindac (舒林酸，14 8 hrs), Piroxicam (吡罗昔康，57 22 hrs),NSAIDs,Reversible Non-Selective COX inhibitors (for mild to moderate pain

46、),Generic Namedose (mg) interval,Ketorolac is indicated for the short-term (up to 5 days) management of moderately severe, acute pain, that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions,(萘普生),(布洛芬),(非诺洛芬),(吲哚美辛),(酮咯酸),COX-1 vs COX-2 Inhibition,CO

47、X-1 compared to COX-2,COX-2 selective inhibitors are generally larger molecules than NSAIDs and therefore preferentially inhibit COX-2 compared to COX-1 because the hydrophobic channel of COX-2 is larger. That is, COX-2 selective inhibitors are too bulky to access the binding pocket of the COX-1 enzyme,COX-2 Selective Drugs,COX-2 is also up-regulated in the CNS and plays an essenti