Part 10.Local anesthetics

( 局部麻醉药 )

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Peripheral mechanisms of pain2

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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.

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Mechanism of effects:

by blocking sodium influx of neural cell membrane.

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(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 ), respiratory para-lysis( 呼吸麻痹 ) dead. ②Cardiovascular effects heart inhibited, vasodilation, BP .

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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 ).

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Peripheral mechanisms of pain

①

② ③④⑤

(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 ).

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3. Local anesthetics most in use:

COCH2CH2N

OC2H5

H2N

C2H5

NHCCH2N

OC2H5

C2H5

CH3

CH3

COCH2CH2N

OCH3

CH3

HN

H9C4

普鲁卡因

procaine

利多卡因

lidocaine

丁 卡 因tetracaine

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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’ 2 ①②③④⑤ Tetracaine( 丁卡因 ): strongest, toxicity high, lipid solubility large, 120’ 10 ①○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 ).

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4. Influencing factors of anesthe- 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.

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

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Part 11. Antipyretic, analgesic, andanti-inflammatory drugs ( 解热镇痛抗炎药 ) —— Non-steroid anti-inflammatory

drugs (NSAIDs, 非甾体抗炎药 )

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1.General pharmacological properties(1)Inhibition of PG biosynthesis:

Phospholipids of cell menbrane Phospholipase A2 (PLA2, 磷脂酶 A2) Arachidonic acid ( 花生四烯酸 ) Cyclooxygenase Lipoxygenenase (Cox, 环氧酶 ) ( 脂氧酶 ) PGG2 5-HPETE

Prostaglandins(PGs) Leukotriene(LTs) ( 前列腺素 ) ( 白三烯 )

NSAIDs (-)

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(2)Products of Cyclooxygenase(COX)

Arachidonic acid ( 花生四烯酸 ) COX PGG2

合成酶 PGI2synthetase TXA2synthetase PGH2 Isomerase Reductase 异构酶 还原酶

PGI2 PGE2 PGF2 TXA2

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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. 17

(3)Cyclooxygenase(COX, 环氧酶 ) It can be divided into two kinds of 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.

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Most antipyretic ( 解热 ) and analgesic ( 镇痛 ) drugs are non-selective inhibitors to COX-1 and COX-2, but some

new drugs(such as celecoxib, 塞来昔布 ) are selective inhibitors to COX-2, the latter’s ADR is less.

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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 )

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(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.

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(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 ). PGs can act on heat-regulating center, to ↑ body temperature. Aspirin can inhibit the synthesis of PGs in hypothalamus, to treat fever.

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(2)Analgesic effect Aspirin inhibits COX-2, decrease

synthesis of PGE2 in the regions of pain. PG is an algogenic ( 致痛 ) substance and hyperalgic substance. (Bradykinin ( 缓激肽 ) is a main algogenic substance)

Aspirin can be used to treat pain of low-to-moderate intensity, such as headache, toothache, dysmenorrhea ( 痛经 ), muscular pain, neuralgia ( 神经痛 ), etc.

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(3)Anti-inflammation and anti-rheumatism:

Aspirin inhibit COX-2 and synthesis of PG in the inflammatory region, to

alleviate inflammation and symptoms. PG is 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 ).

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(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 ) of blood vessel catalyze PGI2 synthesis, promote vasodilation and platelet depolymerization ( 血小板解聚 ).

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Small dose(40mg/day) of Aspirin can inhibit COX-1 in platelet, TXA2 synthesis , inhibit platelet aggregation. Large dose of Aspirin can inhibit COX-1 in in intima of blood vessel, PGI2 synthesis , promote platelet aggregation.

Therefore, small dose Aspirin 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. 26

(5)Other clinical uses: ▲ Senile dementia( 老年性痴呆 ).

▲ Hypertension of pregnancy and preeclampsia( 先兆子痫 )

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2. Pharmacokinatics: (1)Absorption: It is absorbed fast in stomach by po.; (2)Biotransformation: Aspirin is transformed to salicylic acid ( 水

杨酸 ) form in the body;(3)Plasma protein binding rate: 80%-90%;(4) Metabolism: in liver by conjugation with glycine ( 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 ). 28

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 ), angioneurotic edema ( 血管神经性水肿 ), aspirin-induced asthma.

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Aspirin-induced asthma: Phospholipids of cell menbrane

Aspirin PLA2

(-) Arachidonic acid

Cyclooxygenase Lipoxygenenase ( 环氧酶 ) ( 脂氧酶 ) PGG2 5-HPETE

白三烯 Prostaglandin(PGs)

Leukotriene(LTs)

attack of asthma30

(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 )

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(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.32

(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.

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3. Adverse reaction: more and serious. 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.

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(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

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Ibuprofen( 布洛芬 )1. A potent anti-inflammatory agent, the anti-inflammatory effect is the same as Aspirin;

2. Used for rheumatic & rheumatoid arthritis, etc.

3. Adverse reaction: less. blurred vision, toxic amblyopia( 中毒性弱视 ).

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(E)Selective COX-2 inhibitor:

Celecoxib( 塞来昔布 ) 1. Pharmacological effects: Selectively inhibiting COX-2. 2. Clinical uses: to treat rheumatic and rheumatoid arthritis, t½=11.2 hr, 100 mg, bid.

3. Adverse reaction: less, mainly GI stimulation.

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(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%.38

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.

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Part 12.CNS stimulatants

( 中枢兴奋药 )

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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 )41

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 of antipyretic-analgesics( 解热镇痛药 ).

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(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.

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2. Clinical uses: (1)As a composition of drinks: to recover from fatigue ( 疲劳 ) and sleepy; (2)Compatibility( 配伍 ) with other drugs: Compatibility with antipyretic analge-sics( 解热镇痛药 ), can increase the latter’s analgesic effects, to treat common cold and headache; Compatibility with Ergotamine( 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 ): The preparation is caffeine sodium benzoate(CSB, 苯甲酸钠咖啡因 ), sc or im.

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3. Adverse reaction: Insomnia( 失眠 ); Convulsion/overdose, especially children in fever. But, the children in fever should not take the drug contained caffeine, such as APC(复方阿司匹林 ), to avoid leading to cause convulsion.

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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 depressant symptoms; (2)Stimulating respiratory center: but weaker; (3)Overdose: lead to Bp , headache, even convulsion.

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2. Clinical Uses: (1)Child enuresis( 小儿遗尿症 ): lightly stimulating cerebral cortex, easy to wake up by urinary feeling at night. (2)Central respiratory failure: such as severe 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, in 10% glucose 250~500ml, iv. gtt.

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(3)Child hyperactive syndrome: (儿童多动综合征 )

The patients of child hyperactive syndrome lack one of the neurotran-smitters of NA, DA, 5-HT in brain.

Ritalin can promote those neuro-transmitters release from the ending of

CNS, to control child hyperactive syndrome.

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Ⅱ. Drugs that mainly stimulatingrespiratory 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.49

Demifline(二甲弗林 , 回苏灵 ) Directly stimulating respiratory center of medulla oblongata;

The potency of Demifline is 100 times of Nikethamide ( 尼可刹米 ).

Used to central respiratory inhibition. 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. 50

Lobeline (山梗菜碱 , 洛贝林 )

　 Only indirect action: to stimulate chemoreceptor of carotid sinus (颈动脉窦 ) and aortic sinus( 主动脉窦 ), reflex stimulating respiratory center. Effect of stimulating respiration is milder and shorter, the margin of safety

is large, adverse reaction less, suitable to child. 51

应颂敏应颂敏yings@zju.edu.cnyings@zju.edu.cn 5252

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