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Non-steroidal Anti-Inflammatory Drugs Non-opioid Analgesics & Drugs Used in Gout
Shi-Hong Zhang ( 张世红 ), PhD Dept. of Pharmacology,
School of Medicine, Zhejiang University
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IntroductionTreatment inflammation:• Slow down or arrest of the tissue-damaging process • Relief of pain
Pharmacological treatment• Non-steroidal anti-inflammatory drugs (NSAIDs) & Drugs used in
gout• Glucocorticoids• Disease-modifying antirheumatic drugs (DMARDs)• Biologic response modifiers: eg. TNF-α inhibitors (etanercept依那西普 , infliximab英夫利昔单抗 , adalimumab阿达木单抗 ) , etc.
• Hyaluronic acid substitutes: hyalgan透明质酸钠 , synvisc欣维可
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Phospholipase A2
Corticosteroids ⊕BrandykininAngiotensin
Cyclooxygenase ( COX )
PGG2
Prostacyclin(PGI2)
PGE2
PGF2α
Thromboxane A2
Dipyridamole
hydroperoxidase
NSAIDs
Leukotrienes
5-lipoxygenase
Phospholipid
PGH2
Arachidonic acid
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花生四烯酸
PGG25-LOX COX
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感染原和细菌内毒素等外源性致热原
机 体
体温升高(发热)
体温调节中枢
内热原(细胞因子 IL-1 、 IL-6 、 TNF 等)
中枢 PGE2 的合成增加
NSAIDsNSAIDs(—)
COXCOX
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COX-1 COX-2
Synthesis intrinsic induced
Functions Physiological:•gastrointestinal protection•platelet aggregation regulation•vascular resistance regulation•renal blood flow regulation, especially in those with RAAS activation
Physiological: • production of PG
elevated during pregnancy
Pathological:• producing proteinase,
PG, and other inflammatory mediators
Comparison of COX-1 and COX-2
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抑制 COX-2抑制 COX-2
抑制 COX-1抑制 COX-1
解热、镇痛、抗炎
胃黏膜损害、出血
损害肾脏
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Aspirin and other salicylates (阿司匹林及水杨酸类)
Aniline derivatives (苯胺类衍生物):对乙酰氨基酚
Indole derivatives (吲哚类衍生物):吲哚美辛
Propionic acid derivatives (丙酸类衍生物):布洛芬
Others ( 选择性 COX-2 抑制剂,烯醇酸类,杂环芳基乙酸类,茚乙酸类,吡唑酮类,以及灭酸类等 )
Classification of NSAIDs :
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The mechanism of aspirin: acetylating COX enzyme irreversibly
1. Aspirin
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1.1 Actions and therapeutic uses:
A Antipyretic and analgesic actions:
-- resets the thermostat toward normal and lowers
the body temperature by increasing heat dissipation;
-- alleviates pain of low to moderate intensity arising
from integument, especially with inflammation.
1. Aspirin
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1.1 Actions and therapeutic uses:
B Anti-rheumatic actions: at large dose (4-6 g/d).
C Anti-aggregation of platelets and
vasoconstriction: at small dose (~100 mg/d),
irreversibly inhibits thromboxane production in
platelets without markedly affecting PGI2 in the
endothelial cells of the blood vessel.
1. Aspirin
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1.2 Adverse effects:
Gastrointestinal effects: epigastric distress, nausea
and vomiting, bleeding, ulcer (long term use).
Allergic effects:
Urticaria (风疹)Bronchoconstriction (aspirin asthma) angioneurotic edema
1. Aspirin
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1.2 Adverse effects:
Prolonged bleeding time
Excessive ventilation: respiratory alkalosis
Salicylism ( 水杨酸反应 ) : toxicity in the CNS (headache, dizziness, nausea, vomiting, tinnitus)
Reye’s syndrome: liver and brain injury in children with virus infection
1. Aspirin
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A 14-year-old white female was evaluated after a single ingestion of 120
tablets of aspirin 81 mg/tablet, extended-release, and 6 tablets of
ciprofloxacin 环丙沙星 approximately 2 hours prior to arrival to the
emergency department. Upon arrival, she denied nausea, diaphoresis 发汗 , abdominal pain, shortness of breath, or tinnitus. Vital signs were RR
18 breaths/min, HR 100 beats/min, BP 134/74 mm Hg, and T 36.5 °C.
The patient received 50 g of oral activated charcoal 活性炭 with sorbitol 山梨醇 for decontamination; no gastric emptying techniques were used. The
first salicylate concentration, drawn 4 hours after ingestion, was 1 mg/dL
(therapeutic range 10–20 mg/dL). Salicylate concentration 6 hours after
ingestion was 13 mg/dL, and the patient remained asymptomatic.
Case Study
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Serial salicylate concentrations were drawn every 4 hours due to the
persistent non-decreasing concentrations: 13 mg/dL at 8 hours, 14 mg/dL
at 13 hours, 14 mg/dL at 17 hours, and 18 mg/dL at 27 hours. The patient
remained asymptomatic until 35 hours after exposure, when she
developed dizziness, tinnitus, and epigastric discomfort. Her salicylate
concentration at that time was 46 mg/dL. Vital signs were RR 20
breaths/min, HR 80 beats/min, and BP 110/75 mm Hg. Laboratory tests
showed sodium 142 mEq/L, potassium 3.8 mEq/L, chloride 109 mEq/L,
CO2 19 mEq/L, anion gap 14 mEq/L, pH 7.5, pCO2 29 mm Hg, and pO2 96
mm Hg. A second dose of activated charcoal 50 g with sorbitol was
administered. A continuous infusion of sodium bicarbonate was started for
enhanced elimination. Intravenous potassium supplementation was also
started. The bicarbonate infusion was continued for approximately 30
hours with a steady decrease of the salicylate concentration to 10 mg/dL
60 hours after ingestion
Case Study
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2. Acetaminophen ( 对乙酰氨基酚 Tylenol)
• Together with phenacetin, they are aniline derivatives
( 苯胺类衍生物 )
• Slow and prolonged antipyretic and analgesic effects
• No obvious anti-inflammatory effect
• Less stimulation to gastrointestinal tract
• Causes damage of liver and kidney if used for a long
time and at high doses. Alcohol increases the chance
of hepatotoxicity.
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3. Indomethacin (吲哚美辛)
• One of the most potent inhibitors of COX
• High potency of anti-inflammatory, analgesic, and antipyretic activity
• Used for severe rheumatic diseases: ankylosing spondylitis ( 强直性脊柱炎 AS) , Osteoarthritis ( 骨关节炎 OA) and gout ( 痛风 ).
• Effective in treating patent ductus arteriosus (动脉导管未闭)
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• High incidence of adverse effects like:
central nervous system effect
gastrointestinal complaints
allergic reactions
hematopoietic ( 造血的 ) reactions
3. Indomethacin
Sulindac ( 舒林酸 ) and Etodolac ( 依托度酸 ) are less toxic and used for OA, RA, AS and acute gout.
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4. Propionic acid derivatives (丙酸类)
• Include ibuprofen 布洛芬 , naproxen 萘普生 , ketoprofen 酮洛芬 , etc
• Anti-inflammatory, analgesic and antipyretic activities
• Less gastrointestinal effects
• Change platelet function and prolong bleeding time
• Widely used for the treatment of inflammation induced by rheumatic diseases and dysmenorrhea ( 痛经 )
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• Include celecoxib 塞来昔布( selective ) , meloxicam 美洛昔康 , nimesulide 尼美舒利 , etc
• Less adverse effects than non-selective COX inhibitors (platelets aggregation, stomach mucus damage, gastrointestinal hemorrhage)
• Used for the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory pain, including acute gout.
• Selective COX2 inhibitors are suspected to be related to an increase in the risk for heart attack, thrombosis and stroke.
5. COX-2 inhibitors
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6. Other NSAIDs
• Piroxicam ( 吡罗昔康 ): similar efficacy to aspirin in
anti-inflammatory effect, used for long term treatment
of OA and RA, less side effects in GI tract.
• Phenylbutazone ( 保泰松 ) : high potency of anti-
inflammatory activity, low potency of antipyretic
effect, more adverse effects than other NSAIDs.
Chiefly prescribed in short term therapy of acute
gout and in acute rheumatoid arthritis.
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氯丙嗪
效应 抑制体温调节 增加散热
作用机制 抑制体温调节中枢 抑制环加氧酶抑制 PGE2 的合成和释
放特点 1 .环境温度低——降温环境温度越低,降温越显著可降发热、正常体温2 .高温环境——升温
只降发热体温不降正常体温
用途 人工冬眠疗法(降温) 治疗发热
解热镇痛药与氯丙嗪降温作用比较
NSAIDs
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解热镇痛药与阿片类镇痛药镇痛作用比较 阿片类镇痛药 解热镇痛药
作用部位 中枢 外周(主)
作用机制 激动阿片受体 抑制环氧酶,使 PG 合成减少
镇痛特点 强大,伴有镇静作用及欣快感
中等强度,无镇静作用及欣快感
适应证 用其他药无效的急慢性锐痛
慢性炎性痛及体表部位手术后疼痛
不良反应 易成瘾,抑制呼吸 无成瘾性及呼吸抑制
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NSAIDs Glucocorticoid
作用机制
临床应用
主要不良反应 胃肠道反应
风湿、类风湿、创伤导致的炎症
各种炎症
多种不良反应如代谢障碍 , 免疫抑制
抑制 COX ,减少PG 合成
抑制多种炎症因子,包括抑制 PLA2 ,抑制 COX 表达
解热镇痛药与糖皮质激素的抗炎作用比较
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Other drugs used for rheumatic diseases
• Disease-modifying antirheumatic drugs (DMARDs) 甲氨蝶呤 , 羟氯喹 , 柳氮磺胺吡啶 , 硫唑嘌呤,来氟米特 , 金制剂,青霉胺,
雷公藤, etc.
• 用于 NSAIDs 疗效不好的患者,常采用二药或三药的联合用药方案;• 不能迅速抗炎和止痛,通常 2-4 个月显示效果;• 可改善病情和延缓病情进展,患者血沉、血浆蛋白、类风湿因子
(rheumatoid factor , RF) 等较 NSAIDs 更有效地恢复正常 ;
• 需长期治疗,不能使已经受到破坏的关节复原 .
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Other drugs used for rheumatic diseases
• Biologic response modifiers
TNF-α inhibitors (etanercept 依那西普 , infliximab英夫利昔单
抗 , adalimumab 阿达木单抗 );
abatacept 阿巴西普,是 IgG1 的 Fc 片段与 CLTA-4 胞外区域的融合蛋
白,传递抑制信号到 T 细胞,抑制免疫攻击作用;
B 细胞 CD20单克隆抗体 (rituximab利妥昔单抗 ): 抑制 B 细胞功
能 ;
IL-1 受体拮抗剂 (anakinra, 阿那白滞素 ).
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Other drugs used for rheumatic diseases
• Corticosteroids: prednisone, methylprednisolone, etc
1 2
3 4
56 7
810 9
121314 15
16 18
19
A B
C D
H
• 抑制免疫和炎症反应,改善症状;停药易复发,长期用药不良反应多,不作为首选或单独应用 ;
• 小剂量 ( 泼尼松<10mg/d 或等效其他激素 ) 缓解症状 , 作为 DMARDs起效前的桥梁 ;
• 关节腔注射,减轻症状 , 改善功能
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Pharmacology of Local Anesthetics (LAs)
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Local Anesthetics (LAs)
• Reversibly block nerve conduction
• Act on every type of nerve fibers:
non/thin myelinated sensory fibers
myelinated sensory fibers
autonomic fibers
motor fibers
• Also act on cardiac muscle, skeletal muscle and the brain
• No structural damage to the nerve cell
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可卡因
普鲁卡因
丁卡因
苯佐卡因
酯类
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利多卡因
甲哌卡因
布比卡因
依替卡因
丙胺卡因
酰胺类
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Action site: voltage-gated Na+ channels
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Actions of LAs
• Ionic gradient and resting membrane potential are unchanged
• Only bind in the inactivated state: use dependent
• Decrease the amplitude of the action potential
• Slow the rate of depolarization
• Increase the firing threshold
• Slow impulse conduction
• Prolong the refractory period
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Types of local anesthesia
Topical local (surface) anesthesia: for eye, ear, nose, and throat procedures and for cosmetic surgery
Infiltration anesthesia: local injection around the region to be operated.
Conduction anesthesia: local injection around the peripheral nerve trunk
Epidural anesthesia: local injection into the epidural space
Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity
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Infiltration anesthesia
Conduction anesthesia(cervical plexus)
Epidural anesthesia
Spinal anesthesia
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Pharmacokinetics
• LAs bind in the blood to a1-glycoprotein and albumin
• There is considerable first-pass uptake of LAs by the liver
• LAs enter the blood stream by:
– Direct injection
– Absorption• Epinephrine decreases this via vasoconstriction• Peak concentrations vary by site of injection
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Metabolism of LAs
• Esters (rapid)– Hydrolyzed in the plasma by
pseudocholinesterase• Break down product – para-aminobenzoic acid ( 对
苯氨甲酸 )
• Amides (slower)– Occurs in the endoplasmic reticulum of
hepatocytes• Tertiary amines are metabolized into secondary
amines that are then hydrolyzed by amidases
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Allergic Reactions
• Metabolite of ester LAs
– Para-aminobenzoic acid
– Allergen
• Allergy to amide LAs is extremely rare
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CNS Toxicity
• Correlation between potency and seizure threshold– Bupivacaine
• 2 ug/ml
– Lidocaine• 10 ug/ml
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Cardiovascular Toxicity
• Attributable to their direct effect on cardiac muscle
• Contractility
– Negative inotropic effect that is dose-related and correlates with potency
– Interference with calcium signaling mechanisms
• Automaticity
– Negative chronotropic effect
• Rhythmicity and Conductivity– Ventricular arrhythmias
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Comparison of LAs
Potency Toxicity Permeability Application
Procaine Weak Low (allergic)
Weak Not for topical, skin test
Tetracaine Strong High Strong Especially topical ,Not for infiltration
Lidocaine Strong Low Strong All kinds
Ropivacaine Strong Low Strong Epidural and conduction
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Pharmacology of General Anesthetics
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General Anesthetics
• General anesthesia: analgesia, amnesia, loss of
consciousness, inhibition of sensory and autonomic
reflexes, and skeletal muscle relaxation.
• Intravenous anesthetics (barbiturates, etc)
• Inhalational anesthetics (gases, or volatile liquids)
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Intravenous Anesthetics
Usually activate GABAA receptors, or block NMDA receptors
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Induction of iv Anesthesia
Commonly used for initial anesthesia inductionalong with inhalational anesthetics
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Inhalational Anesthetics
• Many different, apparently unrelated molecules produce general anesthesia
– ineert gases (xenon), simple inorganic (N2O) &
organic compounds (diethyl ether), more complex organic compounds (Halothane, etc)
• Characteristics – rapid onset (emergence), rapid recovery, relationship between lipid solubility & potency
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Stages of Anesthesia (ether)
• Stage I: analgesia – sensory block in spinal cord, and later amnesia
• Stage II: paradoxical excitation (irregular respiration, retching, vomiting, struggle, possible asphyxia) due to loss of some inhibitory tone and direct stimulation of excitatory transmission
• Stage III: surgical anesthesia – block of the ascending reticular activating system, loss of eyelash reflex, recovery of regular breath and cessation of spontaneous respiration
• Stage IV: failure – cardiovascular and respiratory collapse due to excessive inhibition
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Signs for Anesthesia Depth
• Tachycardia• Hypertension• Eyelid reflex• Lacrimation• Swallowing• Laryngospasm
(involuntary spasm of the laryngeal cords)
• Movement
TOO LIGHT TOO DEEP• Hypotension• Organ failure
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Inhalational anesthetic delivery system
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Vaporizing the anesthetic liquid
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Gas flowmeters
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N NO
Nitrous Oxide (N2O)
Laughing gas
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Diethyl Ether
Volatile liquids at room temperature
SevofluraneIsoflurane
Halothane
Rapid induction and recovery, less irritating to the trachea and less toxic to the heart
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Speed of anesthesia induction
Higher solubility (shown as a larger blood box) means gas rapidly moves into blood, but concentration that reaches brain increases more slowly.
Blood:gas partition coefficient(an index for solubility): =[blood]/[alveoli]
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MAC –minimum alveolar anesthetic concentration
MAC: The minimum alveolar concentration that results in immobility in 50% of subjects
Addition of MAC
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Factors that alter MAC• Increase MAC – Being young, hyperthermia,
chronic ETOH, CNS stimulants, hyperthyroidism
• Decrease MAC – Old age, hypothermia, acute ETOH, CNS depressant drugs including narcotics & benzodiazepines
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General characteristics
• Analgesia – weak except for nitrous oxide• Potency – high, except for nitrous oxide• Muscle Relaxation – some, but weak• Airway irritation – desflurane worst, sevoflurane
best tolerated• Primary effect on conductive tissue – inhibitory• Primary effect on smooth muscle – relaxation• Primary effect on macrophages -- inhibitory
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Effects on ventilation
Respiratory Rate; Tidal Volume
Ventilation; PaCO2; Hypoxia Risk
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Effects on brain
• Transition to unconsciousness 0.4 MAC
O2 consumption but Cerebral Blood Flow means potential injury with brain tumors/head injury (↑ pressure)
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Liver toxicity
• “Halothane Hepatitis”
• Incidence post Halothane – 0.003%
• Symptoms – fever, anoreexia, nausea & vomiting that occur 2 - 5 days post-op
• Eosinophilia; altered liver function
• Rare – liver failure & death
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Malignant hyperthermia
• Hypermetabolic syndrome – hyperthermia, CO2, tachycardia, cyanoosis, muscle rigidity
• Triggered by halogenated anesthetics & depolarizing muscle relaxants
• Familial relationship, i.e. genetic heterogeneity– mutation in Ca2+ reuptake
• Incidence, ~ 1/14,000 anesthesia (0.01%)
• Specific Treatment – Dantrolene (inhibit Ca2+ release from the sarcoplasmic reticulum)
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Nitrous oxide toxicity
• Bone Marrow Depression – megaloblastic, inhibition of B12 dependant enzymes
• Peripheral neuropathy
• Expansion of closed air spaces – bowel obstruction, pneumothorax, bullous emphysema, middle ear obstruction, pneumocephalus
• CNS injury – adults & neonates
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NITROUS OXIDE KILLS NEURONS IN THE YOUNG AND THE OLD
• Developing rat brain
• Exposure to a combination including nitrous, isoflurane & midazolam
• Persistent learning deficits
Early apoptosisEarly apoptosis
Late apoptosisLate apoptosis
control
exposed