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Antipyretic, analgesic and antiinflammatory drugs

Department of pharmacology
Zhang xiaojie

Overview

This kind of drug is a group of chemically


dissimilar agents that have antipyretic, analgesic
and anti-inflammatory effects.
Nonsteroidal anti-inflammatory drugs ( NSAIDs )

Share similar pharmacological effects, mechanism of


action and adverse effects.

All inhibit the biosynthesis of prostaglandins (PGs)

Prostaglandin, PG
Prostaglandins are a family of
unsaturated eicosenoic fatty
acids containing a five-carbon
ring and two side chains, widely
exists in most tissues and body
fluids of humans and mammals,
playing a very important role in
homeostatic functions

HO
COOH
O

OH

PGE2
HO
COOH
O

OH

PGF2a

Production and Actions of Prostaglandins


membrane phospholipids
phospholipase A2
lipoxygenase

Arachidonic acid

glucocorticoid
COX

cyclooxygenase
PGI2 synthetase
(vascular endothelium)
5-HPETE

PGG2
PGH 2

iosmerase

synthetase
(platelet)
leukotrienes

NSAIDs

PGI2

PGE2

reductase

PGF2

TXA2

TXA2

Allergy
inhibit platelet aggregation induce inflammation vasoconstriction
platelet
aggregation
vasodilation
cause fever and pain bronchial constriction vasoconstriction
bronchial constriction hyperalgesia
vasodilation
vascular permeability
hyperalgesia
Induce inflammation

Biological Effects of Prostaglandins

PGE2: vasodilation, protect gastric mucosa


induce inflammation, fever and pain

PGF2: bronchial constriction and vasoconstriction

PGI2:

TXA2: platelet aggregation and vasoconstriction.

vasodilation, inhibit platelet aggregation

Cyclo-oxygenase (COX), is the key enzyme for


synthesis PGs, include two isoforms :
COX-1 constitutive enzyme, involved in tissue
homeostasis
COX-2 inducible enzyme, responsible for the
production of the prostanoid mediators of
inflammation, pain and fever

Comparison between COX-1 and COX-2


COX-1
production constitutive

COX-2
induced

function physiological
pathological
protection of the gastric mucosa facilitate inflammatory
regulation of platelet aggregation cause fever and pain
regulation of renal blood flow
regulation of peripheral vascular resistance

Most currently available traditional NSAIDs inhibit


both COX-1 and COX-2 with little selectivity

NSAIDs,s inhibition of COX-2 is the base of their


therapeutic effects while their inhibition of COX-1 is
the reason of their adverse reactions (GIT)

But this is not absolute the antithrombosis effect of


aspirin is based on its inhibition of COX-1

According to the selection of COX they are classified


into selective COX-2 inhibitor and non-selective COX
inhibitor

Common pharmacological effects


These drugs show the same pharmacological
effects

-- antipyretic effect

-- analgesic effect

-- anti-inflammatory effect

Pharmacological Actions of NSAIDs


1.

Antipyretic effect

Mechanism:
Blocks pyrogen-induced prostaglandin production
in thermoregulatory center (CNS)

Characteristics
They only decrease the body temperature of those
who have a fever and no effect on normal ones
The higher temperature, the more potent

NSAIDs

(-)

Endogenous pyrogens
(IL-1,IL-6,TNF-
neutrophilic granulocyte

Pathogen
(virus,bacteria,endotoxin,
Ag-Ab)

Prostaglandins
PGE2

thermoregulatory
center
set point
heat production
heat loss

Fever

The Difference between NSAIDs and Chlorpromazine

Inhibit the thermoregulatory center and make it


out of function

Cause the body temperature to alter with the


environment temperature

Not only decrease the body temperature of those


who have a fever but also the normal ones

2. Analgesic Effect

Cause of pain:
in injury tissue or inflammation, some chemical
algesiogenic substances are produced and released
such as bradykinin and so on together with PGs.

Bradykinin: cause pain through stimulating the


algesireceptors directly.
PG: (1) hyperalgesia
(2) PG(E1 E2 F2) also have algesiogenic effect

Mechanism: inhibit the synthesis of PGs in periphery

The Cause of Pain

Inflammation
algesireceptor
Injury

BK,histamine
et,al
BK,
pain

PGs
NSAIDs

hyperalgisia

Analgesic Effect
Characteristics

Only effective to mild to moderate pain


little effect on sharp pain and viscera angina

No euphoria and no respiratory inhibition

No addiction and no tolerance

3.Anti-inflammatory Effect
inflammation is the defensive reaction to lesion factors of live
tissues having vascular system

Lesion
factor
neutrophilic
granulocyte
cytokines induce
IL-1,6,8 TNF
adhesive

phospolipids
PLA2
arachidonic acid

COX-2
PGs

BK

molecules

inflammation

Anti-inflammatory Effect
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

Characteristics
Symptomatic Treatment

NSAIDs only relieve the main clinical


symptoms (erythema, edema, fever, pain and
dysfunction) of inflammation

have no effect on the autoimmunological


process of rheumatic and rheumatoid arthritis.

Classification of NSAIDs
selectivity

chemical
structure

Non-selective COX inhibitor


Selective COX-2 inhibitor
Salicylates: aspirin
Para-aminophenol: acetaminophen
Pyrazoly ketons : phenylbutazone
Other organic acids :Indomethacin

Salicylates
COOH
OH

Salicylic acid
COONa
OH

Sodium
salicylate

COOH
OOCCH3

Aspirin
Acetylsalicyclic acid

Aspirin
Process in the body
1. Absorption

rapidly
tpeak= 0.5~2 hrs p.o.
In stomach and small intestine (mainly in the latter)

2. Distribution

widely almost throughout the body.


synovial fluid, cerebrospinal fliud,pass placenta.
PPBR=80%~90%

3. Metabolism
Hydrolyzed rapidly to acetic acid and salicylate
by esterases
plasma t1/2 =15 min.
Salicylates are metabolized by cytochrome P 450 in
the liver,most of the product are bound to
Glycines few of them are bound to glucuronic
acids.

Aspirin

aspirin p.o. <1.0g: first-order kinetics


t1/2=2~3hrs

aspirin p.o. 5.0g: zero-order kinetics


t1/2=15~30hrs

Process in the Body


4.Excretion

The metabolites are mainly excreted by kidney.

low dose: most are excreted in the form of


bound, few in the form of free salicylate.
in large dose: many of them will be excreted in
the form of free salicylate.

Process in the Body

Urine pH have a strong influence on the


excretion amount of free salicylate from kidney
Alkaline pH : free SA up to 85%
Acidic pH : free SA low as 5%

So we can reduce the blood concentration of free


salicylate through alkalizing the urine

Pharmacological Effects
1. Antipyretic and analgesic effect
strong and rapid, in low dose (300-600mg)
2. Ant-inflammatory and antirheumatic effect
(1) relatively weaker
(2) need large dose (3-6g)

3.Inhibit platelet aggregation and prevent thrombosis


Inhibition of platelet COX-1-derived TXA2 can
inhibit platelet aggregation
Endothelial COX-1 derived PGI2 can dilate vessel
and inhibit platelet aggregation
Aspirin administrated in low dose can covalently
modifies and irreversibly inhibits platelet COX.
The enzyme is inhibited for the lifetime of the
platelet (~8 -11 days) remarkably but have no
apparent influence on PGI2 . So PGI2> TXA2

Clinical Indications
low dose, long term use produce therapeutic efficacy in
stroke and MI (reduces mortality and prevents recurrent
events).

The Effect of Aspirin on Platelet Cyclooxygenase-1

Platelet cyclooxygenase-1 is a dimer. Arachidonic


acid substrate gains access to the catalytic site (red
area) through a hydrophobic channel that leads into
the core of the enzyme (Panel A).
Aspirin blocks the access of arachidonic acid to the
catalytic site by irreversibly acetylating a serine
residue at position 529 in platelet cyclooxygenase-1
(Panel B).

Clinical Uses
1. Antipyresis and analgesia
headache, toothache, myalgia, neuralgia,
dysmenorrhea and fever of influenza
2. Anti-inflammation and antirheumatism

diagnosis and therapy of acute rheumatic fever

rheumatic and rheumatoid arthritis to relieve


the symptoms
High dose needed (5-8 g/day). But many pts cannot
tolerate these doses (GIT); so, proprionic acid
derivatives, ibuprofen, naproxen tried first

3. Antithrombosis

Ischemic cardiopathy including stable and variant


angina pectoris and progressive myocardial
infarction patients. It can reduce mortality and reischemia
In transient ischemic attack patients to prevent
cerebral thrombosis
in angioplasty, bypass transplant operations to
prevent thrombosis

Other Effects
(1) Alzheimer,s disease(AD):
AD is related to the over-expression of COX-2 in brain
Aspirin 100mg 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

Adverse Reactions
1. Gastrointestinal reactions
short-term: nausea, vomit, abdominal pain
long-term: gastritis, ulcer, gastrorrhagia
Mechanism:
irritate gastric mucosa directly
irritate chemoreceptor trigger zone(CTZ)
Inhibit the gastric mucosa protection effect of PGE2
Methods:
Take it after meal
Take enteric coating tablets
Take it along with antacids and misoprostol

2. Blood Coagulation Disorders

In usual dose:
inhibit platelet coagulation and prolong the bleeding time

Contraindications:
Hemophilia
Severe hepatic damage
Vitamin K deficiency
one week before operation
ante partum

3. Allergy

Urticaria, allergic shock, angioneurotic edema

Aspirin-asthma: Asthma induced by the


administration of aspirin or other NSAIDS
in some asthma patients.
Mechanism:
It is not caused by allergic reaction based
on antigen-antibody reaction.

COX
Lipoxygenase

PGS
leukotrienes

Allergy
Treatment:

Adrenaline has no effect on it,


but we can treat it with antihistamines and
glucocorticoids.

Controundications: nasal polyp, asthma,


chronic urticaria, histroy of hypersensitivity

Adverse Reactions
4. Salicylism

When the dose of aspirin is too high, 5/d, the


patients may suffer from headache, dizziness,
nausea, vomiting, tinnitus, sight and hearing
failure.Severe patients may suffer from
hyperventilation, acid-base in balance, even
mental confusion, these are all called salicylism.
Treatment: sodium bicarbonate iv.drip

Adverse Reactions
5. Reyes syndrome

Occur rarely but can result death in children

Severe hepatic dysfunction with complication


of encephalopathy

Contraindicated in children and young adults less


than 20 years old with fever associated viral illness
Substitute aspirin with acetaminophen for children
fever, Reyes syndrome has disappeared

Drug Interactions
Compete the banding site to plasma albumin

Replace dicoumarol( ) enhance its anticoagulation


effect even cause hemorrhage

Replace tolbutamide and cause


hypoglycemia

Replace glucocorticoids ( )enhance its antiinflammatory effect also enhance its effect of inducing ulcer

Acetaminophen & Phenacetin


Inhibit the synthesis of PG in CNS but has little


effect on the COX in periphery
Similar antipyretic and analgesia to aspirin
Weak anti-inflammatory properties
Used in usual dose with few adverse reactions, if
used overdose, it can cause hepatic injury.
Phenacetin it is transformed into toxic
metabolites by the liver which can change
hemoglobin into methemoglobin and cause
hemolysis.

Therapeutic uses
Acetaminophen provides an effective
alternative when aspirin is contraindicated
(e.g., in patients with peptic ulcer or
hemophilia) and when the anti-inflammtory
action of aspirin is not required.

Indomethacin
Pharmacologic effects :
(1) Inhibit COX nonselectively .
(2) Inhibit phospholipase A and C.
(3) Decrease T cell and B cell proliferation.
(10-40 time more potent anti-inflammatory than
aspirin)

Indomethacin

Therapeutic uses:
Because of its toxicity and side effect, it is not
routinely used for analgesia or antipyresis.
The major uses of indomethacin are in the
treatment of rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis, and acute gout.

Indomethacin

(1)
(2)
(3)
(4)

Adverse effect:
Gastrointestinal complaint:
CNS effects: 25%-50%
Hematologic reactions:
Hypersensitivity reactions: asthma (aspirinsensitive patients may exhibit cross-reactions
to indomethacin).

Naproxen and Ibuprofen

They have prominent anti-inflammatory action.

Therapeutic uses: rheumatoid arthritis,


osteoarthritis, ankylosing spondylitis, acute
tendinitis, dysmenorrhea, et al.

Adverse effect: gastrointestinal effects,


dermatologic problems, thrombocytopenia.

apply to long-term treatment because they are


better-tolerated.

Phenylbutazone

Powerful anti-inflammatory effects


Weak analgesic & antipyretic activities
Promote excretion of uric acid
Used for acute gout, rheumatic &
rheumatoid arthritis
More adverse reaction
Can induce activities of drug metabolize-E
Can displace other drugs from plasma
proteins

Selective COX-2 inhibitor


Celecoxib and Rofecoxib
more selective for COX-2 than for COX-1.
Adverse effects are slighter than other NSADs.
Long-term studies of the incidence of clinically
significant gastrointestinal ulcers and bleeding are
not yet completed.
Rofecoxib withdrawn from market in 2004

Clinical uses of the NSAIDs


For analgesia in painful conditions (e.g.
headache, dysmenorrhoea, backache, bony
metastases of cancers, postoperative pain):
The drugs of choice for short-term analgesia are
aspirin, Acetaminophen and ibuprofen; more
potent, longer-acting drugs (diflunisal, naproxen,
piroxicam) are useful for chronic pain
The requirement for narcotic analgesics can be
markedly reduced by NSAIDs in some patients with
bony metastases or postoperative pain

Clinical uses of the NSAIDs


For anti-inflammatory effects in chronic or acute
inflammatory conditions (e.g. rheumatoid
arthritis and related connective tissue disorders,
gout and soft tissue diseases)
For many NSAIDs, the dosage required for
chronic inflammatory disorders is usually greater
than for simple analgesia and treatment may
need to be continued for long periods; Treatment
could be initiated with an agent known to have a
low incidence of side-effects. If this proves
unsatisfactory, more potent agents should be used

Clinical uses of the NSAIDs


To lower body temperature
Acetaminophen is preferred because it lacks
gastrointestinal side-effects and, unlike aspirin,
has not been associated with Reyes syndrome in
children
There is substantial individual variation in clinical
response to NSAIDs and considerable
unpredictable patient preference for one drug
rather than another