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Chapter 22 Antipyretic-analgesic and anti-inflammatory drugs

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introduction

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Antipyretic-analgesic and anti-

inflammatory drugs

non-steroidal anti-inflammatory

drugs(NSAIDs)

Aspirin-like drugs

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Antipyretic-analgesic and anti-inflammatory drugs

• Be grouped in different classes according to their chemical structures

• Share similar pharmacological effects

mechanism of action and adverse reactions

• They all inhibit the biosynthesis of PGs

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Membrane phospholipids

Arachidonic acid

PGG2

PGH2

PGI2 PGF2 PGE2 TXA2

(vascular (bronchial (vascular dilation; (vascular dilation; constriction) GI protection; constriction; platelet pain,fever) thrombosis) disaggregate; pain)

PLA2

LTs

LTC4/D4/E4

LTB4

chemotaxisBronchialconstriction ;Alteration of

vascularpermeability

COX lipoxygenase

glucocorticoid

NSAIDs

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The Different biological Activities of the Products of AA

• PGI2: vasodilation hyperalgesia inhibit platelet aggregation • TXA2: platelet aggregation and vasoconstriction.• PGE2: induce inflammation fever and pain vasodilation and hyperalgesia• PGF2α: bronchial constriction and vasoconstriction.

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The Different biological Activities of the Products of AA

• LTs : allergy, bronch-constriction

leukocytotaxis

increase vascular permeability

induce inflammation

The different anti-inflammatory mechanism

• Glucocorticoids : inhibit PLA2

• NSAIDs: inhibit COX and reduce the production of PGs

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COX-1 COX-2

Production Constitutive Inducible

Function Physiological function Pathological function

gastric protection facilitate inflammation

platelet aggregation cause fever and pain

peripheral vessel regulation

renal blood distribution

NASIDs effects unwanted side effects therapeutic effects

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【 Three major actions of NSAIDs 】

Antipyretic effect

Analgesic effect

Anti-inflammatory effect

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mechanism

characteristics

clinical applications

1. Antipyretic effect :

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Mechanism

heat production

heat dissipation

pathogen and toxins

neutrophils

endogenous pyrogens (IL-1,IL-6,TNF)

set point body temperature

cox NSAIDsPGE2 (hypothalamus)

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Characteristics

① Central

“② Elevated” temperature — reduced

“Normal ” temperature — no influence

③ To what extent the COX inhibited is consistent with the intensity of NSAIDs’s pharmacological effects.

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Clinical applications

symptomatic treatment.

attention

As fever is a defense reaction of the body and heat patternis an important evidence in diagnosis, we should not hurry to use antipyretic drugs for mild fever; but for high fever and chronic fever, antipyretic drugs should be used in timeto reduce body temperature, avoid or alleviate the complications.

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What is the difference between NSAIDs and

chlorpromazine in body temperature regulation

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Comparison betweenComparison between NSAIDs and Chlorpromazine NSAIDs and Chlorpromazine

• NSAIDs Chlorpromazine

Mechanism inhibit COX in inhibit thermoregulator CNS → PGE2↓ make it out of function

Effect set point ↓ BT alters with the BT ↓ environmental temperature

Clinical uses fever artificial hibernation rheumatic fever

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mechanism

characteristic

clinical application

2. Analgesic effect :

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Mechanism

injury

PGs

painOther algesiogenic substance(BK,histamine etc.)

nociceptive

nerve endings

+

NSAIDs

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Bradykinin: cause pain through stimulating the

algesireceptors directly.

PG: (1) hyperalgesia

(2) PG(E1 E2 F2α) also have algesiogenic

effect

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Characteristics

① Peripheral

② mild to moderate pain.

③ No addiction or respiratory inhibition

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Clinical applications ① have good effects on chronic dull pain—

headache , toothache, neuralgia, muscle pain,arthralgia,dysmenorrhea.

② are not effective for traumatic pain, severe visceral pain—myocardial infarction or renal or biliary colic

③ Non-narcotic and no euphoria.

No respiratory inhibition.

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What is the difference between NSAIDs

and analgesics in analgesic effect

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Drug location mechanism characteristics representative

Analgesics

NSAIDs

CNS

peripheryCNS( ？ )

(+)opium receptor

(-)PG synthesis

morphinedolantin

aspirin

powerful ； sharp pain ； cause euphoria and addiction ; respiratory inhibition

moderate ； chronic dull pain ； not addictive no respiratory inhibition

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mechanism

characteristic

3.Anti-inflammatory effect :

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3. Anti-inflammatory effect

Mechanism of inflammation:Mechanism of inflammation: phospolipids injury factor PLA2

neutrophilic arachidonic acid granulocyte cytokines induce COX-2

( IL-1,6,8 TNF) PGs BK cell adhesion molecules

inflammation ( redness, swelling, heat and pain )

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The role of PGs in inflammation

1.cause vasodilation and tissue edema

2.coordinate with bradykinin to cause

inflammation

♣ Mechanism of anti-inflammatory effect

(1)Reducing biosynthesis of

prostaglandins by inhibiting COX.

(2)inhibition of the expression of some cell

adhesion molecules

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Characteristics

① Peripheral

② They have certain effect on the control

of rheumatoid arthritis.

③ can’t effect a radical cure. They can

neither alter the course nor prevent

complications.

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According to selectivity for COX: ①Non-selective COX inhibitors

②Selective COX-2 inhibitorsAccording to chemical structures:

① Salicylates ② Anilines ③ Pyrazolones ④ Other organic acids

【 NSAIDs classifications 】

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Section 1

Nonselective COX inhibitors

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Salicylates

Anilines

Pyrazolones

Other organic acids

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Aspirin (Acetylsalicylic acid)

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【 Pharmacokinetics 】

Absorption: stomach ， upper small intestine aspirin acetic acid ＋ salicylate

Distribution: in the form of salicylate articular cavity, CSF and placenta PPBR= 80~90%

CSF :cerebrospinal fluid

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Metabolism: ＜ 1g,first-order kinetics,t1/2=2~3h;

≥1g,zero-order kinetics,t1/2=15~30h;

Still larger dosage→intoxication

Excretion: renal

the PH of urine: alkaline→85%;

acidic→5%

In salicylate acute intoxication, we can increase the

excretion of free salicylates by alkalizing the urine!

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【 pharmacological actions

and clinical uses 】

(1)Antipyretic-analgesic effect

(2)Anti-inflammatory and antirheumatic effects

(3)Platelet effect

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(1)Antipyretic-analgesiceffects:

most effective for fever and mild to moderate pain

fever—profuse sweating,enough water supplement

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(2)Anti-inflammatory and antirheumatic effects:

①used in therapy and differential diagnosis

of acute rheumatic fever

②the preferred drug for rheumatoid arthritis

③adult: 3~5g/d

④In rheumatism treatment, we should

monitor the blood drug level

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(3)Platelet effect:

AA

TXA2PGI2

(-)platelet aggregation；vascular dilation

(+)platelet aggregation；vascular constriction

plateletblood vessel endothelium

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Aspirin irreversibly acetylates and blocks platelet COX →TXA2 biosynthesis(-)→platelet aggregation(-)→ thrombosis (-). (8-10d)

TXA2↓ Low dose thrombosis is inhibited PGI2 not affected TXA2↓ High dose unbeneficial for thrombosis inhibition PGI2↓

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Clinical uses:

①low aspirin dose (50~100mg) is recommended;

②prevent thrombosis:

cardiac or brain ischemic diseases.

angioplasty,coronary artery bypass grafting.

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Others

(1)Alzheimer,s disease(AD): AD is related to the over-expression of COX-2 in

brain. Aspirin 100 mg p.o. daily has repression effect

on AD

(2) Pregnancy-induced hypertension syndrome and preeclampsia:

is related to the increase of the ratio of TXA2 to PGI2 in blood

Aspirin 40-100mg p.o. daily can reduce the incidence of PIH and the danger of

preeclamapsia

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【 Adverse effects 】Gastrointestinal side effects

Disturbance of blood coagulation

Salicylism reaction

Hypersensitivity reactions

Reye’s syndrome

Nephrotoxicity

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1 、 Gastrointestinal side effects gastric upset ， gastric ulcer ， gastric hemorrhage

Due to： ① direct irritation of the gastric mucosa ② high concentration→irritate CTZ: nausea and vomiting ③ inhibition of production of protective PGs Countermeasures: ① take after meals, chew up the tablet,antacids ② enteric-coated aspirin

Contraindications: patients with peptic ulcer

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2. Disturbance of blood coagulation

general dose—prolong bleeding time; high dose or long-term use—inhibit prothrombin

biosynthesis (VitK can prevent)

contraindications: hemophilia, pregnancy, sever hepatic insufficiency, hypoprothrombinemia, VitK deficiency

be stopped 1 week prior to surgery

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3. Salicylism reaction

Large dosage(>5g/d)

headache, vertigo, nausea, vomiting, tinnitus,

decreased vision and hearing ； hyperpnea, acid-base disturbance, insanity.

Therapy: ①aspirin be stopped at once,

②sodium bicarbonate infusions.

(fluid replacement)

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4. Hypersensitivity reactions

urticaria ， angioneuro edema ， allergic shock

“aspirin asthma”: related to PG biosynthesis inhibition

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When COX pathway is inhibited,LOX pathway is strengthened,whose metabolites increase accordingly

PGs AA LTs

COX

LOX

NSAIDs

aspirin asthma

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4. Hypersensitivity reactions

aspirin asthma ①mechanism: AA: → PG↓

→LTs↑→bronchospasm→asthma

②therapy: adrenalin ( )

antihistaminic, glucocorticoid ( )

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4. Hypersensitivity reactions

contraindications: asthma

chronic urticaria

nasal polyps

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5. Reye’s syndrome

Severe hepatic dysfunction with

complication of encephalopathy

Substitute aspirin with acetaminophen

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6. Nephrotoxicity

Also has been observed.

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Anilines

Acetaminophen (paracetamol):

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Similar antipyretic and analgesic effects to aspirin,no significant anti-inflammatory effect

It inhibits synthesis of PG in CNS more effectively than in periphery

Less frequent gastrointestinal irritation

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Ibuprofen ： Less frequent gastrointestinal irritation

It can be slowly released into synovial fluid and remains there with a high concentration

Widely used in rheumatoid arthritis(RA), and osteoarthritis

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Section 2

Selective COX-2 inhibitors

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In 1998 and 1999,highly selective

COX-2 inhibitors (Celecoxib,Rofecoxib)

have been developed.

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Celecoxib

a highly selective COX-2 inhibitor ， COX-2:COX-1 =375:1

gastrointestinal adverse effects are less frequent

not affect TXA2 biosynthesis, but PGI2 synthesis can be inhibited

Contraindications: patients with thrombosis tendency

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Rofecoxib

a highly selective COX-2 inhibitor

does not inhibit platelet aggregation

is approved mainly for osteoarthritis

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Drugs used in gout

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purine uric acid excretion xanthine oxidase

hyperuricemia

joints kidney connective tissue

arthritis Kidney damage

Connective tissue damages

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Treatment aim Drug Mechanism

Acute gout

①relieve the acute

gouty arthritis

attack

②control the

hyperuricemia

colchicine (-) inflammation

NSAIDs

Indomethacin

(-) inflammation

chronic gout

reduce the serum level of uric acid

allopurinol ↓uric acid

synthesis

probenecid ↑uric acid

excretion

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purine uric acid excretion xanthine oxidase

hyperuricemia

joints kidney Other tissues

arthritis Kidney damage

Other tissue damages

probenecidallopurinol

NSAIDsIndomethacin

colchicine

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