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Are unsaturated fatty acid derivatives, these compounds are sometimes referred to as
eicosanoids. Prostaglandins and related compounds produced in minute quantities by virtually
all tissues. They generally act locally on the tissues in which they synthesized.
1. Uterine Contractions. Prostaglandin E2 (PGE2) increase uterine activity.
2. Body Temperature. PGE2, PGF2, and PGI2 induce fever.
3. Airway Effects. PGE and PGI cause bronchodilation, whereas PGF, PGD, and TXA lead
to bronchoconstriction.
4. GI Effects. PGE and PGI2 decrease gastric acid secretions. Misoprostol (Cytotec) is a
PGE1 derivative that is used to reduce gastric ulcerations from the NSAIDs.
5. Pain Sensitization. PGE and PGI2 sensitize afferent nerve endings to pain
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6. Cardiovascular:
a. TXA2 from platelets and PGI2 from vessel walls are important local hormones in the
control of microcirculation
b. Prostaglandin E1 (PGE1) relax vascular smooth muscle, inhibit platelet
aggregation, and maintain a patent ductus arteriosus.
(Indomethacin [Indocin] induces closure of ductus arteriosus by blocking
prostaglandin synthesis.)
7. Immunologic. PGE2 and PGI2 limit T-cell proliferation, whereas leukotrienes and
TXA2 stimulate T-cell proliferation.
The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic,
analgesic, and anti-inflammatory activities.
Mechanism of action
NSAIDs act primarily by inhibiting the cyclooxygenase enzymes (COX) that catalyze
the first step in prostanoid biosynthesis. There are two COX isoforms:
1-The constitutive COX1 isoform tends to be homeostatic in function, While,
2-COX2 induced during inflammation and tends to facilitate the inflammatory response
Differences in safety and efficacy of the NSAIDs may explained by relative selectivity
for the COX1 or COX2 enzyme. Inhibition of COX-2 is thought lead to the antiinflammatory and analgesic actions of NSAIDs, while inhibition of COX-1 is responsible
for prevention of cardiovascular events and most adverse events.
Pharmacological actions of NSAIDs
1 • An anti-inflammatory action:
the signs
the decrease in prostaglandin E2 and
reduces vasodilatation and, indirectly,
and symptoms
action on underlying
of inflammation;
oedema. NSAIDs
they have little or no
chronic disease itself.
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2 • An analgesic effect: decreased prostaglandin
generation means less
sensitization of nociceptive nerve endings to inflammatory mediators such
as bradykinin
and 5-hydroxytryptamine.
a result of decreased
Relief of headache is probably
prostaglandin-mediated vasodilatation.
NSAIDs are effective against mild
moderate pain.
3• An antipyretic effect: interleukin-1 releases prostaglandins in the
nervous system,
where they elevate the hypothalamic set point for
control, thus causing fever. NSAIDs prevent this.
4• GI effects:
 PGI2 (prostacyclin) inhibit gastric acid secretion
 PGE2 and PGF2α stimulate the synthesis of protective mucus in both stomach and
small intestine.
NSAIDs inhibit the formation of these PGs resulting in increased gastric acid
secretion and decreased mucus production which may cause epigastric pain,
ulceration, and/or hemorrhage.
NSAIDs classification.
1-Non selective COX inhibitors:
Naproxen, Indomethacin, Piroxicam.
2- Newer agents with more selective inhibition of COX-2 (and thus fewer
adverse effects on the gastrointestinal tract) include:
Celecoxib and Etoricoxib.
Clinical indications
1-Antithrombotic: e.g. aspirin
for patients
high risk of arterial
thrombosis (e.g.following myocardial infarction). Low doses of aspirin can irreversibly
inhibit thromboxane production in platelets via acetylation of cyclooxygenase .and
because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of
thromboxane persists for the lifetime of the platelet (3–7 days). As a result of the decrease
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in TXA2 production, platelet aggregation (the first step in thrombus formation) is
reduced, producing an antiplatelet effect with a prolonged bleeding time.
2-An anti-inflammatory: The majority of NSAIDs are anti-inflammatory. An important
exception is (paracetamol).
3-Analgesia (e.g. for headache, dysmenorrhoea,
postoperative pain):
backache, bony
• –Short-term use: e.g. aspirin, paracetamol, ibuprofen.
• –Chronic pain: more potent, longer lasting drugs (e.g. naproxen,
piroxicam) often combined with a low-potency opioid (e.g. codeine)
4-Antipyretic: paracetamol.
Many stemming from inhibition of the constitutive housekeeping enzyme COX-1
isoform, are common, particularly in the elderly, and include the following:
1. Dyspepsia, nausea, vomiting
and other gastrointestinal effects.
Gastric and
damage may occur in chronic users, with risk of
hemorrhage, ulceration and perforation, which
can be life threatening. The
cause is suppression of gastro protective prostaglandins
in the gastric
mucosa. (see
GIT effect).
2. Skin reactions.
3. Reversible renal insufficiency. Seen mainly in individuals with compromised renal
when the compensatory prostaglandin
I2/E2-mediated vasodilatation
is inhibited.
4. Adverse cardiovascular effects.
These can occur with many NSAIDs and
coxibs and may related to inhibition of COX-2
in the macula densa or
elsewhere leading to hypertension.
5. Nephropathy.
This can occur following long-term high-dose regimes
NSAIDs and is often irreversible.
6. Closure of patent ductus arteriosus (PDA ):Indomethacin is used to achieve
closure of a patent ductus arteriosus in neonates. However,
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Prescription of NSAIDs should generally avoided in pregnant women,
particularly in 3rd trimester, owing to the risk of premature closure of the
ductus arteriosus.
Pharmacokinetics of NSAIDs
In general, NSAIDs are absorbed almost completely from GIT, tend not to undergo
1st-pass elimination, are highly bound to plasma albumin and have small volume of
distribution. Their t1/2 values in plasma tend to group into:
a- short (1-5) hours or b- long (10-60) hours
The vast majority of NSAIDs are weakly acidic drugs that localise preferentially in the
synovial tissue of inflamed joints.
(acetylsalicylic acid (ASA).
Is the oldest NSAIDs drug. It acts by irreversibly inactivating COX-1 and COX-2.
In addition to its anti-inflammatory actions, aspirin inhibits platelet
aggregation, and its main clinical use now is in the therapy of
cardiovascular disease.
•It is given orally and is rapidly absorbed; 75% is metabolized in the
•Elimination of its metabolite salicylate follows first-order kinetics with low
doses (half-life 4h), and saturation kinetics with high doses (half-life over
15 h).
1- With therapeutic doses: some
gastric bleeding is
common. When aspirin
enters the gastric epithelial cells (pH=7.4) it will ionise, become less diffusible and so will
localise there. This ION TRAPPING is one mechanism whereby ASA is concentrated in,
and so harms the gastric mucosa.
2- With larger doses: dizziness,
deafness and tinnitus (‘salicylism’);
respiratory alkalosis may occur.
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3- With toxic doses
from self-poisoning):
may occur, particularly In children.
4-Aspirin has linked with a rare but serious post viral encephalitis
(Reye’s syndrome: which is an often fatal, fulminating hepatitis with cerebral edema):
Aspirin and other salicylates given during viral infections have been associated with an
increased incidence of Reye syndrome, (especially encountered in children), who,
therefore, should given paracetamol instead of aspirin in case fever.
5- If given concomitantly with warfarin, aspirin can cause a potentially
hazardous increase in the risk of bleeding.
Aspirin is not given, at least 1 week prior to surgery.?
Doses of 75-150 mg/day used to prevent thrombotic vascular occlusion;
300 mg as immediate treatment for myocardial infarction;
300-900 mg every 4-6 h for analgesia.
Is a commonly used drug that is available over the counter. It has potent
analgesic and antipyretic actions but rather weaker anti-inflammatory effects than other
NSAIDs. Its COX inhibitory action seems to be specific to the CNS enzyme.
• It given orally and metabolized in the liver by conjugation reaction (half-life2–4 h).
•Toxic doses cause nausea and vomiting, then, after 24–48 h, potentially fatal liver
• Agents that increase glutathione
can prevent
(intravenous acetylcysteine or oral
liver damage if given early.
Dose. The oral dose is 500 mg to 1 g every 4 to 6 h, maximum daily dose 4 g.
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COX2- selective NSAIDs
COX2-inhibitors, as a group, have an advantage by showing a lower risk for the
development of GI bleeding. These agents also have no significant effects on platelets.
However, the COX2-selective agents (like the traditional NSAIDs) may cause renal
insufficiency and increase the risk of hypertension. The incidence of gastroduodenal
ulcers in patients taking Celecoxib was less than that found in patients taking Naproxen,
Diclofenac or ibuprofen.
NB: Celecoxib inhibits COX2-derived synthesis of endothelial prostacyclin (PGI2)
“which inhibit platelets aggregation and cause vasodilation but allow the continued
production of COX1-derived thromboxane (TXA2) (which promote platelet aggregation
and vasoconstriction).These effects may increase the risk of cardiovascular events.
For that reason, “Coxibs” used cautiously in patients with history of heart failure,
hypertension and other risk factors for heart disease; and they are contraindicated in
ischaemic heart disease (angina, myocardial infarction “MI”), cerebrovascular disease,
and peripheral arterial disease.
Celecoxib approved for osteoarthritis and rheumatoid arthritis; pain including bone pain
,dental pain, and headache; and ankylosing spondylitis.
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