Part 10. Local anesthetics (局部麻醉药)

1. Part 10. Local anesthetics (局部麻醉药)

2. Peripheral mechanisms of pain

4. 1. Pharmacological effects: (1)Local anesthetic effects: local analgesia(局部痛觉消失) ① Characteristics of effects: ▲non-specific. ▲reversibility. ② Mechanism of effects: by blocking sodium influx of neural cell membrane.

5. Mechanism of effects: by blocking sodium influx of neural cell membrane.

6. (2)Systemic effects(全身作用) (absorptive effects, 吸收作用): ①CNS effects: Initial time,exciting: vertigo(眩晕),dysphoria(烦躁),anxi-ety(焦虑), muscular tremor(肌肉震颤), Later mental confusion(精神错乱), convulsion(惊厥), Last coma(昏迷),respiratorypara-lysis(呼吸麻痹) dead. ②Cardiovascular effects heart inhibited,vasodilation, BP .

7. 2. Main methods of local anes-thesia(主要的局麻方法): (1)Surface anesthesia(表面麻醉) (2)Infiltration anesthesia(浸润麻醉) (3)Conduction anesthesia(传导麻醉) (4)Epidural ansthesia(硬膜外麻醉) (5)Subarachoid anesthesia(蛛网膜下腔麻醉)or Spinal anesthesia(脊髓麻醉或腰麻).

8. (1)Surface anesthesia(表面麻醉) (2)Infiltration anesthesia(浸润麻醉) (3)Conduction anesthesia(传导麻醉) (4)Epidural ansthesia(硬膜外麻醉) (5)Subarachoid anesthesia(蛛网膜下腔麻醉)or Spinal anesthesia(脊髓麻醉或腰麻). ① ④ ⑤ ③ ② Peripheral mechanisms of pain

10. 3. Local anesthetics most in use: 普鲁卡因procaine 利多卡因lidocaine 丁 卡 因tetracaine

11. 3. Local anesthetics most in use: Procaine(普鲁卡因): weak, lipid solubility small, toxicity small, safety. 30’～ 45’ 1○②③④⑤ Lidocaine(利多卡因): stronger, toxicity small, lipid solubility large, safety. 90’ 2①②③④⑤ Tetracaine(丁卡因): strongest, toxicity high, lipid solubility large, 120’ 10①○③④⑤ Bupivacaine(布比卡因): 3 ～ 4 times stronger than Lidocaine. 120’6.5○②③④○ (1)Surface anesthesia(表面麻醉) (2)Infiltration anesthesia(浸润麻醉) (3)Conduction anesthesia(传导麻醉) (4)Epidural ansthesia(硬膜外麻醉) (5)Subarachoid anesthesia(蛛网膜下腔麻醉)or Spinal anesthesia(脊髓麻醉或腰麻).

12. 4. Influencingfactorsofanesthe- tic effect: (1)Size of nerves & nerve fibers; (2)pH of body fluid; (3)Medicated with vasoconstrictors: ▲prolong duration of action; ▲decrease systemic absorption; ▲decrease operative bleeding.

13. 5. Adverse reactions: (1)Toxic reaction: ①CNS effects; ②Cardiovascular effects: Preventive measures: ▲separate administration; ▲put a littleadrenalineintolocal anesthetics solution: 1/250,000 ～ 1/500,000. (2)Anaphylaxis(过敏反应): Preventive measures: ▲skin test; ▲small dose begin; Emergency treatment.

14. Part 11. Antipyretic, analgesic, and anti-inflammatory drugs (解热镇痛抗炎药) —— Non-steroid anti-inflammatory drugs(NSAIDs, 非甾体抗炎药)

15. NSAIDs 1.Generalpharmacologicalproperties (1)Inhibition of PG biosynthesis: Phospholipids of cell menbrane PhospholipaseA2 (PLA2, 磷脂酶A2) Arachidonic acid (花生四烯酸) CyclooxygenaseLipoxygenenase (Cox, 环氧酶)(脂氧酶) PGG2 5-HPETE Prostaglandins(PGs)Leukotriene(LTs) (前列腺素)(白三烯) (-) 

16. (2)Products ofCyclooxygenase(COX) Arachidonic acid (花生四烯酸) COX PGG2 合成酶 PGI2synthetase TXA2synthetase PGH2 IsomeraseReductase 异构酶还原酶 PGI2 PGE2 PGF2TXA2

17. Effects of products of COX: PGE2 : inducing inflammation, fever, algogenic (致痛) effect, uterine constriction (子宫收缩); PGF2: bronchoconstriction, vaso- constriction; PGI2 :platelet depolymerization (血小板解聚); vasodilation, TXA2 :platelet aggregation (血小板聚集), vasoconstriction.

18. (3)Cyclooxygenase(COX, 环氧酶) It can be divided intotwo kindsof isoforms(同功酶):COX-1, COX-2. COX-1 is a constitutive isoform found in blood vessel, stomach, and kidney, it regulates vessel constriction and relaxation, secretion of gastric acid, and renal blood flow. COX-2 is a induced isoform that can be induced by cytokines and inflammatory mediators in settings of inflammation, to promote inflammation.

19. Most antipyretic (解热) and analgesic (镇痛) drugs are non-selective inhibitors toCOX-1andCOX-2, butsomenew drugs(such as celecoxib, 塞来昔布) are selective inhibitors to COX-2, the latter’s ADR is less.

20. 2. Classification of antipyretic, anal- gesic and anti-inflammatory drugs according to chemical structure: (A)Salicylates:Aspirin(阿司匹林) (B)Aminobenzene derivatives: Paracetamol(对乙酰氨基酚) (C)Indole derivatives: Indomethacin(吲哚美辛) (D)Propionic acid derivatives: Ibuprofen(布洛芬) (E)Selective COX-2 inhibitor: Celecoxib(塞来昔布) (F)Others:Phenylbutazone(保泰松)

21. (A)Salicylates: Acetylsalicylic acid(乙酰水杨酸, Aspirin,阿司匹林) 1. Pharmacological effects and clinical uses: Aspirin can inhibit COX-1 and COX-2,there are antipyretic, analgesic, anti-inflammatory and anti-rheumatic effects, etc.

22. (1)Antipyretic effect: Endogenous pyrogen(内源性致热原, interleukin-1, 白介素-1, IL-1) can stimulated synthesis of PGs (especially PGE2 ) in hypothalamus (下丘脑). PGscan act on heat-regulating center, to ↑ body temperature. Aspirincan inhibit the synthesis of PGs in hypothalamus, to treat fever.

23. (2)Analgesic effect Aspirininhibits COX-2, decreasesynthesis of PGE2 in the regions of pain. PGis an algogenic (致痛) substance and hyperalgicsubstance.(Bradykinin (缓激肽)is a main algogenic substance) Aspirin can be used to treat pain of low-to-moderate intensity, such asheadache, toothache, dysmenorrhea (痛经), muscular pain, neuralgia (神经痛), etc.

24. (3)Anti-inflammation and anti-rheumatism: AspirininhibitCOX-2 and synthesisof PGintheinflammatoryregion, toalleviateinflammationandsymptoms. PGis an inflammatory substance. Aspirin can be used ① to treat acute rheumatic fever(急性风湿热), ② to abate pain and symptoms of rheumatic & rheumatoid arthritis (风湿性和类风湿性关节炎).

25. (4)Inhibition of platelet aggregation: COX-1 and TXA2 (血栓素) synthetase in platelet catalyze TXA2 synthesis, to promote platelet aggregation. COX-1 and PGI2 synthetase in intima(内膜)ofbloodvesselcatalyze PGI2 synthesis, promote vasodilationand platelet depolymerization (血小板解聚).

26. Small dose(40mg/day) of Aspirin can inhibit COX-1 in platelet, TXA2 synthesis , inhibit platelet aggregation. Large doseof Aspirin can inhibit COX-1 in in intimaof blood vessel, PGI2 synthesis , promote platelet aggregation. Therefore, small doseAspirin can be used to prevent coronary artery thrombosis (血栓形成),to treat ischemic (缺血) heart disease, and reduce the mortality of myocardiac infarction (心肌梗死), and prevent cerebral thrombosis (脑血栓) too.

27. (5)Other clinical uses: ▲Senile dementia(老年性痴呆). ▲Hypertensionof pregnancy and preeclampsia(先兆子痫)

28. 2. Pharmacokinatics: (1)Absorption: It isabsorbed fast instomach by po.; (2)Biotransformation: Aspirinis transformed to salicylic acid (水杨酸) form in the body; (3)Plasmaproteinbindingrate: 80%-90%; (4) Metabolism: inliverbyconjugationwithglycine (甘氨酸) and glucuronic acid (葡糖醛酸); (5) Elimination: When the dose ＞1g, Nonlinear elimination kinetics (zero-order kinetics 零级动力学).

29. 3. Adverse reaction: (1)Gastrointestinal reactions: irritation and hemorrhea (大出血). (2)Prolongation of bleeding time: inhibit platelet aggregation and synthesis of thrombogen(凝血酶原). Contraindications: One week prior to surgery; Severe hepatic damage, Vitamin K deficiency, Prothrombinopenia(凝血酶原减少症). (3)Allergy: urticaria(荨麻疹), angioneuroticedema (血管神经性水肿), aspirin-induced asthma.

30. Aspirin-induced asthma: Phospholipids of cell menbrane AspirinPLA2 (-) Arachidonic acid Cyclooxygenase Lipoxygenenase (环氧酶) (脂氧酶) PGG2 5-HPETE 白三烯 Prostaglandin(PGs)Leukotriene(LTs) attack ofasthma

31. (4)Salicylism (水杨酸反应): dose > 5g/d: CNS symptoms, even mental disorder; hyperventilation (换气过度). iv NaHCO3 can promote the excretion of Aspirin. (5)Hepatic damage: Overdose  hepatic damage; Reye’s syndrome(瑞夷综合征): in children,severe hepatic damage(严重的肝损害) and encephalopathy(脑病)

32. (B)Aminobenzene derivatives: Acetaminophen(对乙酰氨基酚, Paracetamol, 扑热息痛) It is the metabolite of phenacetin(非那西丁)in the body.Its antipyretic and analgesic effects are mild and lasting, but anti-inflammatory effects is less. It is a higher selectivity to COX in the central nervous system. Common mainly used in cold, fever, and headache, etc. Overdose can damage liver & kidney.

33. (C)Indole derivatives: Indomethacin(吲哚美辛) 1. Potent anti-inflammatory agent It is a non-selective inhibitor to COX.Its antipyretic, analgesic, and anti-inflammatory effects are very strong. 2. Clinical uses: Rheumatic and rheumatoid arthritis; Ankylosing spondylitis(强直性脊髓炎); Osteoarthritis(骨关节炎); Some types of fever.

34. 3. Adverse reaction: more andserious. GI reaction; CNS symptoms (headache, vertigo); hematological reactions (WBC↓, platelet↓); allergy(skin rash, asthma). Sulindac(苏林酸) It is a prodrug and appears inactive in vitro, but its metabolite in vivo is very active and as an strong inhibitor of COX. Its GI reaction is very mild.

35. (D)Propionic acid derivatives: There are Naproxen(萘普生), Ibuprofen(布洛芬), etc. Naproxen(萘普生) 1. Anti-inflammatory effect: A potent anti-inflammatory agent, the potency is stronger than Aspirin 20 times; 2. Clinical uses: Used for rheumatic and rheumatoid arthritis, t ½ 14 hr, bid. 3. Adverse reaction:less, blurred vision

36. Ibuprofen(布洛芬) 1. Apotentanti-inflammatoryagent, the anti-inflammatory effect is the same as Aspirin; 2. Usedforrheumatic&rheumatoid arthritis, etc. 3. Adverse reaction: less. blurred vision, toxic amblyopia(中毒性弱视).

37. (E)Selective COX-2 inhibitor: Celecoxib(塞来昔布) 1. Pharmacological effects: Selectively inhibiting COX-2. 2. Clinical uses: totreatrheumaticandrheumatoid arthritis, t½=11.2 hr, 100 mg, bid. 3.Adverse reaction: less, mainly GI stimulation.

38. (F)Others: Oxyphenbutazone(羟基保泰松) 1. Potent anti-rheumatic agent; 2. Clinical uses: Rheumatic & rheumatoid arthritis; 3. Adverse reaction: GI reaction; retention of water and sodium (水钠潴留); Allergy; lever & kidney damage; thyroid enlargement (甲状腺肿大) and mucous edema (黏液水肿), etc. 4. Drug interaction: Plasma protein binding rate: 98%.

39. Diclofenac(双氯芬酸) 1. Effects: Belong to fenamates(灭酸类), the potency inhibiting COX is stronger than indomethacin (吲哚美辛). 2. Clinical Uses: Used for rheumatic & rheumatoid arthritis, etc. 3. Adverse reaction: More.

40. Part 12. CNS stimulatants (中枢兴奋药)

41. CNS stimulatants can be divided into 3 kinds: (1)Drugs that mainly stimulating cerebral cortex (大脑皮层): Caffeine (咖啡因) (2)Drugs that mainly stimulating medulla oblongata (延髓) respiratory center: Nikethamide (尼可刹米) (3)Drugs stimulating spinal cord (脊髓): Strychnine (士的宁)

42. Ⅰ. Drugs that mainly stimulating cerebral cortex: Caffeine (咖啡因) 1. Pharmacological effects: (1)Small dose: ① stimulating cerebral cortex, in high spirits, eliminating tire, promoting work efficiency; ② can contract cerebral vessel, bring down the intracranial pressure (颅内压); ③ can strengthen the effects ofantipyretic-analgesics(解热镇痛药).

43. (2)Larger dose: To excite respiratory center and vasomotor (血管舒缩) center of medulla oblongata (延髓) directly, to make respiration deep and fast, myocardial contractive force, heart rate, cardiac output, Bp. lead to insomnia. (3)Overdose: lead to convulsion (抽搐), especially in children.

44. 2. Clinical uses: (1)As a composition of drinks: to recover from fatigue (疲劳) and sleepy; (2)Compatibility(配伍)withother drugs: Compatibility withantipyretic analge-sics(解热镇痛药), can increase the latter’s analgesic effects,to treat common cold and headache; Compatibility withErgotamine(麦角胺)can be used to treat migraine(偏头痛). (3)Emergency treatment of respiratory and circulatory failure (呼吸循环衰竭): Thepreparation iscaffeinesodium benzoate(CSB, 苯甲酸钠咖啡因), sc or im.

45. 3. Adverse reaction: Insomnia(失眠); Convulsion/overdose, especially children in fever. But, the children in fever should nottake the drug containedcaffeine,suchasAPC(复方阿司匹林), to avoid leading to cause convulsion.

46. Methylphenidate(哌甲酯, Ritalin, 利他林) 1. Pharmacological effect: a milder central stimulants. (1)Stimulating mental activity: more potent,can excite spirit & eliminate depressantsymptoms; (2)Stimulating respiratory center: but weaker; (3)Overdose: lead to Bp , headache, even convulsion.

47. 2. Clinical Uses: (1)Child enuresis(小儿遗尿症): lightlystimulatingcerebralcortex, easy to wake up by urinary feeling at night. (2)Central respiratory failure: such assevere infection disease, overdose of central inhibitor, etc. 呼吸三联针: Ritalin (利他林) 20 mg, Lobeline (洛贝林)12 mg, Demifline (回苏灵)16 mg, in10% glucose 250~500ml, iv.gtt.

48. (3)Child hyperactive syndrome: (儿童多动综合征) The patients of child hyperactive syndrome lackoneoftheneurotran-smitters of NA, DA, 5-HTinbrain. Ritalincan promote those neuro-transmittersreleasefromtheendingofCNS, tocontrolchild hyperactive syndrome.

49. Ⅱ. Drugs that mainly stimulating respiratory center: Nikethamide(尼可刹米, Coramine,可拉明) (1)Direct action: stimulating respiratory center of medulla oblongata; (2)Indirect action: stimulating chemoreceptor of carotid sinus (颈动脉窦)& aortic sinus (主动脉窦), reflexly stimulating respiratory center. The effect is shorter(5’~10’) and milder. Convulsion/overdose.

50. Demifline(二甲弗林, 回苏灵) Directly stimulatingrespiratory center of medulla oblongata; The potency of Demifline is 100 times of Nikethamide (尼可刹米). Usedto centralrespiratoryinhibition. im. or iv. Characteristics : to take effect fast, the curative effect well, and the rate of resuscitation high. Convulsion/overdose. if iv, should inject slowly after dilution.