Antipyretic-analgesic
and Anti-inflammatory
Overview
Drugs
Aspirin-like drugs
Aspirin is the representative drug.
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs differ from glucocorticoids in the mechanism of anti-inflammatory action.
[Shared characteristics of NSAIDs]
mechanism of actions
pharmacological effects
adverse reactions
The shared mechanism of reactions
Metabolism of arachidonic acid
Phospholipids
phospholipase A2
glucocoids
lipoxygenase
Arachidonic acid
COX
5-HPETE
NSAIDs
PGG2
PGI2 synthetase
(vascular endothelium)
iosmerase
leukotriens
PGI2
PGE2
PGH2
reductase
PGF2α
TXA2 synthetase
(platelet)
TXA2
PG is a family of polyunsaturated fatty acids, almost existing in each kind of tissue
and body fluid. It can promote inflammation, pain,fever and support the function of
platelet and protect the lining of stomach and regulate the resistance of peripheral
vessels, etc.
TXA2 : promote platelet aggregation
vasoconstriction
PGI2 : inhibit platelet aggregation
vasodilatation
gastric protection
PGE2 : induce inflammation
cause fever and pain
cause vasodilatation
PGF2α : vasoconstriction
causing pain
LTs :
allergy
contraction of bronchial smooth muscle
[Introduction of COX]
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COX exists in two enzyme isoforms:
COX-1 and COX-2.
Each of them has different characteristics.
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
[The shared mechanism of NSAIDs]
inhibit the enzyme cyclo-oxygenase (COX) and cause inhibition of biosynthesis of
prostaglandins (PGs).
Three major actions of NSAIDs
1. Antipyretic effect The antipyretic effect of NSAIDs locates in center.
2. Analgesic effect
3. Anti-inflammatory effect
1. Antipyretic effect
Mechanism:
inhibit the biosynthesis of PGs in the CNS
Characteristic:
NSAIDs reduce elevated temperature, whereas normal body temperature is slightly
affected.
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Table 21-2 Comparison between NSAIDs and Chlorpromazine
Mechanism
Effect
heat-regulating
center
Clinic uses
on
NSAIDs
Inhibit hypothalamic COX, decrease
the generation of PGE
Reduce elevated temperature, but
normal body temperature is only
slightly affected.
Fever, rheumatic fever,
chlorpromazine
Directly
inhibit
hypothalamic
heat-regulating center
Changed according to the variation
of environment
Low environment temperature：T↓；
high environment temperature：T↑
Artificial hibernation
2. Analgesic effect
[Mechanism]:
inhibit the synthesis of PGs in periphery
[Characteristics]:
most effective to mild to moderate pain
(eg. toothache, neuralgia, courbature, arthralgia and dysmenorrhea) no euphoria and
addiction
no respiratory inhibition
Table 21-2 Comparison with morphine
NSAIDs
morphine
mechanism
decreased prostaglandin
Excite opioid-receptor, release P
generation
structure,
inhibit the transformation of
algesic information
Clinic uses
Mild-to-moderate pain
All kinds of pain
Narcosis respiratory inhibitory
（－）
（＋）
and addiction
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3. Anti-inflammatory effect
injury
Phospholipids
PLA2
AA
cytokine↑
(IL-1,6,8 TNF)
COX-2 COX-1
NSAIDs
PGs
BK
inflammation
[The role of PGs in inflammation]
1. They cause vasodilatation and increase vascular permeability.
2. They also coordinate with BK and cell adhension molecules, amplifing inflammatory
effect.
[Mechanism of anti-inflammation]
1. Inhibit biosynthesis of PGs in inflammatory sites
2. Inhibit the expression of some cell adhesion molecules
3.Additional possible mechanisms
–inhibition of leukocyte chemotaxis
–down regulation of interleukin-1 production
–decrease the production of free radicals and superoxide
–interference with calcium-mediated intracellular events.
Section 1 Salicylates
Aspirin (ASA)
[Process in the body]
1. Absorption:
* absorbed rapidly, tpeak=1~2 hours, t 1/2=15min
* from stomach but mostly from the upper small intestine
2. Distribution: (metabolite-salicylate)
* distribute widely throughout most body tissues, including articular cavity,
cerebrospinal fluid and placenta.
* is extensively bound to albumin , PPBR highly reaching 80%-90%
3. Metabolism and excretion
Most of the salicylates are metabolized in the liver.The product will be excreted by
urine,influenced by urine pH.
in alkaline urine up to 85%
in acidic urine
as low as 5%
In salicylate acute intoxication, we can reduce the blood concentration and increase
the excretion of free salicylates by alkalizing the urine with sodium bicarbonate.
[Pharmacological effect and clinical use]
1. Analgesic and antipyretic effect
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one of the most frequently employed drugs in reducing pain and body temperature. it
widely used in headache, toothache,neuralgia, courbature, dysmenorrhea, cold and
fever,etc.
2. Anti-inflammation and anti-rheumatic effect
relieve the symptoms of redness, swelling, heat and pain caused by inflammation. In
high doses, it can be responsible for the treatment of rheumatoid fever, rheumatoid
arthritis and other inflammatory joint conditions.
[clinical uses]
general inflammation
rheumatoid and rheumatic arthritis and other inflammatory joint conditions .
differential diagnosis and therapy of acute rheumatoid fever
3. Effect on platele
Low doses of aspirin produce an effect of anticoagulation. This is due to its
irreversible inhibition of platelet COX to reduce the production of TAX2 in platelet. But
high doses of aspirin may play an opposite effect. Because high doses of aspirin inhibit
PG synthetase directly in vessel endothelium, so as to reduce the synthesis of PGI2. PGI2
is the antagonizer of TAX2, and its reduction may stimulate clot formation.
[Clinical uses] ( in low doses )
① prevent thrombosis
② myrocardial infarction
③ transient cerebral ischemic attack
4.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 danger of preeclamapsia
[Adverse Reactions]
1. Gastrointestinal effects:
At
the usual dosage, aspirin’s main adverse reaction is gastric upset. The ingestion of aspirin
sometimes result in epigastric distress, nausea, and vomiting. Aspirin also causes gastric ulcer, or even
gastrointestinal hemorrhage (on high-dose).
1) stimulate stomach mucous: epigastric distress
 Directly stimulation
 By inhibiting COX
2) irritate chemoreceptor trigger zone(CTZ):nausea and vomiting
[prevention]
* take aspirin after meals, or followed by antacids
* take aspirin with endogenous enteric tablet
 Patients with ulcer should stop aspirin therapy.
contraindication: gastric ulcer.
2. Aggravation of bleeding tendency
Symptom and Cause
* usual dose:
inhibit platelet aggregation and prolong the bleeding time
* high dose or in long term:
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inhibit the formation of thrombinogen and prolong the clotting time
contraindication
* severe hepatic damage
* hypoprothrombin-vitamin k deficiency
* hemophilia
* Aspirin therapy should be stopped 1 week prior to surgery.
3. Allergic effect:angioedema , urticaria, bronchospasm, bronchial asthma ,shock.
Aspirin-asthma : a hypersensitive reaction not based on antigen-antibody reaction
inhibiting COX →reducing synthesis of PGs → analysing AA into LTs↑ →
bronchospasm →bronchial asthma
Therapy
It can’t be cured by adrenaline, but antihistamine drug and glucocorticoid have good therapy
effects.
Caution: history of hypersensitivity, asthma and nasal polypus.
4. Salicylism:
large dose(>5g)
*symptom:With higher doses, patients may experience “salicylism”(special reaction
of
salicylates)—headache,vertigo,vomiting,tinnitus,sight
and
hearing
failure,hyper-ventilation, acid-base imbalance and even mental disorder
* therapy: sodium bicarbonate.
5.Rey’s syndrome
* symptom:
Children, who are infected by viral disease given aspirin to relieve heat, may be
caused Reye’s syndrom. It is shown as severe hepatic dysfunction and encephalopathy.
Although it is still in a low incidence, its prognosis is not optimistical.
* Prevention:
* restriction in children infected with influenza, varicella, and other virus.
* substitute aspirin with acetaminophen
Drug Interactions
1. Compete the banding to plasma albumin
Replace dicoumarol enhance its anticoagulation effect even cause hemorrhage
Replace tolbutamide and cause hypoglycemia
Replace glucocorticoids enhance its anti-inflammatory effect also enhance its effect of
inducing ulcer
 2.Compete the autosecretion carriers in renal tubular
valproate，furosemide, penicililn, methotrexate and other weak alkaline drugs
Section 2 Acetaminophen( Paracetamol)
[Pharmacological actions]
* similar analgesic and antipyretic effects to aspirin, no significant
anti-inflammatory effect
* inhibit synthesis of PG in CNS more effectively than in periphery
[Clinical uses]:
substitutor for antipyretic and analgesic effects of aspirin in:
* those patients with gastric complaints
* those for whom prolongation of bleeding time would be a disadvantage
* Children with viral infections or chicken pox
[Adverse reactions]:
* Usual dose is safe
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Frequent symptoms include nausea, vomiting , skin rash, and drug fever.
mucous membrane damage occur occasionally.
* large doses: hepatic damage
Section 3 Other organic anti-inflammatory acids
Indomethacin
[Pharmacological actions]
* the most powerful COX inhibitor,also inhibit PLA2 and PLC
* marked anti-inflammatory and anti-pyretic effects
[Clinical uses]
* rheumatic and rheumatoid arthritis
* ankylosing spondylitis
* gout
* cancerous fever
* other unmanageable fever
[Adverse effect]
① gastrointestinal effect
② central nervous system effect
③ Hematopoietic system reactions
④ Allergy: In severe patients it can induce asthma. Aspirin-asthma patients is forbidden
from the therapy of indomethacin.
Sulindac
• * half potency of indomethacin
• * similar actions and indications to indomethacin
• * mainly used for rheumatic arthritis, osteoarthritis
• * fewer adverse effects
Phenylbutazone & Oxyphenbutazone
Pharmacological actions:
* strong anti-inflammatory and anti-rheumatic effects
* weak antipyretic and analgesic effects
Clinical uses
* rheumatic and rheumatoid arthritis,* ankylosing spondylitis
Ibuprofen
• naproxen, ketoproten
• * effective COX inhibitor
• * slightly gastrointestinal effects
• * well tolerant
• * widely used in the therapy of rheumatic arthritis and osteoarthritis
Piroxicam and Meloxicam
1.Piroxicam
* Efficacy of inhibition of COX is similar to indomethacin.
* similar therapeutic effects and fewer adverse reactions than aspirin
* Main advantage: plasma t1/2 = 50 hours,permits one-daily dosing
2. Meloxicam
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•
•
•
* One of COX-2 inhibitors
* similar indications to piroxicam
* strong anti-inflammatory effect and few adverse reactions
section 4
selective COX-2 inhibitor
Celecoxib
* highly selective COX-2 inhibitor,COX-2: COX-1 =375:1
* effective for rheumatic and rheumatoid arthritis, osteoarthritis, postoperational pain
and toothache
* few adverse effects
Nimesulide
• *A new type of NSAIDs
• * highly selective COX-2 inhibitor
• *strong anti-inflammatory effect and few adverse reactions
• *used in therapy of rheumatoid arthritis, osteoarthritis, backleg pain, and toothache
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