Antipyretic, Analgesic, and Anti-inflammatory Drugs

(Non-steroidal anti-inflammatory drugs, NSAIDs)

Arachidonic acid

Phospholipase A2

Corticosteroids ⊕ BradykininAngiotensin

Cyclooxygenase (COX)

PGG2Prostacyclin(PGI2)

PGE2

PGF2α

Thromboxane A2 Dipyridamole

hydroperoxidase

NSAIDs

Leukotrienes

5-lipoxygenase

Phospholipid

PGH2

TXA synthase

花生四烯酸

COX-1 COX-2

Synthesis intrinsic induced

Functions physiological:

gastrointestinal protection

platelet aggregation regulation

vascular resistance regulation

renal blood flow regulation

physiological: production of PG elevated during pregnancy

pathological:

producing proteinase, PG, and other inflammatory mediators

Characteristics comparison between 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）

Indole derivatives （吲哚类衍生物）

Propionic acid derivatives （丙酸类衍生物）

Others ( 烯醇酸类，灭酸类，杂环芳基乙酸类，茚乙酸类，吡唑酮类，以及选择性 COX-2 抑制剂 )

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

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 PG的合成增加 解热镇痛药解热镇痛药（—）

氯丙嗪

效应 抑制体温调节 解热

作用机制 抑制体温调节中枢 抑制环加氧酶抑制 PGs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 用其他药无效的急性锐痛 慢性钝痛

不良反应 易成瘾，抑制呼吸 无成瘾性及呼吸抑制

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

2. Acetaminophen （对乙酰氨基酚） Slow and prolonged antipyretic and

analgesic effects No obvious anti-inflammation effect Less stimulation to gastrointestinal tract Damage of liver and kidney if used for a

long time and at high dose

3. Propionic acid derivatives （丙酸类）

Includes ibuprofen ( 布洛芬 ), naproxen ( 萘普生 ), etc Anti-inflammatory, analgesic and antipyretic activity Less gastrointestinal effects Change platelet function and prolong bleeding time Used for the treatment of various arthritis and

dysmenorrhea ( 痛经 )

4. Indomethacin （吲哚美辛）

One of the most potent inhibitors of COX High potency of anti-inflammatory, analgesic, and

antipyretic activity Used for 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 reactions

Sulindac ( 舒林酸 ) and Etodolac ( 依托度酸 ) are less toxic and used for OA, RA, AS and acute gout.

4. Indomethacin

5. Selective COX-2 inhibitors

Less incidence of gastrointestinal upset

(peptic ulceration, bleeding)

Related to an increase in the risk for heart attack, thrombosis and stroke.

Include celecoxib ( 塞来昔布 ), refecoxib ( 罗非昔布 ), nimesulide ( 尼美舒利 ), etc

6. Inhibitors of TNF-

TNF- is the predominant factor in inflammatory reaction.

Include etanercept ( 依那西普 ), infliximab ( 英夫利西单抗 ), adalimumab ( 阿达木单抗 )

Used for the treatment of RA, AS and other autoimmune diseases.

General anesthetics and barbiturates for anesthesia ( 麻醉 )

Local anesthetics and opioids for both anesthesia and analgesia ( 镇痛 )

Clinical relief of acute pain

What is anesthesia?

Definition – “induced, reversible insensibility to surgical stimulation”

Anesthesia is necessary for some diagnostic, therapeutic, and surgical intervention

Anesthetics are a class of drugs that produce anesthesia, not all induce unconsciousness

Anesthetics

General anesthetics: Some administered as gases or “vapors”, others can be given intravenously

Local anesthetics: local application

Before October 16, 1846 "Suffering so great as I underwent cannot be

expressed in words . . . but the blank whirlwind of emotion, the horror of great darkness, and the sense of desertion by God and man, which swept through my mind, and overwhelmed my heart, I can never forget.”

-Ashhurst J Jr , Surgery before the days of anesthesia, 1997

http://content.nejm.org/cgi/reprint/348/21/2110.pdf

On October 16, 1846, William Morton, a dentist at Massachusetts General Hospital, employed ether in the surgical removal of a tumor

with no signs or reports of pain in the patient.

History 1846, Ether 1860, Cocaine 1884, N2O 1905, Procaine 1934, Thiopental 1943, Lidocaine ……

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)

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 LAsPotency 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) Inhaled anesthetics (gases, or volatile

liquids)

Intravenous Anesthetics

Usually activate GABAA receptors, or block NMDA receptors

硫喷妥钠

咪达唑仑

丙泊酚

依托咪酯 氯胺酮

Induction of iv anesthesia

Commonly used for initial anesthesia inductionalong with inhalation anesthetics

Inhaled anesthetics Many different, apparently unrelated

molecules produce general anesthesia

– innert gases, simple inorganic & organic compounds, more complex organic compounds

Characteristics – rapid onset (emergence), rapid reversibility, 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 breath, retching, vomiting, struggle) due to loss of some inhibitory tone and direct stimulation of excitatory transmission

Stage III: surgical anesthesia – block of the ascending reticular activating system

Stage IV: failure – cardiovascular and respiratory collapse due to inhibition

Signs for anesthetic depth

Tachycardia Hypertension Eyelid reflex Lacrimation 流泪 Swallowing Laryngospasm 喉痉

挛 (involuntary spasm of the laryngeal cords

Movement

TOO LIGHT TOO DEEP• Hypotension• Organ failure

Inhaled anesthetic delivery system

Vaporizing the anesthetic liquid

Gas flowmeters

N NO

Nitrous Oxide (N2O)

Laughing gas

Diethyl Ether

Volatile liquids at room temperature

Sevoflurane ( 七氟烷 )Isoflurane

Halothane

Induction of anesthesia

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 median concentration that results in immobility in 50% of patients

Addition of MAC

Factors that alter MAC

Increase MAC – Being young, hyperthermia, chronic ETOH, CNS stimulants, hyperthyroidism ( 甲状腺功能亢进 )

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, anorexia, nausea & vomiting that occur 2 - 5 days post-op

Eosinophilia; altered liver function

Rare – liver failure & death

Malignant hyperthermia

Hypermetabolic syndrome – hyperthermia, CO2, tachycardia, cyanosis, 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 ( 气胸 ), bullous emphysema ( 大泡性肺气肿 ), middle ear obstruction, pneumocephalus ( 颅腔积气 )

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