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Non-Steroidal Anti-inflammatory drugs

(Analgesic, Anti-pyretic and Anti-inflammatory drugs OR Non-narcotic analgesics

or non-opioid analgesics)

These are chemically diverse but most are organic acids. They are different from
opioid analgesics in several respects.
1. Effective only in superficial pain of somatic origin but not of deep visceral
2. Effective in pain of low to moderate intensity.
3. Cause respiratory depression only in very high doses.
4. Have no abuse liability.

A) Analgesics and Anti-inflammatory
a. Salicylates
i. Aspirin
ii. Salicylamide
iii. Benorylate
iv. Diflunisal

b. Pyrazolone derivatives
i. Phenylbutazone
ii. Oxyphenbutazone

c. Indole derivatives
i. Indomethacin
ii. Sulindac

d. Propionic acid derivatives

i. Ibuprofen
ii. Ketoprofen
iii. Naproxen

e. Anthranilic acid derivatives

i. Mefenamic acid

f. Aryl-acetic acid derivatives

i. Diclofenac
ii. Tolmetin

g. Oxicam derivatives
i. Piroxicam
ii. Tenoxicam
iii. Meloxicam

h. Pyrrolo-pyrrole derivatives
i. Ketorolac

i. Sulfonanilide derivatives
i. Nimesulide

j. Alkanones
i. Nabumetone

B) Analgesic but poor anti-inflammatory

a. Para-aminophenol derivatives
i. Paracetamol (acetaminophen)
b. Pyrozolone derivatives
i. Metimazol (Dipyrone)
ii. Propiphenazone
c. Benzoxazocine derivatives
i. Nefopam

The principal therapeutic effects of NSAIDS derive from their ability to inhibit
prostaglandin production. The first enzyme in the prostaglandin synthesis is
prostaglandin endoperoxidase synthase, or fatty acid cyclooxygenase.
Prostaglandins, Prostacyclin (PGI2) and thromboxane A2 (TXA2) are produced
from arachidonic acid by the enzyme cyclo-oxygenase. There are two forms of
cyclooxygenase, termed COX-1 and COX- 2. The COX- 1 is a constitutive
isoform found in most normal cells and tissues. The COX-2 is induced in settings
of inflammation by cytokines and inflammatory mediators. The eicosanoids
produced by COX-1 participate in the physiological functions such as secretion of
mucus in the gastric mucosa, hemostasis and maintenance of renal function, while
those produced by COX-2 lead to inflammatory and other pathological changes. In
stomach COX-1 is constitutively expressed but not COX-2. This accounts for the
markedly reduced occurrence of gastric toxicity with the use of selective inhibitors
of COX-2. Arachidonic acid also can be converted, via the 5-lipoxygenase
pathway, to a variety of leukotrienes.
Inhibition of synthesis: Synthesis of cyclo-oxygenase products can be inhibited
by NSAIDs. Aspirin causes irreversible inhibition while other NSAIDs are
competitive and reversible inhibitors. Most NSAIDs are non-selective and inhibit
both COX-1 and COX-2 but some newer ones are relatively selective for COX-2,
such as Nimesulide, Nabumetone, Meloxicam.
Aspirin and NSAIDs inhibit cyclooxygenase and prostaglandin production, but do
not inhibit lipoxygenase and leukotrienes formation.
Glucocorticoids suppress the expression of COX-2 and thus COX-2 mediated
prostaglandin production. This effect may contribute in part to the anti-
inflammatory actions of glucocorticoids.
Aspirin covalently modifies both COX-1 and COX-2 and irreversibly inhibits
cyclooxygenase. Thus duration of effects of aspirin is related to the turnover rate
of cyclooxygenases. In the structure of COX-1, aspirin acetylates serine 530,
preventing the binding of arachidonic acid to the active site of the enzyme and
thus the ability of the enzyme to make prostaglandins. In COX-2, aspirin
acetylates a homologous serine at position 516. Although aspirin also blocks
COX-2, an interesting property of COX-2, not shared by COX-1, is that acetylated
COX-2 now synthesizes 15 ( R )-HETE. Interestingly, this aspirin-induced product
can undergo trans-cellular metabolism by the 5-lipoxygenase enzyme to yield 15-
epilipoxin A4, which exerts potent antiinflammatory actions and therefore may
potentiate the antiinflammatory action of aspirin.

Beneficial actions due to inhibition of PG synthesis.

Analgesia – prevention of pain nerve ending sensitization
Closure of ductus arteriosus

Shared toxicities due to inhibition of PG synthesis

Gastric mucosal damage
Bleeding due to inhibition of platelet function
Limitation of renal blood flow: Na+ and water retention
Delay / prolongation of labour
Asthma and anaphylactoid reaction in susceptible individuals

Respiration: the effects are dose-dependant. At anti-inflammatory doses

respiration is stimulated by peripheral increased CO2 production and central action
causing increased sensitivity of respiratory centre to CO2. Hyperventilation is
prominent in salicylate poisoning.

Acid-Base and electrolyte balance: Anti-inflammatory doses produce significant

changes. Initially respiratory stimulation washes out CO2 despite increased
production Respiratory alkalosis, which is compensated by increased renal
excretion of HCO3 (with accompanying Na+, K+, water).

Most adults treated with 4-6g/day of aspirin stay in a state of compensated

respiratory alkalosis, still higher doses cause respiratory depression with CO2
retention. While excess CO2 production continues Respiratory acidosis.
To this is added dissociated salicylic acid as well as metabolic acids (lactic,
pyruvic, acetoacetic) which are produced in excess. All these combine to cause
Uncompensated Metabolic Acidosis, since plasma HCO3- is already low.
Dehydration occurs in poisoning due to increased water loss in urine, increased
sweating, hyperventilation.

Cardiovascular system: Therapeutic doses have no effect. Larger doses increase

cardiac output to meet increased peripheral O2 demand and cause direct
vasodilatation. Toxic doses depress vasomotor centre.

GIT: Aspirin and released salicylic acid irritate mucosa, cause epigastric distress
and nausea. Aspirin remains unionized and diffusible in acid gastric juice because
its pKa = 3.5. But on entering the mucosal cell (pH 7.1) it ionizes and becomes in-
diffusible. This ‘ion trapping’ in gastric mucosal cell enhances gastric toxicity.
Further, aspirin particle coming in contact with gastric mucosa promotes local
back diffusion of acid focal necrosis of mucosal cells and capillaries
acute ulcers. The occult blood loss in stools is increased with any dose of aspirin.
Soluble aspirin tablets containing CaCO3 + citric acid are less liable to cause
gastric ulceration.

Urate excretion: Dose related effect is seen --- < 2g/day – urate retention and
antagonism of uricosuric drugs.
2-5g/day – often no change
> 5g/day increase urate excretion.
Aspirin in not suitable for use in chronic gout because high doses are required.

Blood: Aspirin, even in small doses, irreversibly inhibit TXA2 synthesis by

platelets. Thus it interferes with platelet aggregation and bleeding time is
prolonged to nearly twice the normal value. This effect lasts for about a week
(turn-over time of platelets).

Analgesia: PGs (E2 and I2) sensitize afferent nerve endings to pain. They affect
the transducing property of nerve endings – stimuli that normally do not elicit pain
are able to do so. Thus PGs induce hyperalgesia. NSAIDs block the pain
sensitizing mechanism.

Antipyresis: NSAIDs reduce body temperature in fever but do not cause

hypothermia in normothermic individuals. Fever, during infection is produced

through generation of pyrogens, ILs etc. which induce production of PG in

hypothalamus – raise its temperature set point. NSAIDs block the action of

Anti-inflammatory: NSAIDs inhibit PG synthesis at the site of injury. NSAIDs

inhibit COX, but inhibition of COX does not depress the production of other
mediators like LTs, PAF, cytokines etc.

Dysmenorrhoea: PGs are involved in dysmenorrhoea. NSAIDs lower utrine PG

levels and afford relief.

Ductus arteriosus closure: During feotal circulation the ductus arteriosus is kept
patent by local PGE2 and PGI2. At birth the synthesis of PG is switched off and the
ductus closes. If this fails to occur, small doses of aspirin or indomethacin bring
about closure in majority of cases. Administration of NSAIDs in late pregnancy
may promote premature closure of the ductus arteriosus.

Parturition: Sudden spurt of PG synthesis by uterus triggers labour. NSAIDs may

delay and retard labour.

Gastric mucosal damage: NSAIDs inhibit the synthesis of gastro-protective PGs

( PGE2 and PGI2). Deficiency of PGs reduces mucus and HCO3 – secretion, tends
to enhance gastric acid secretion. Thus NSAIDs are ulcerogenic. Paracetamol, a
very week inhibitor of COX is free of gastric toxicity and selective COX-2

Aspirin is absorbed from stomach and intestine. Its poor water solubility is the
limiting factor in its absorption. Microfining the drug and inclusion of an alkali
(solubility is more at higher pH) enhances absorption. However, higher pH also
favours ionization thus decreasing the diffusible form. Aspirin is deacetylated in
liver and plasma. It is conjugated with glycine and with glucoronic acid.

Adverse Effects:
a) Side-effects that occur at analgesic dose (0.3-1.5g/day) are nausea,
epigastric distress, increased occult blood loss in the stools, peptic
b) Hypersensitivity: Infrequent; urticaria, angioedema, anaphylactic
c) Anti-inflammatory doses (3-6g/day) produce the syndrome called
‘salicylism’ – dizziness, tinnitus, vertigo, excitement,
hyperventilation, electrolyte imbalance. In children having viral
infections (vericella, influenza), salicylate therapy may cause
‘Reye’s syndrome’ (hepatic encephalopathy)
d) Acute salicylate poisoning: It is more common in children,
manifestations are : vomiting, dehydration, acidotic breathing,
electrolyte imbalance, delirium, hallucinations, hyperpyrexia,
convulsions, coma, death.

It is symptomatic and supportive. Most important is external cooling and I.V fluids
with Na+, K+, HCO3-, and glucose.
Gastric levage.
Forced alkaline diuresis.

Precautions and contraindications:

1. Contraindicated in patients who are sensitive to it and in peptic ulcer,
bleeding disorders, in children suffering from chicken pox or influenza
( risk of Reye’s Syndrome)
2. Aspirin should be avoided in diabetes, CHF
3. Aspirin should be stopped one week before elective surgery
4. Given during pregnancy it may be responsible for low birth weight babies.
If taken near term, aspirin may cause prolonged labour, greater blood loss
(post-partum) and premature closure of ductus arteriosis.

1. Aspirin displaces warfarin, naproxen, phenytoin, sulphonyl ureas, and
methotrexate from plasma protein binding sites; toxicity of these drugs
may occur. Its anti-platelet action increases the risk of bleeding in patients
on oral anti-coagulants.
2. It inhibits tubular secretion of uric acid, at low doses and antagonizes
uricosuric action of probenecid.
3. It decreases the diuretic action of furosemide and thiazides and blocks the
action of spironolactones.

1. As analgesic. Headache, toothache, myalgia.
2. An antipyretic. Effective in fever of any origin.
3. Acute rheumatic fever. Dose 4-6g/day
4. Rheumatoid arthritis. Dose 3-5g/day
5. Osteoarthritis
6. Post myocardial infarction and post stroke patients. Aspirin inhibits TXA 2
synthesis in platelets.
7. Pregnancy induced hypertension and pre-eclampsia – imbalance between
TXA2 and PGI2.
8. Patent ductus arteriosis. Aspirin can bring about closure.

These comprise two classes.1: Esters of salicylic acid, obtained by substitution in
carboxyl group., e.g., methyl salicylate. 2: Salicylate esters of organic acids, in
which substitution is made in hydroxyl group, e.g.,aspirin, which is an ester of
acetic acid.
Pharmacological Properties:
Analgesia: Salicylates relieve pains of low intensity that arise from integumental
structures, rather than from viscera, especially headache,myalgia and arthralgia.