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NONSTEROIDAL ANTIINFLAMMATORY DRUGS

AND ANTIPYRETIC-ANALGESICS
All drugs grouped in this class have analgesic, antipyretic and
antiinflammatory actions in different measures. Compared to morphine they are
weaker analgesics (except for inflammatory pain); do not depress CNS, do not
produce physical dependence and have no abuse liability. They are also called
nonnarcotic, nonopioid or aspirin like analgesics.
CLASSIFICATION
A. Nonselective COX inhibitors.
1. Salicylates: Aspirin, Diflunisal.
2. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone, Metamizol
3. Indole derivatives: Indomethacin, Sulindac.
4. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
5. Anthranilic acid derivative: Mephenamic acid.
6. Aryl-acetic acid derivatives: Diclofenac.
7. Paraaminophenol derivative: Paracetamol (Acetaminophen).
8. Oxicam derivatives: Piroxicam, Tenoxicam.
9. Pyrrolo-pyrrole derivative: Ketorolac.
B. Selective COX-2 inhibitors
Celecoxib, Rofecoxib, Nimesulide, Meloxicam, Nabumetone

MECHANISM OF ACTION OF NSAIDS

Prostaglandins, prostacyclin (PG I2) and thromboxane A2 (TXA2) are
produced from arachidonic acid by the enzyme cyclooxygenase which exists in a
constitutive (COX-1) and an inducible (COX-2) isoforms. Eicosanoids produced
by COX-1 participate in physiological functions such as secretion of mucus for
protection of gastric mucosa, haemostasis and maintenance of renal functions,
while those produced by COX-2 lead to inflammatory and other pathological
changes.
Most NSAIDs inhibit COX- 1 and COX-2 nonselectively, but now some
selective COX-2 inhibitors have been produced.
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Analgesia. NSAIDs are therefore more effective against inflammation
associated pain, for headache, myalgia, joint pain, pulled muscle, toothache,
neuralgias.
 NSAIDs block PG generation, which induce hyperalgesia. NSAIDs
block the pain sensitizing mechanism induced by bradykinin, TNFa, interleukins
(ILs) and other algesic substances.
 analgesia is caused also by mechanical factors. Nonnarcotic analgetics
have antiinflammatory effect  the edema and infiltration decreases  pressure
upon peripheral pain receptors decreases, and painful sensations are weakened.
 a central subcortical action raising threshold to pain perception also
contributes, but the morphine like action on psychic processing or reaction
component of the pain is missing. This drugs block PG generation in brain, render
oppressing influence on the thalamic centers of a pain, increase release of
endorphines.

Antipyresis. NSAIDs reduce body temperature in fever, but do not cause

hypothermia in normothermic individuals. NSAIDS inhibit production and action
of pyrogens: PGE1 and ILs  they reset the hypothalamic thermostat and rapidly
reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but
does not decrease heat production.
Antiinflammatory. NSAIDs inhibit all stages of an inflammation: alteration,
exudation and proliferation.
1). Alteration:
 Reduce damage of tissues by mediators of an inflammation (PGs,
cytokines, serotonin, histamine).
 Stabilize lysosomal membrane; reduce damage of cells by proteolytic
enzymes.
 Reduce an immune inflammation and damage of tissues by immune
complexes.
 Quench free radicals.
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2). NSAIDs brake activity of hyaluronidase and reduce permeability of blood
vessels  reduce exudation.
3). In high doses activate synthesis ACTH and glucocorticoids.

ADVERSE EFFECTS OF NSAIDS

A) Gastrointestinal: gastric irritation, erosions, peptic ulceration, gastric
bleeding/perforation, esophagitis
B) CNS: headache, mental confusion, behavioural disturbances, seizure
precipitation
C) Renal: Na+ and water retention, chronic renal failure, interstitial
nephritis, papillary necrosis (rare)
D) Haematological: bleeding, thrombocytopenia, haemolytic anaemia,
agranulocytosis
E) Hepatic: raised transaminases, hepatic failure (rare)
F) Others: asthma exacerbation, nasal polyposis, skin rashes, pruritus,
angioedema

SALICYLATES
Aspirin (acetylsalicylic acid)
It is one of the oldest analgesic-antiinflammatory drugs and is still widely
used.
PHARMACOLOGICAL ACTIONS
1. Analgesic, antipyretic, antiinflammatory actions. Aspirin is a weaker
analgesic than morphine type drugs.
2. Metabolic effects. There is increased utilization of glucose  blood sugar may
decrease (specially in diabetics). Chronic use of large doses cause negative N 2
balance. Plasma free fatty acid and cholesterol levels are reduced.
3. Respiration is stimulated by peripheral (increased CO 2 production) and central
(increased sensitivity of respiratory centre to CO2) actions. Further rise in salicylate
level causes respiratory depression; death is due to respiratory failure.
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4. Acid-base and electrolyte balance. It causes respiratory alkalosis, which is
compensated by increased renal excretion of HCO3. Aspirin is acid, it causes
metabolic acidosis.
5. GIT Aspirin and released salicylic acid irritate gastric mucosa  cause
epigastric distress, nausea and vomiting. Aspirin causes focal necrosis of mucosal
cells and capillaries  acute ulcers, erosive gastritis, congestion and microscopic
haemorrhages. Soluble aspirin tablets containing calcium carbonate + citric acid
and other buffered preparations are less liable to cause gastric ulceration.
6. Urate excretion. In higher dose aspirin increases urate excretion.
7. Blood Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by
platelets and decreases aggregation. Long term intake of large dose decreases syn-
thesis of clotting factors and predisposes to bleeding; can be prevented by
prophylactic vit K therapy.
ADVERSE EFFECTS
(a) Side effects. that occur at analgesic dose (0.3-1.5 g/day) are nausea, vomiting,
epigastric distress, increased occult blood loss in stools. The most important
adverse effect of aspirin is gastric mucosal damage and peptic ulceration.
(b) Hypersensitivity and idiosyncrasy. Reactions include rashes, fixed drug
eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction.
Profuse gastric bleeding occurs in rare instances.
(c) Antiinflammatory doses (3-6 g/day) produce the syndrome called salicylism—
dizziness, tinnitus, vertigo, reversible impairment of hearing and vision,
excitement and mental confusion, hyperventilation and electrolyte imbalance.
(d) An association between salicylate therapy and 'Reye's syndrome', a rare form of
hepatic encephalopathy seen in children having viral (varicella, influenza)
infection has been noted.
USES
1. As analgesic. For headache, backache, myalgia, joint pain, pulled muscle,
toothache, neuralgias and dysmenorrhoea.
2. As antipyretic.
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3. Acute rheumatic fever, rheumatoid arthritis, osteoarthritis.
4. Postmyocardial infarction and poststroke patients. By inhibiting platelet
aggregation it lowers the incidence of reinfarction (60-100 mg/day).

PYRAZOLONES
Metamizol (Dipyrone) It is a potent and promptly acting analgesic and
antipyretic but poor antiinflammatory and not uricosuric. It can be given orally,
i.m. as well as i.v. but gastric irritation, pain at injection site occurs. Occasionally
i.v. injection produces precipitous fall in BP.
Metamizol was banned in USA and some European countries, because it causes
bone marrow depression, agranulocytosis, epigastric distress and edema. However,
it has been extensively used in India and other European countries.

INDOLE DERIVATIVES
1. Indomethacin It is a potent antiinflammatory drug, comparable to
phenylbutazone. In addition, it is a potent and promptly acting antipyretic.
Analgesic action is better than phenylbutazone, but it relieves only inflammatory
or tissue injury related pain. It is a highly potent inhibitor of PG synthesis and
suppresses neutrophil motility..
Adverse effects. A high incidence (upto 50%) of gastrointestinal and CNS side
effects is produced. Gastric irritation, nausea, anorexia, gastric bleeding and
diarrhoea are prominent. Headache, dizziness, ataxia, mental confusion,
hallucination, depression and psychosis. Leukopenia, rashes and other
hypersensitivity reactions are also reported.
Uses. In rheumatoid arthritis, ankylosing spondylitis, acute exacerbations of
destructive arthropathies and psoriatic arthritis.
It has been the most common drug used for medical closure of patent ductus
arteriosus: three 12 hourly doses of 0.1-0.2 mg/kg.

ARYL-ACETIC ACID DERIVATIVE

Diclofenac sodium. An analgesic-antipyretic-antiinflammatory drug. It
inhibits PG synthesis and has short lasting antiplatelet action.
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It is well absorbed orally.
Adverse effects of diclofenac are generally mild: epigastric pain, nausea,
headache, dizziness, rashes.
Diclofenac is among the most extensively used NSAID; employed in
rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis, dysmenorrhoea,
post-traumatic and postoperative inflammatory conditions—affords quick relief of
pain and wound edema.

PYRROLO-PYRROLE DERIVATIVE
Ketorolac. A novel NSAID with potent analgesic and modest
antiinflammatory activity. In postoperative pain it has equalled the efficacy of
morphine, but does not interact with opioid receptors and is free of respiratory
depressant, dependence producing.
Ketorolac is rapidly absorbed after oral and i.m. administration.
Ketorolac has been used concurrently with morphine. However, it should not
be given to patients on anticoagulants.
Use. Ketorolac is frequently used in postoperative and acute musculoskeletal
pain. It may also be used for renal colic, migraine and pain due to bony metastasis.
Continuous use for more than 5 days is not recommended.

PARA-AMINO PHENOL DERIVATIVES

Paracetamol (acetaminophen).
The central analgesic action of paracetamol is like aspirin, i.e. it raises pain
threshold, but has weak peripheral antiinflammatory component. Paracetamol is a
good and promptly acting antipyretic.
Paracetamol has negligible antiinflammatory action. It is a poor inhibitor of PG
synthesis in peripheral tissues, but more active on COX in brain.
In contrast to aspirin, paracetamol does not stimulate respiration or affect
acid-base balance; does not increase cellular metabolism. Gastric irritation is
insignificant— mucosal erosion and bleeding occur rarely only in overdose. It does
not affect platelet function or clotting factors and is not uricosuric.
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Adverse effects In isolated antipyretic doses paracetamol is safe and well
tolerated. Nausea and rashes occur occasionally, leukopenia is rare.
Acute paracetamol poisoning.
Early manifestations are just nausea, vomiting, abdominal pain and liver
tenderness with no impairment of consciousness. After 12-18 hours centrilobular
hepatic necrosis occurs which may be accompanied by renal tubular necrosis and
hypoglycaemia that may progress to coma.
Mechanism of toxicity N-acetyl-p-benzoqui-noneimine (NABQI) is a highly
reactive arylating minor metabolite of paracetamol which is detoxified by
conjugation with glutathione. When a very large dose of paracetamol is taken,
glucuronidation capacity is saturated, more of minor metabolite is formed—hepatic
glutathione is depleted and this metabolite binds covalently to proteins in liver
cells (and renal tubules) causing necrosis.
Treatment. N-acetylcysteine
Uses. Paracetamol is one of the most commonly used analgesic for headache,
musculoskeletal pain, dysmenorrhoea, etc. where antiinflammatory action is not
required. It is one of the best drugs to be used as antipyretic.