non-steroidal anti-inflammatory drugs non-opioid analgesics & drugs used in gout shi-hong zhang...

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

shzhang713@zju.edu.cn

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

Phospholipase A2

Corticosteroids ⊕BrandykininAngiotensin

Cyclooxygenase （ COX ）

PGG2

Prostacyclin(PGI2)

PGE2

PGF2α

Thromboxane A2

Dipyridamole

hydroperoxidase

NSAIDs

Leukotrienes

5-lipoxygenase

Phospholipid

PGH2

Arachidonic acid

花生四烯酸

PGG25-LOX COX

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

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

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

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 :

The mechanism of aspirin: acetylating COX enzyme irreversibly

1. Aspirin

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

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

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

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

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

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

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.

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）

• 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.

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 )

• 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

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.

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

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

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

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 .

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 ).

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

Pharmacology of Local Anesthetics (LAs)

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

可卡因

普鲁卡因

丁卡因

苯佐卡因

酯类

利多卡因

甲哌卡因

布比卡因

依替卡因

丙胺卡因

酰胺类

Action site: voltage-gated Na+ channels

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

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

Infiltration anesthesia

Conduction anesthesia(cervical plexus)

Epidural anesthesia

Spinal anesthesia

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

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

Allergic Reactions

• Metabolite of ester LAs

– Para-aminobenzoic acid

– Allergen

• Allergy to amide LAs is extremely rare

CNS Toxicity

• Correlation between potency and seizure threshold– Bupivacaine

• 2 ug/ml

– Lidocaine• 10 ug/ml

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

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

Pharmacology of General Anesthetics

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)

Intravenous Anesthetics

Usually activate GABAA receptors, or block NMDA receptors

Induction of iv Anesthesia

Commonly used for initial anesthesia inductionalong with inhalational anesthetics

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

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

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

Inhalational anesthetic delivery system

Vaporizing the anesthetic liquid

Gas flowmeters

N NO

Nitrous Oxide (N2O)

Laughing gas

Diethyl Ether

Volatile liquids at room temperature

SevofluraneIsoflurane

Halothane

Rapid induction and recovery, less irritating to the trachea and less toxic to the heart

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]

MAC –minimum alveolar anesthetic concentration

MAC: The minimum alveolar concentration that results in immobility in 50% of subjects

Addition of MAC

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

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

Effects on ventilation

Respiratory Rate; Tidal Volume

Ventilation; PaCO2; Hypoxia Risk

Effects on brain

• Transition to unconsciousness 0.4 MAC

O2 consumption but Cerebral Blood Flow means potential injury with brain tumors/head injury (↑ pressure)

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

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)

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

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