NONSTERIODAL ANTI-INFLAMMATORY

DRUGS (NSAIDs)
Biosynthesis of Eicosanoids:
Eicosanoids, unlike histamine, are not preformed in
cells but are formed from phospholipid precursors on
demand. They are involved in many physiological
processes and are the most important mediators and
modulation of inflammatory react.
Arachidonic acid is the main eicosanoid precursor in
mammals. Arachidonic acid (5,8,11,14-
eicosatetraenoic acid), is a 20-carbon unsaturated fatty
acid containing four double bonds
(hence eicosa, referring to 20 carbon atoms and
tetraenoic, referring to four double bonds).

The principal eicosanoids are:

i- Prostaglandins(PG)
ii- Thromboxanes
iii- Leukotrienes
The term prostanoid is used to encompass
prostaglandins, thromboxanes and prostacyclins.
The following figure gives summary of
inflammatory mediators from phospholipids with
their actions and site of action of anti-
inflammatory drugs.
Figure…………………
Summary diagram of inflammatory mediators
derived from phospholipids with an outline of their
actions and the sites of actions of anti-inflammatory
drugs:
The arachidonate metabolites are eicosanoids. The
glucocorticoids inhibit transcription of the gene for
COX-2 induced in inflammatory cells by inflammatory
mediators. The effects of PGE2 depend on which of the
three receptors for this prostanoid are activated.
HETE, hydroxyeicosatetraenoic acid; HPETE,
hydroperoxyeicosatetraenoic acid; LT, leukotriene;
PAF, platelet activating factor; PGI2, prostacyclin;
TX, thromboxane.
Arachidonic acid is present as component of the
phospholipids of cell membranes. Free arachidonic
acid is liberated from tissue phospholipids by the
action of cytosolic phospholipase A2 (PLA2), which is
activated by many stimuli such as thrombin action on
Platelets, C5a on neutrophils, bradykinin on
fibroblasts and antigen antibody reaction on mast
cells. The free arachidonic acid is metabolized by
several pathways including the following:
i- Fatty acid cyclo-oxygenase (COX)
ii- Lipoxygenases.
i- Cyclo-Oxygenase Pathway:
All eicosanoids are synthesized via COX pathway.
Two isoforms of cyclo-oxygenase enzyme have been
described as cyclo-oxygenase-1(COX-1) is
constitutive enzyme, present in most cells and
produces prostanoids which act as homeostatic
regulators. COX-2 is not normally present (at least in
most cells) but is strongly induced by inflammatory
stimuli. Differences in biding site have permitted the
development of selective COX-2 inhibitions without
having side-effects caused by COX-1 inhibition.
ii-Lipoxygenases Pathway:
Several lipoxygenases can act on archidonic acid to
form leukotrienes and anti-leukotriene drugs are
treatment options for diseases such as asthma
(montelukast).
Cyclo-Oxygenase Inhibitors:
This group includes NSAIDs (traditional) and new
selective COX-2 inhibitors. Sometime these drugs are
called aspirin-like drugs or antipyretic analgesics.
These drugs are of great clinical value in providing
symptomatic relief from pain and swelling in chronic
joint disease (osteo-and rheumatoid arthritis)
They are also effective in more acute inflammatory
conditions like fractures, sprains, soft tissue injuries,
postoperative, dental and menstrual pain. They are useful
in treatment of minor aches and pain and migraine.
Selectivity for COX-1 and COX-2 is variable for old
NSAIDs but many selective COX-2 inhibitors have been
synthesized. COX-1 is constitutive enzyme and plays
‘housekeeping’ role in the body. It produces
prostaglandins which are involved in:
i- Gastric Cytoprotection.
ii- Platelet Aggregation
iii- Renal blood flow auto-regulation and initiation of
parturition.
COX-2 is induced in inflammatory cells when they
are
i- Damaged
ii- Infected
iii- Activated by cytokines (interleukin, IL-1) tumour
necrosis factor (TNF)-α
Most traditional NSAIDs inhibit both COX-1 and
COX-2 enzymes but differ in degree to which they
inhibit each isoform. Generally, it is believed that
anti-inflammatory, analgesic and antipyretic effects
are due to inhibition of COX-2 and unwanted effects
(particularly on GIT) are associated with inhibition
of COX-1. In contrast, COX-2 inhibitors selectively
inhibit COX-2 and show little effects on GIT.
Chemical Classification of NSAIDs:
1- Propionic derivatives e.g. Ibuprofen
2- Pyrroloealkanoic acid derivatives e.g. Tolmetin
3- Phenylalkanoic acid derivatives e.g. Flurbiprofen
4- Indole derivatives e.g. Indomethacine
5-Pyrazolone acid derivatives e.g. Phenylbutazone
6- Phenyl acetic acid derivatives e.g. Diclofenac
7- Fenamate e.g. Meclofenamic acid
8- Oxicam --- Piroxicam
Mechanism of Action:
Vane and his colleagues established in 1971 that main
action of NSAIDs is due to inhibition of COXs. Some of
them also have oxygen radical-scavenging effects in
addition to COX inhibitory activity and hence may
decrease tissue damage.
Pharmacological Actions:
All NSAIDs have pharmacological profile similar to that of
aspirin (an archetypal NSAID) that was introduced in
clinical medicine in 1890’s. The main action mediated by
COX-2 inhibition are as under:
1- Anti inflammatory:
The decrease in prostaglandin E2 and PGI2 (Prostacyclin)
reduces vasodilation that results in reduced edema.
2- Analgesic:
Decreased PG formation causes less sensitization of
nociceptive nerve endings to inflammatory mediators
such as bradykinin and 5HT. Relief of headache is
brought by reduced PG-mediated vasodilation.
3- Antipyretic:
Interleukin-1 releases PG in CNS where they raise
hypothalamic set point thermostat for temperature
control resulting in fever. NSAIDs prevent this action.
Therapeutic Effects:
i- Anti inflammatory Effects:
NSAIDs suppress the generation of PGE2 and PGI2 that
results into diminishing the signs and symptoms of
inflammation. They do not have any influence on
underlying chronic disease.
ii- Antipyretic Effects:
NSAIDs reset the elevated thermostat in hypothalamus
to the normal set point. Once it returns to normal level,
the temperature regulating mechanisms (dilatation of
superficial blood vessels, sweating etc.) come into
operation to bring the temperature down. NSAIDs do
not alter the normal body temperature.
 iii- Analgesic Effects:
The NSAIDs effectively provide relief in mild or
moderate pain, especially arising from inflammation
or damaged tissue. Two possible mechanisms
identified are as under:
a) These drugs diminish the synthesis of PG, in the
periphery, that sensitize nociceptors to inflammatory
mediators like bradykinin. Thus NSAIDs are useful in
treating bruritis, arthritis, muscular and vascular pain,
dymenorrhoea, toothache, pain of postpartum state
and pain of cancer metastases, as all these conditions
are related to increased local PG synthesis due to
induced COX-2.
b) Inhibition of PG release in spinal cord that occurs
due to inflammatory lesions.
Adverse Effects:
Side effects occurs due to inhibition of COX-1 as it is
responsible for secretion of substances that play
pivotal role in homeostasis.
I-GIT disturbance:
The most commonly occurring gastrointestinal side-
effects are gastric discomfort, dyspepsia, nausea,
vomiting diarrhea. In some cases ulceration and
bleeding may occur.
II- CNS: Headache, tinnitus and dizziness.
III-Skin Reaction: Rashes are common idiosyncratic
unwanted effects of NSAIDs.
IV- Renal adverse effects:
Renal adverse reactions occur due to inhibition of
synthesis of PGE2 and PGI2 which are involved in
maintenance of renal blood flow. The adverse effects
include renal insufficiency, renal failure and proteinuria.
V- CVS side-effects:
Fluid retention, hypertension, oedema and heart failure.
Rofecoxib and valdecoxib (COX-2 inhibitors) were
withdrawn from market due to their association with
increased CVS thrombotic events.
VI- Hepatic:
Abnormal liver function tests and rare liver failure.
VII- Pulmonary:
Asthma (Aspirin- sensitive asthma)
VIII- Hematological:
Thrombocytopenia, neutropenia and even aplastic
anemia.
Aspirin:
Aspirin( acetylsalicylic acid) is common ingredient of
many OTC products. It is rarely used as anti-
inflammatory and has been replaced by other NSAIDs.
Now-a-days, aspirin is used mainly as cardiovascular
drug due to its ability to provide prolonged inhibition of
platelet COX-1 and hence decrease platelet aggregation.
The drug may reduce some types of colorectal cancer.
Pharmacokinetics: Being weak acid aspirin is rapidly
absorbed from stomach, but major portion of the drug is
absorbed from small intestine due to large surface area
of microvilli and greater blood flow. It is absorbed as
such and rapidly (serum half-life 15 min)
hydrolyzed into acetic acid and salicylate by esterases in
tissues and blood. Alkalization of urine increases rate of
excretion of free salicylates and its water soluble
conjugates.
Mechanism of action: Aspirin irreversibly inhibits platelet
COX so that antiplatelet effect lasts for 8-10 days (the life
of Platelet)
Clinical Uses:
1- Aspirin is used to inhibit platelet aggression. Low doses
(doses less than 325mg; many classify it as doses of 75 to
162mg) of aspirin are used prophylactically to
a) Reduce the risk of recurrent cardiovascular event and/or
death in patients with previous MI or unstable angina
pectoris.
 b) Reduce the risk of recurring transient ischemic attacks
and stroke or death in those who have had a prior transient
ischemic attack or stroke.
c) Reduce the risk of CVS event or death in high-risk
patients such as those with chronic stable angina or
diabetes.
2- long term use of aspirin at low dose is associated with
lower incidence of colon cancer.
Unwanted Effects:
Aspirin shares many of general side-effects of NSAIDs.
However, some specific unwanted effects of aspirin are as
under:
i- Salicylism: It is characterized by tinnitus, vertigo
decreased hearing, nausea and vomiting.
 ii- Reye’s Syndrome: Aspirin has been linked with Reye’s
syndrome, So use of aspirin is contra-indicated in children
under 12 years of age.
Reye’s Syndrome most often affects children and teen
agers recovering from viral infection, most commonly flu
and chickenpox. The condition causes swelling in liver and
brain resulting in confusion, seizures and consciousness. It
needs emergency treatment.
STROKE:
A stroke occurs when the blood supply to part of brain is
interrupted or severely reduced, depriving brain tissue of
oxygen and nutrients. Within minutes, brain cells begin to
die.
 Paracetamol ( Acetaminophen)
It was synthesized more than century ago. Since 1950,
paracetamol had been widely used as OTC product for
minor pains and aches. Paracetamol differs from other
NSAIDs in following respects:
a) Analgesic and antipyretic effects
b) Lacks anti-inflammatory effects ( or has very weak
activity)
c) Also lacks tendency to cause gastric ulceration and
bleeding.
d) No effect on platelet aggregation.
The difference between NSAIDs and paracetamol is
not clear. Bio-tests show that it is weak COX inhibitor
with selectively for brain COX(COX-3, not a separate
gene product but a splice variant of COX-1) Some
researcher think it relieves pain by inhibiting COX-2
at low rate of enzyme activity.
 Paracetamol is absorbed well following oral
administration. Peak plasma concentration is achieved
in 1/2 to 1 hour. Plasma half-life is 2-4 hours. It is
inactivated by liver forming sulphate or glucuronide
conjugates, and excreted in urine.
Paracetamol has few side-effects but toxic dose (10-
15gm) can cause fatal hepatotoxicity, which is due to
formation of toxic metabolite N-acetyl-p-
benzoquinone imine ( which is inactivated by
glutathione). The treatment is done by giving agents
that increase glutathione formation in liver. For this
purpose acetylcystine is given intravenously or
methionine orally.
Ibuprofen:
It is phenylpropionic acid. Its half-life is 2 hours. It is
prescribed in lower doses for analgesic effect (less than
2400 mg/day). Its anti-inflammatory effect is about
double of aspirin ( 2400 mg ibuprofen is equivalent to
4000 mg aspirin). Ibuprofen is effective in closing
patent ductus arteriosus in preterm infants with the
same efficacy as indomethacin. Its local application is
effective in providing relief in knee osteoarthritis and
postsurgical dental pain. The concomitant use of
ibuprofen and aspirin antagonizes the platelet
aggregation effect of aspirin. The combined use of both
drugs may result in decreased less anti-inflammatory
effect than sum of
their individual effects.
Diclofenac:
It is non selective COX inhibitor. Its half-life is 1.1
hours. Gastrointestinal ulceration occurs less
frequently than other NSAIDs. When misoprostol is
given with diclofenac, upper gastrointestinal ulceration
decrease. Administration of proton pump inhibitor with
the drug is effective in preventing recurrent
gastrointestinal bleeding but renal side effects are
common in high risk patients. Diclofenac is effective
in the prevention of postoperative opthalmic
inflammation and solar keratoses. Diclofenac in rectal
suppository form can be considered for preemtive
analgesia and postoperative nausea.
Piroxicam:
It is also a non-selective COX inhibitor. Additionally
inhibits polymorphonuclear migration and
lymphocyte function and decreases oxygen radical
production. It has half-life of 57 hours and hence
given once daily. The drug is used for usual rheumatic
indications. If the drug is used at doses higher than 20
mg/day, the incidence of peptic ulcer and bleeding
increases, the risk being as much as 9.5 times greater
than traditional NSAIDs. The drug has all the side
effects of NSAIDs.
COXIBS: Cox-2 inhibitors are restricted for use in
patients for whom conventional NSAIDs pose serious
GIT side-effects. These are prescribed after assessing
cardiovascular risk. Many COX-2 inhibitors were
withdrawn from market due to their association with
cardiovascular events(e.g. Rofecoxib, Valdecoxib).
Celecoxib and etoricoxib are used in osteoarthritis and
rheumatoid arthritis. Both drugs are given orally.
Plasma Cmax is achieved within 1-3 hour. Commonly
occurring side-effects are headache, dizziness and
peripheral edema. Therapy should be given after
considering the cardiovascular events.
Fig:

Fig:
 Anti-rhematoid drugs
Arthritis:- Greek(arthron-joint, itis-inflammation)
Arthritis is inflammation of one or more of joints. Main
symptoms include joint pain and stiffness that worsens
with age. The most common forms are:
i- Osteoarthritis
ii- Rheumatoid arthritis
Osteoarthritis causes hardness of cartilage that covers the
ends of bones where they form a joint.
Rheumatoid arthritis (RA): It is an autoimmune disorder
that first targets the lining of joints (synovium).The joint
changes involve inflammation, proliferation of synovium
and erosion of cartilage and bone.
IL-1 and TNF-α play major role in pathogenesis.
NSAIDs provide mainly symptomatic relief i.e.
reduce inflammation and pain but they have little or
no effects on the progression of bone and cartilage
destruction. Therefore, interest is centered on finding
treatments that might arrest or at least slow the
progression by modifying the disease process.
Disease-Modifying Antirheumatic Drugs (DMARD)
The DMARD were often considered as second-line
therapy with implication that they are given when
other treatments (NSAIDs) failed. However, today,
DMARD therapy may be initiated the moment a
definite diagnosis is reached.
DMARD may take six weeks to six months to become
evident clinically. They are slow acting as compared
to NSAIDs. Thus it is usual practice to provide
NSAIDs “cover” during induction phase. If therapy is
successful then NSAIDs or glucocorticoids therapy
can be reduced markedly
The potential drugs in this group are as under:
i-Methotrexate: It is folic acid antagonist having
cytotoxic and Immunosuppressant activities. Now-a-
days, it is considered as first choice to treat RA. It is
active in this condition at much lower doses than
cancer chemotherapy dose.
Its dose for RA is 15-25 mg weekly and increased
effect has been observed up to 30-35 mg weekly. It is
used in juvenile chronic arthritis, psoriasis, ankylosing
spondylitis, polymyositis, systemic lupus
erythematosus and vasculitis. The drug therapy should
be monitored as it has potential to cause blood
dyscrasias and liver cirrhosis.
ii- Sulfasalazine:
It is complex of sulfonamide (sulfapyridine) and
salicylate. In the colon, the drug is metabolized, by
bacteria, into sulfapyridine and 5-aminosalicylic acid.
It is also used to treat inflammatory bowel disease.
 It acts by scavenging toxic oxygen metabolites
produced by neutrophils. It is used in juvenile chronic
arthritis, RA and it reduces radiologic disease
progression. Folic acid should be supplemented with
therapy as it impairs folic acid absorption. A
reversible decrease in sperm count has also been
reported. Bone marrow depression and anaphylactic
type reactions may occur.
iii- Gold compounds: Two organic complexes of gold,
sodium aurothiomalate (given deep intramuscularly)
and auranofin (given orally) are used clinically. Their
effects become observable in 3-4 months. Pain and
joint swelling diminish and progression of bone
and joint damage decreases. They are thought to act by
inhibiting induction of IL-1 and TNF-α. These
compounds accumulate in many tissues of body. Half-life
is seven days initially but increases with treatment. Thus
drugs are given initially at weekly and then at monthly
intervals. Unwanted effects are skin rashes, flu-like
symptoms, blood dyscrasias, encephalopathy, peripheral
neuropathy and hepatitis can occur.
iv- Antimalarials: Hydroxychloroquine and chloroquine
are used as DMARD. Chloroquine is reserved for cases
that do not respond to other therapies. They are used to
treat autoimmune disease, lupus erythematosus.
Penicillamine: Penicillamine is used in RA. Exact
mechanism is not yet established but it is thought to act
 by decreasing IL-1 generation and partly by inhibiting
collagen synthesis. It is given orally. Penicillamine is good
for treating Wilson’s disease (copper deposition causing
neurodegeneration). Main side effects are blood
dyscrasias, anorexia,fever, nausea and vomiting.
Immunosuppressants: They are classified as under:
1- Drugs inhibiting IL-2 production, e.g. ciclosporin,

tacrolimus.
2- Drugs that inhibit cytokine gene expression, e.g.
corticosteroids.
3- Drugs inhibiting purine or pyrimidine synthesis,
e.g. azathioprine, mycophenolate, mofetil.
 Drugs Used in Treatment of Gout
Gout is a metabolic disease characterized by recurrent
episodes of acute arthritis due to deposition of crystals of
monosodium urate in synovium of joints and cartilage.
An inflammatory response is evoked, involving the
activation of kinin, complement and plasmin systems,
leading to generation of lipoxygenase products such as
leukotriene B4 and local accumulation of neutrophils.
These phagocytize crystals, releasing tissue damaging
oxygen metabolites and subsequently causing lysis of
cells with release of proteolytic enzymes. Urate crystals
are also thought to produce IL-1 and cytokines.
Classification of drugs Used to Treat Gout:
1- Inhibitors of uric acid synthesis , (allopurinol)
2- Uricosuric agents, causing increased excretion of
uric acid , e.g. probenecid
3- Inhibitors of leukocyte migration into joint,
(colchicine)
4- NSAIDs
Allopurinol: It is an isomer of hypoxanthine. It
reduces uric acid synthesis by competitively inhibiting
xanthine oxidase. Allopurinol is itself metabolized by
xanthine oxidase to alloxanthine, which retains the
capacity to inhibit xanthine oxidase for long enough
duration so that allopurinol is given once daily.
Fig:
Allopurinol reduces the concentration of relatively
insoluble urates and uric acid in tissues, plasma and urine
while increases the concentration of their more soluble
precursors, the xanthines and hypoxanthines. The deposit
of urate crystals in tissues is reversed. As well renal stone
formation is inhibited.
Allopurinol is effective orally and its half-life is 1-2 hours
while half-life of alloxanthine is 18-30 hours.
Adverse-effects include GIT upset, allergic reactions and
some blood problems. Acute attacks of gout occur during
early stages of therapy due to physiochemical changes in
the surfaces of urate crystals as these start to re-dissolve,
so allopurinol is combined with NSAIDS in acute attacks
of gout. Allopurinol increases the effects of
mercaptopurine and cyclophosphamide ( both
anticancer) and warfarin (anticoagulant).
Uricosuric agents: (probenecid, sulfinpyrazone,
benzbromarone)
These drugs increase the excretion of uric acid by
directly acting on renal tubules. These drugs should be
given with NSAIDs. Aspirin and salicylates
antagonize the actions of uricosuric drugs, hence
should not be given concurrently.
Colchicine:
It is an alkaloid obtained from autumn crocus
Colchicum autumnale. Colchicine relieves pain and
inflammation without altering metabolism and
excretion of urates. It produces anti-inflammatory
effects by binding to intracellular protein tubulin
thereby preventing its polymerization that leads into
inhibition of leukocytes migration and phagocytosis.
It also inhibits formation of leukotriene B 4. Cholcicine
is given orally. Its commonly occurring side-effects
are GIT upset, nausea, vomiting and diarrhea and
abdominal pain.

Images of Autumn Crocus

 Important Notes
Patent Ductus Arteriosus
Definition
Patent ductus arteriosus (PDA) is a heart defect that 
occurs when the ductus arteriosus (the temporary fetal 
blood vessel that connects the aorta and pulmonary
artery) does not close at birth.