Department of pharmacology
Zhang xiaojie
Overview
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
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
PGI2:
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
-- antipyretic effect
-- analgesic effect
-- anti-inflammatory effect
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
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.
Inflammation
algesireceptor
Injury
BK,histamine
et,al
BK,
pain
PGs
NSAIDs
hyperalgisia
Analgesic Effect
Characteristics
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
Classification of NSAIDs
selectivity
chemical
structure
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
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
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)
Clinical Indications
low dose, long term use produce therapeutic efficacy in
stroke and MI (reduces mortality and prevents recurrent
events).
Clinical Uses
1. Antipyresis and analgesia
headache, toothache, myalgia, neuralgia,
dysmenorrhea and fever of influenza
2. Anti-inflammation and antirheumatism
3. Antithrombosis
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:
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
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
COX
Lipoxygenase
PGS
leukotrienes
Allergy
Treatment:
Adverse Reactions
4. Salicylism
Adverse Reactions
5. Reyes syndrome
Drug Interactions
Compete the banding site to plasma albumin
Replace glucocorticoids ( )enhance its antiinflammatory effect also enhance its effect of inducing ulcer
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).
Phenylbutazone