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1
Chapter 22
Antipyretic-analgesic
and anti-inflammatory
drugs
2
introduction
3
Antipyretic-analgesic and antiinflammatory drugs
non-steroidal anti-inflammatory
drugs(NSAIDs)
Aspirin-like drugs
4
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
5
Membrane phospholipids
PLA2
Arachidonic
acid
NSAIDs
PGG2
glucocorticoid
COX
PGH2
PGI2
PGF2
PGE2
TXA2
(vascular (bronchial (vascular dilation; (vascular
dilation;
constriction) GI protection;
constriction;
platelet
pain,fever)
thrombosis)
disaggregate;
pain)
lipoxygenase
LTs
LTC4/
D4/E4
Bronchial
constriction ;
Alteration of
vascular
permeability
LTB4
chemotaxis
6
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.
7
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
8
COX-1
Production
Function
Constitutive
Physiological function
gastric protection
platelet aggregation
COX-2
Inducible
Pathological function
facilitate inflammation
cause fever and pain
peripheral vessel regulation
renal blood distribution
NASIDs effects unwanted side effects
therapeutic effects
9
【Three major actions of
NSAIDs】
Antipyretic effect
Analgesic effect
Anti-inflammatory effect
10
1. Antipyretic effect :
mechanism
characteristics
clinical applications
11
Mechanism
pathogen and toxins
neutrophils
endogenous pyrogens (IL-1,IL-6,TNF)
cox
NSAIDs
PGE2 (hypothalamus)
heat production
set point
heat dissipation
body
temperature
12
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.
13
Clinical applications
symptomatic treatment.
attention
As fever is a defense reaction of the body and heat pattern
is 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 time
to reduce body temperature, avoid or alleviate the
complications.
14
What is the difference between
NSAIDs and chlorpromazine in body
temperature regulation
15
Comparison between
NSAIDs and Chlorpromazine
•
NSAIDs
Mechanism
Chlorpromazine
inhibit COX in
CNS → PGE2↓
inhibit thermoregulator
make it out of function
Effect
set point ↓
BT ↓
BT alters with the
environmental temperature
Clinical uses
fever
rheumatic fever
artificial hibernation
16
2. Analgesic effect :
mechanism
characteristic
clinical application
17
Mechanism
Other algesiogenic substance
(BK,histamine etc.)
injury
nociceptive
nerve endings
pain
+
PGs
NSAIDs
18

Bradykinin: cause pain through stimulating the
algesireceptors directly.

PG: (1) hyperalgesia
(2) PG(E1 E2 F2α) also have algesiogenic
effect
19
Characteristics
① Peripheral
② mild to moderate pain.
③ No addiction or respiratory inhibition
20
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.
21
What is the difference between NSAIDs
and analgesics in analgesic effect
22
Drug
location mechanism
characteristics
representative
powerful ;
 sharp pain ;
 cause euphoria and
addiction ;
 respiratory inhibition
morphine
dolantin

Analgesics
NSAIDs
CNS
(+)opium
receptor
periphery
(-)PG
CNS(?) synthesis

moderate ;

chronic dull pain ;

not addictive

no respiratory
inhibition
aspirin
23
3.Anti-inflammatory effect :
mechanism
characteristic
24
3. Anti-inflammatory effect
Mechanism of inflammation:
phospolipids
injury
factor
PLA2
neutrophilic
granulocyte
cytokines
( IL-1,6,8 TNF)
arachidonic acid
induce
COX-2
PGs BK cell adhesion
molecules
inflammation
( redness, swelling, heat and pain )
25
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
26
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.
27
【 NSAIDs classifications 】

According to selectivity for COX:
①Non-selective COX inhibitors
②Selective COX-2 inhibitors

According to chemical structures:
① Salicylates
② Anilines
③ Pyrazolones
④ Other organic acids
28
Section 1
Nonselective COX inhibitors
29
Salicylates
Anilines
Pyrazolones
Other organic acids
30
Aspirin (Acetylsalicylic acid)
31
【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
32

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!
33
【pharmacological actions
and clinical uses】
(1)Antipyretic-analgesic effect
(2)Anti-inflammatory and antirheumatic effects
(3)Platelet effect
34
(1)Antipyretic-analgesiceffects:
most effective for fever and mild to
moderate pain
fever—profuse sweating,enough water
supplement
35
(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
36
(3)Platelet effect:
AA
blood vessel endothelium
platelet
PGI2
TXA2
(-)platelet
aggregation;
vascular
dilation
(+)platelet
aggregation;
vascular
constriction
37
 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↓
38

Clinical uses:
①low aspirin dose (50~100mg) is recommended;
②prevent thrombosis:
cardiac or brain ischemic diseases.
angioplasty,coronary artery bypass grafting.
39
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
40
【Adverse effects】
Gastrointestinal side effects
Disturbance of blood coagulation
Salicylism reaction
Hypersensitivity reactions
Reye’s syndrome
Nephrotoxicity
41
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
42
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
43
3. Salicylism reaction
 Large dosage(>5g/d)
 headache, vertigo, nausea, vomiting, tinnitus,
decreased vision and hearing;hyperpnea, acidbase disturbance, insanity.
 Therapy: ①aspirin be stopped at once,
②sodium bicarbonate infusions.
(fluid replacement)
44
4. Hypersensitivity reactions
urticaria,angioneuro edema,allergic
shock
“aspirin asthma”: related to PG biosynthesis
inhibition
45
When COX pathway is inhibited,LOX pathway is
strengthened,whose metabolites increase accordingly
CO
X
PGs
LOX
AA
LTs
NSAIDs
aspirin
asthma
46
4. Hypersensitivity reactions
aspirin asthma
①mechanism: AA: → PG↓
→LTs↑→bronchospasm→asthma
②therapy: adrenalin ( )
antihistaminic, glucocorticoid (
)
47
4. Hypersensitivity reactions
 contraindications: asthma
chronic urticaria
nasal polyps
48
5. Reye’s syndrome
 Severe hepatic dysfunction with
complication of encephalopathy
 Substitute aspirin with acetaminophen
49
6. Nephrotoxicity
Also has been observed.
50
Anilines
Acetaminophen (paracetamol):
51
Similar antipyretic and analgesic
effects to aspirin,no significant antiinflammatory effect
 It inhibits synthesis of PG in CNS more
effectively than in periphery
 Less frequent gastrointestinal irritation

52
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
53
Section 2
Selective COX-2 inhibitors
54
In 1998 and 1999,highly selective
COX-2 inhibitors (Celecoxib,Rofecoxib)
have been developed.
55
Celecoxib

a highly selective COX-2 inhibitor,COX-2:COX1 =375:1

gastrointestinal adverse effects are less frequent

not affect TXA2 biosynthesis, but PGI2 synthesis
can be inhibited

Contraindications: patients with thrombosis
tendency
56
Rofecoxib

a highly selective COX-2 inhibitor

does not inhibit platelet aggregation

is approved mainly for osteoarthritis
57
Drugs used in gout
58
purine
xanthine oxidase
uric acid
excretion
hyperuricemia
joints
kidney
arthritis
Kidney
damage
connective
tissue
Connective tissue
damages
59
Treatment aim
①relieve the acute
Acute
gout
chronic
gout
gouty arthritis
attack
②control the
hyperuricemia
Drug
Mechanism
colchicine (-) inflammation
NSAIDs
Indometha (-) inflammation
cin
allopurinol
reduce the serum
level of uric acid
probenecid
↓uric acid
synthesis
↑uric acid
excretion
60
allopurinol
purine
xanthine oxidase
uric acid
probenecid
excretion
hyperuricemia
NSAIDs
joints
kidney
Other
tissues
arthritis
Kidney
damage
Other tissue
damages
Indomethacin
colchicine
61
62