TOPIC 11: NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDS). DRUGS USED TO TREAT GOUT AND RHEUMATOID
ARTHRITIS.
NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs)
Inflammation – triggered by release of chemical mediators from injured tissues and
migrating cells. The specific chemical mediators include: histamine, 5-HT,
prostaglandins, bradykinin, interleukins.
Classification:
A. Non-selective COX inhibitors (traditional NSAIDs)
1. Salicylates: Acetylsalicylic acid (аspirin).
2. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
3. Indole derivatives: Indomethacin.
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5. Оxicam derivatives: Pyroxicam, Tenoxicam.
6. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
Has minimal ulcerogenic effect.
7. Pyrrolo-pyrrole derivatives: Ketorolac.
Similar to narcotic analgesics.
8. Anthranilic acid derivatives (fenamates): Mephenamic acid.
B. Preferential COX-2 inhibitors: Nimuselide, Meloxicam, Nabumetone.
C. Selective COX-2 inhibitors (coxibs): Celecoxib, Etoricoxib, Rofecoxib,
Valdecoxib, Parecoxib (for injections, for postoperative pain).
D. Analgesic-antipyretics with poor anti-inflammatory action:
1. Pyrazolone derivatives: Metamizole, Propiphenazone.
2. Para-aminophenol derivatives: Acetaminophen (paracetamol).
3. Benzoxazocine derivative: Nefopam.
Classification of NSAIDs
1. Short-acting (Т1/2 = 2-8 hours):
Aspirin; Ibuprofen; Ketoprofen; Indomethacin; Fenoprofen; Diclofenac; fenamates
(Mefenamic acid, Meclofenamate); Tolmetin; Flurbiprofen.
2. Intermediate-acting (Т1/2 =10-20 hours): Naproxen; Sulindac; Diflunisal,
Nabumetone, Fenbufen.
3. Long-acting (Т1/2 = 24 and more hours): oxicams (Piroxicam);
Phenylbutazone
Mechanism of Action:
They inhibit enzyme cyclooxygenase (COX) and, subsequently, prostaglandin
synthesis.
Pharmacological effects:
• Anti-inflammatory
• Analgesic
• Antipyretic
• Antiplatelet effect
• Gastrointestinal effects (ulcerogenic)
• Renal effect (Decreases Renal Blood Flow).
• Respiration: Aspirin at the therapeutic doses inc. alveolar respiration.
• Uric acid excretion:
2 gm/day – retention of uric acid and inhibition of action of uricosuric drugs.
2-5 gm/day – variable effect.
>5 gm/day – increases urate excretion but this dose is not tolerated on chronic basis.
Uses.
For the symptomatic relief of the following conditions:
• Rheumatoid arthritis, rheumatic fever
• Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis,
Reiter's syndrome)
• Acute gout
• Dysmenorrhoea (menstrual pain)
• Metastatic bone pain
• Headache and migraine, arthralgia, myalgia
• Postoperative pain
• Mild-to-moderate pain due to inflammation and tissue injury
• Pyrexia (fever)
• Ileus
• Renal colic
• Preventing thrombosis (aspirin 100-325 mg/day) in MI, DVT, TIAs, stroke.
They are also given to neonate infants whose ductus arteriosus is not closed within
24 hours of birth.
Pharmacokinetics:
• Salicylates are absorbed through intact skin.
• After oral administration, salicylates are absorbed from the stomach and the
small intestine.
• Rectal absorption of salicylates is slow and unreliable, but it is a useful route
of administration for vomiting children.
• Salicylates cross the blood-brain barrier and the placenta.
Dose of aspirin:
• Antipyretic-analgesic dose is 300-600 mg repeated every 4 hours and given
after meal.
• Anti-inflammatory dose (arthritis, in acute rheumatic fever: 4-6 gm/day in
divided doses of 1 gm.
Side Effects:
1. Gastritis and peptic ulcer.
2. Bleeding, aspirin should not be taken for at least 1 week prior to surgery.
3. Decreasing in renal blood flow and interstitial nephritis.
4. Hypersensitivity: urticaria, bronchoconstriction, shock.
5. Reye’s syndrome: hepatitis with cerebral edema in infants who have a fever
secondary to a viral infection.
Cautions and C/I for aspirin
Cautions:
• Patients who are sensitive.
• Patients with peptic ulcer, bleeding tendencies.
• Children under the age of 12 years old suffering from chicken pox or influenza
due to the risk of Reye’s syndrome.
• In chronic liver disease.
• In Patients with diminished cardiac reserve or frank CCF.
Contra-indications:
• Patients with hemophilia
• Stop 1 week before elective surgery
• When given during pregnancy, it produces low birth babies, delayed and
prolonged labor, greater post-partum hemorrhage and premature closure of
ductus arteriosus if aspirin is taken near term.
Salicylism: vertigo, tinnitus, difficulty in hearing, drowsiness, dizziness,
restlessness; delirium, mental confusion, lethargy; hallucinations, convulsions,
coma, respiratory and metabolic acidosis, death from respiratory failure.
A – asthma.
S – salicylism.
P – peptic ulcer, phosphorylation-oxidation uncoupling/PPH/Platelet
disaggregation/Premature closure of PDA.
I – intestinal blood loss.
R – Reye’s syndrome.
I – Idiosyncrasy.
N – Noise (tinnitus).
Treatment of aspirin toxicity:
✓ Decrease absorption - activated charcoal, emetics, gastric lavage.
✓ Enhance excretion - alkalinize urine, forced diuresis, hemodialysis.
✓ Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes,
glucose, etc.
PARACETAMOL
Has analgesic and antipyretic actions but only weak anti-inflammatory effects.
It is given orally and metabolized in liver (t1/2 = 2-4 h).
Toxic doses cause nausea and vomiting, then, after 24-48 hours, potentially fatal
liver damage by saturating normal conjugating enzymes causing the drug to be
converted by mixed function oxidases to N-acetyl-p-benzoquinone imine. This, if
not inactivated by conjugation with glutathione, reacts with cell proteins and kills
the cell.
Agents which increase glutathione (acetylcysteine IV or methionine orally) can
prevent liver damage if given early.
SELECTIVE COX-2 INHIBITORS
Though NSAIDs are extremely useful drugs, they are poorly tolerated particularly
when they are used for long periods. Gastric irritation is the common side effect
which limits its use.
Selective inhibition of COX-2 was found to be advantageous because COX-2 is
involved in inflammation and COX-1 which is gastroprotective is spared. Some of
the older NSAIDs have relative selectivity for selective COX-2 (meloxicam) but
highly selective COX-2 inhibitors with several times greater selectivity for COX-2
have been synthesized – like the coxibs – celecoxib, rofecoxib, parecoxib,
etoricoxib and valdecoxib.
Nimesulide is also a selective COX-2 inhibitor.
Advantages
• These drugs have analgesic, anti-inflammatory and antipyretic effects like
non-selective NSAIDs but with much less gastric ulcerogenic effects.
• They also do not inhibit platelet aggregation because COX-1 is involved in
platelet function.
Disadvantages:
Clinical studies have shown that the use of selective COX-2 inhibitors increases the
risk of CV and cerebrovascular thrombotic events – may increase the risk of
myocardial infection and stroke.
They are indicated only in patients who cannot tolerate NSAIDs and are at a high
risk of developing peptic ulcer.
Celecoxib can cause hypertension and edema which can be troublesome in patients
with CV problems.
It can be used in acute painful conditions like postoperative pain, dysmenorrhea and
dental pain as well as in osteoarthritis and rheumatoid arthritis in patients who cannot
tolerate other NSAIDs.
DRUGS USED TO TREAT RHEUMATOID ARTHRITIS
The drugs used in rheumatoid disease are the NSAIDs and the disease modifying
anti-rheumatoid drugs (DMARDs).
DMARDs are slow-acting drugs and can improve symptoms and reduce the
inflammatory process. They retard progress of the disease but do not halt it entirely.
Classification of anti-rheumatoid drugs
I. NSAIDs
II. DMARDs:
a. Immunosuppressants: Methotrexate, Cyclophosphamide, Azathioprine,
Cyclosporine, Leflunomide.
b. Biological agents:
• TNF-alpha blockers – Etanercept, Infliximab, Adalimumab.
• Inhibitors of T-cell activation – Abatacept.
• IL-1 antagonist – Anakinra.
• Anti B lymphocyte antibody – Rituximab.
c. Gold salts: Aurothiomalate, Auronofin.
d. Others: Penicilamine, Sulphasalazine, Chloroquine, Hydroxychloroquine.
III. Adjuvants: glucocorticoids.
DRUGS USED TO TREAT GOUT
Gout is characterized by deposition of sodium urate crystals in the joint, causing
painful arthritis.
Acute attacks are treated with indomethacin, naproxen, piroxicam or other
NSAIDs but not with aspirin, which raises plasma urate levels at low doses by
inhibiting uric acid secretion in the renal tubules.
Colchicine is effective in gout. It binds to tubulin in leucocytes and prevents their
migration to the areas of uric acid deposition, and hence reduces the inflammatory
responses. However, colchicine causes nausea, vomiting, diarrhoea, and abdominal
pain.
Prophylactic treatment of gout
Allopurinol reduces plasma urate by inhibiting xanthine oxidase, the enzyme,
responsible for urate synthesis. It is useful in patients with recurrent attacks of gout.
Uricosuric drugs, such as sulfinpyrazone and probenecid, inhibit renal tubular
reabsorption of uric acid, increasing its excretion.
Plenty of water should be taken to avoid the crystallization of urate in the urine.
These drugs are less effective and more toxic than allopurinol. They are normally
used in patients who cannot tolerate allopurinol.
Side Effects of allopurinol: GIT distress, peripheral neuropathy, rash, vasculitis,
and stone formation.
Side Effects of probenecid and sulfinpyrazone: GIT distress, rash, nephritic
syndrome, crystallization if high excretion of uric acid. ASA may decrease effects.
