Nonsteroidal anti-infl ammatory drugs (NSAIDs) are used
primarily to treat infl ammation, mild-to-moderate pain, and fever. Specifi c
uses include the treatment of headache, arthritis, sports injuries, and
menstrual cramps. Aspirin is used to inhibit the clotting of blood and prevent
strokes and heart attacks in individuals at high risk. NSAIDs are also included
in many cold and allergic preparations.
Synthesis
NSAIDs are associated with a number of side effects. The
frequency of side effects varies according to the drugs; the most common side
effects are gastro intestinal tract (GIT) disturbances, such as nausea,
diarrhoea, constipation, vomiting, decreased appetite, and peptic ulcer. NSAIDs
may also cause fl uid retention, leading to oedema; the most serious side
effects are kidney failure, liver failure, ulcers, and prolonged bleeding after
an injury of surgery. Some individuals are allergic to NSAIDs and may develop
shortness of breath when NSAIDs are administered. People with asthma are at a
higher risk for experiencing serious allergic reaction to NSAIDs. Use of
aspirin in children and teenagers with chicken pox or infl uenza has been
associated with the development of Reye’s syndrome. Therefore, aspirin and
salicylate should not be used in children and teenagers with suspected or confi
rmed chicken pox or infl uenza.
Antipyretics,
Antipyretics are the drugs that reduce the elevated body
temperature. Anti-infl ammatory agents are used to cure or prevent infl ammation
caused by prostaglandin (PGE2). These drugs are widely utilized for the
alleviation of minor aches, pains, fever, and symptomatic treatment of
rheumatic fever, rheumatoid arthritis, and osteoarthritis.
General Structure of PG
PG is a naturally
occurring 20-carbon cyclopentano fatty acid derivative, derived from
arachidonic acid.
Mode of action: NSAIDs inhibit cycloxygenase (COX), the
enzyme that catalyses the synthesis of cyclic endoperoxides, from the
arachidonic acid to form PGs. The two COX isoenzymes are COX-1 and COX-2. The function
of COX-1 is to produce PGs that are involved in normal cellular activity,
(protection of gastric mucosa, maintenance of kidney function). While, COX-2 is
responsible for the production of PGs at the infl ammation sites. Most NSAIDs
inhibit both COX-1 and COX-2 with varying degree of selectivity. Selective
COX-2 inhibitor may eliminate the side effects associated with NSAIDs due to
COX-1 inhibition, such as gastric and renal effect.
Side effects in stomach:: Biosynthesis of PGs, especially
PGE2 and PGI2, serves as cytoprotective agents in gastric mucosa; these PGs
inhibit acid secretion by the stomach, enhance mucosal blood fl ow, and promote
the secretion of cytoprotective mucus in the GIT. Inhibition of the PGs
synthesis may make the stomach more susceptible to damage and lead to gastric
ulcer.
In platelets: Platelet’s function get disturbed because NSAIDs prevent
the formation of Thromboxane A2 (TXA2) in platelets, as TXA2 is a potent
platelet-aggregating agent. This accounts for the tendency of these drugs to
increase the bleeding time and this side effect has been exploited in the
prophylactic treatment of thromboembolic disorder.
In uterus: NSAIDs prolong gestation because of the
inhibition of PGF2 in uterus. PGF2 is a potent uterotropic agent and their
biosynthesis by uterus increase dramatically in the hours before parturition.
Accordingly, some anti-infl ammatory drugs have been used as a colytic agent to
inhibit preterm labour. In kidney: NSAIDs decrease renal blood fl ow and the
rate of glomerular fi ltration in patients with congestive heart failure,
hepatic cirrhosis, and with chronic renal disease, in addition, they prolong
the retention of salt and water, this may cause oedema in some patients.
CLASSIFICATION
I.
Salicylic acid derivatives: Aspirin, Difl unisal,
Salsalate, Sulphasalazine.
II.
p-Amino phenol derivatives: Paracetamol,
Phenacetin.
III.
Pyrazolidine dione derivatives: Phenyl butazone,
Oxyphenbutazone, Sulphin-pyrazone.
IV.
Anthranilic
acid derivatives: Mefenemic acid, Flufenemic acid, Meclofenamate.
V.
Aryl alkanoic acid derivative.
a. Indole acetic acid:
Indomethacin.
b. Indene acetic acid:
Sulindac.
c. Pyrrole acetic acid: Tolmetin,
Zormipirac.
d. P henyl acetic (propionic)
acid: Ibuprofen, Diclofenac, Naproxen, Caprofen, Fenoprofen, Keto-profen, Flurbiprofen, Ketorolac,
Etodaolac.
VI.
Oxicams: Piroxicam, Meloxicam, Tenoxicam
VII.
Selective COX-2 inhibitors: Celecoxib,
Rofecoxib, Valdecoxib.
VIII.
Gold compounds: Auronofi n, Aurothioglucose,
Aurothioglucamide, Aurothiomalate sodium.
IX.
Miscellaneous: Nabumetone, Nimesulide, Analgin.
X.
Drug used in gout: Allopurinoll, Probenecid,
sulphinpyrazone
I. Salicylates Salicylates not only posses antipyretic, analgesic, and
anti-infl ammatory properties, but also other actions that have been proven to
be therapeutically benefi cial because salicylates promote the excretion of uric
acid and they are useful in the treatment of gouty arthritis. More attention
has been given to the ability of salicylates (aspirin) to inhibit platelet
aggregation, which may contribute to heart attack and strokes, and hence,
aspirin reduces the risk of myocardial infarction. In addition, a recent study
suggested that aspirin and other NSAIDs might be protective against colon
cancer.
Structural Activity Relationship (SAR) of Salicylates
• The active moiety
of salicylates is salicylate anion, side effects of aspirin, particularly GIT
effects appear to be associated with the carboxylic acid functional group.
•
Reducing the acidity of the carboxy group results in a change
in the potency of activity. Example— the corresponding amide (salicylamide) retain
the analgesic action of salicylic acid, but is devoid of anti-infl ammatory
properties.
•
Substitution on either the carboxyl or phenolic hydroxyl group
may affect the potency and toxicity. Benzoic acid itself has only week
activity.
•
Placement of the phenolic hydroxyl group at meta or para to
the carboxyl group abolish the activity.58 Drugs Acting on InŃ ammation/AllergyAnalgesics, Antipyretics, and NSAIDs 59
•
Substitution of halogen atom on the aromatic ring enhances
potency and toxicity. • Substitution of aromatic ring at the 5th position of
salicylic acid increase anti-infl ammatory activity (difl unisal). Metabolism of
salicylic acid derivatives: The initial route of metabolism of these
derivatives is their conversion to salicylic acid, which is excreted in urine
as free acid (10%) or undergoes conjugation with either glycine to produce the
major metabolites of salicylic acid (75%) or with glucuronic acid to form
glucuronide (15%). In addition, small amount of metabolites resulting from microsomal
aromatic hydroxylation leads to gentisic acid.
Image salicilicate derivatives
i.
Aspirin (Emipirin, Bufferin)
Properties and uses: Aspirin is a white crystalline powder, slightly
soluble in water and soluble in alcohol, indicated for the relief of minor
aches and mild-to-moderate pain in the conditions such as arthritis and related
arthritic condition. Also used in myocardial infarction prophylaxis.
Assay: Dissolve the sample in alcohol and add 0.5 M sodium hydroxide.
Allow to stand and titrate against 0.5 M hydrochloric acid using
phenolphthalein as an indicator. Perform a blank titration.
Dose: Usual adult dose: 300 to 650
mg every 3 or 4 h orally or 650 mg to 1.3 g as the sustained-release tablet
every 8 h; rectal, 200 mg to 1.3 g three or four times a day.
Dosage forms: Aspirin tablets I.P., B.P., Dispersible aspirin tablets
B.P., Effervescent soluble aspirin tablets B.P., Gastro-resistant aspirin
tablets B.P., Aspirin and Caffeine tablets B.P., Co-codaprin tablets B.P.,
Dispersible co-codaprin tablets B.P.
ii.
Sodium salicylate
Synthesis
Properties and uses: Sodium salicylate is a white crystalline powder,
soluble in water, sparingly soluble in alcohol. It is used for fever and for
the relief of pain. It also possesses anti-infl ammatory actions similar to
aspirin and symptomatic therapy of gout.
Assay: Dissolve the sample in anhydrous acetic acid and titrate against
0.1 M perchloric acid. Determine the end-point potentiometrically.
iii.
Salsalate (Disalacid, Saloxium)
Synthesis
Properties and uses: Salsalate or
salicylsalicylic acid is a dimer of salicylic acid. It is insoluble in gastric
juice, but is soluble in the small intestine where it is partially hydrolyzed
into two molecules of salicylic acid and absorbed. It does not cause GI blood
loss. It has antipyretic, analgesic, and anti-infl ammatory properties similar
to those of aspirin. It is employed in the treatment of rheumatoid arthritis
and other rheumatic disorders. Dose: Usual adult dose is 325–1000 mg 2–3 times
a day, orally.
iv. Sulphasalazine (Azultidine, Azaline)
Properties and uses:
Sulphasalazine is a bright yellow or brownish-yellow fi ne powder, practically
insoluble in water and methylene chloride, very slightly soluble in alcohol,
soluble in dilute solutions of alkali hydroxides. Sulphasalazine is a mutual
prodrug. In large intestine, it is activated to liberate 5-amino salicylic
acid, which in turn inhibits PG synthesis and the sulphapyridine is useful for
the treatment of infection. Hence, sulphasalazine is used in the treatment of
ulcerative colitis.
Synthesis
Assay: Dissolve and dilute the
sample in 0.1 M sodium hydroxide and add 0.1 M acetic acid and measure the
absorbance at the maxima of 359 nm using ultraviolet spectrophotometer. Prepare
a standard solution at the same time and in the same manner, using sulphasalazine
reference standard. Dose: Dose orally is initially 3–4 g daily, followed by 500
mg four times a day for maintenance. Dosage forms: Sulphasalazine tablets B.P.
v.
Diflunisal
Synthesis
Properties
and uses: Difl unisal is a white crystalline powder, practically insoluble in
water, soluble in alcohol, and dilute solutions of alkali hydroxides. It is
more potent than aspirin, but produces fewer side effects, and has a biological
half-life 3–4 times greater than that of aspirin. It is a nonselective cyclooxygenase
inhibitor used as antipyretic, analgesic, and anti-infl ammatory.
Assay:
Dissolve the sample in methanol, add water, and titrate against 0.1 M sodium
hydroxide using phenol red as indicator, until the colour changes from yellow
to reddish-violet.