1. 2 Chapter 22 Antipyretic-analgesic and anti-inflammatory drugs.
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Transcript of 1. 2 Chapter 22 Antipyretic-analgesic and anti-inflammatory drugs.
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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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