Pharmacology: NSAIDs

Mechanism of action:
Non-steroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory activity, which is
attributable in large part to inhibition of the cyclo-oxygenase pathway by which
prostaglandins (some of which are pro-inflammatory) are formed from arachidonic acid. They
also possess analgesic and antipyretic activity but not all NSAIDs manifest these three actions
to the same extent.

Effects & side effects:

Regular use of NSAIDs is associated with unwanted effects such as dyspepsia, gastric
damage, ulcers and bleeding and renal insufficiency, particularly in the elderly. These effects
are attributable to the inhibition of the synthesis of cytoprotective prostaglandins in the gut
and the inhibition of the synthesis of vasodilator prostaglandins in the kidney.

Two types of cyclo-oxygenase (COX) have been identified and these are designated COX-1
and COX-2. Selective inhibitors of COX-2, an enzyme which is inducible in inflammatory cells,
were expected to provide anti-inflammatory effects without inhibiting the physiological
prostaglandin synthesis which is carried out predominantly by the constitutive (ie always
present) enzyme, COX-1. The most commonly available NSAIDs (such as naproxen, aspirin )
are non-selective inhibitors of both COX-1 and COX-2 and the majority of them have greater
inhibitory effect on COX-1 than COX-2. Selective COX-2 inhibitors (celecoxib and rofecoxib),
were introduced in Australia several years ago and they were prescribed quite extensively.

The COX 2 selective inhibitors are as efficacious as the non-selective inhibitors but they do
have less (although not negligible) incidence of gastro-intestinal side effects. The risk for
other adverse effects, such as renal toxicity appears to be similar for conventional NSAIDs
and the COX 2 selective drugs. In 2004, rofecoxib was withdrawn worldwide by its
manufacturer because of an increased risk of vascular events (two fold increase in myocardial
infarction, stroke or cardiovascular death). Whilst the same risks have not been demonstrated
with celecoxib, current guidelines recommend the use of celecoxib to patients without known
cardiovascular risk factors and who do not tolerate conventional NSAIDs.

Aspirin is far more potent at inhibiting platelet cyclo-oxygenase than the other NSAIDs. This
action inhibits the synthesis of the pro-aggregatory substance thromboxane A2 so aspirin is
associated with a higher degree of bleeding than other NSAIDs.

Pharmacokinetics:
Whilst most NSAIDs have relatively short plasma half lives (< 6 hours), a once or twice daily
dosage may be sufficient to provide symptomatic relief because effective drug concentrations
persist in synovial fluid well beyond the duration of the plasma half life. Most NSAIDs are
metabolised by the liver.

ANTI-INFLAMMATORY CORTICOSTEROIDS

Mechanism of action:
The anti-inflammatory activity of corticosteroids relates to their ability to decrease the
production of many pro-inflammatory cytokines such as TNF and many interleukins.
Corticosteroids also decrease the clonal T and B cells and decrease the activity of cytokine
secreting T cells.

Effects:
In addition to anti-inflammatory activity corticosteroids have diverse metabolic effects.
Glucocorticoid activity includes increased gluconeogenesis, decreased uptake and utilisation
of glucose, resulting in a tendency to hyperglycaemia. Corticosteroids increase protein
catabolism, leading to side effects such as muscle wasting. The mineralocorticoid activity of
corticosteroids may lead to sodium and fluid retention and an increase in blood pressure.

Prednisolone is the most commonly used anti-inflammatory corticosteroid. It is approximately

four times more potent than hydrocortisone in terms of glucocorticoid activity and it has
approximately 80% of the mineralocorticoid activity of hydrocortisone. Since the anti-
inflammatory activity parallels the glucocorticoid activity, prednisolone is four times more
potent than hydrocortisone as an anti-inflammatory agent.

Pharmacokinetics:
Prednisolone has a plasma half-life of approximately three hours but its biological half-life
(which is the half-life of the biological responses it causes in the body) range from 18 to 36
hours. Thus, it is usually given once a day. A dose of 7 or 8 mg (which is equivalent to
approximately 35mg of hydrocortisone) represents the daily requirement of corticosteroids.

If the daily dose of prednisolone increases above this level, there is increasing likelihood of
side effects.

Side effects:
include hyperglycaemia, oedema, increased blood pressure. With chronic administration
suppression of hypothalamic pituitary adrenal axis, decreased response to infection and
osteoporosis may occur.

HEPARIN AND LOW MOLECULAR WEIGHT HEPARIN (LMWH)

Mechanism of action:
Unfractionated heparin (UN) comprises a family of mucopolysaccharides with molecular
weights ranging from 3,000 to 40,000. The anticoagulant action of heparin relates to its
ability to enhance the activity of antithrombin III, which is an endogenous inhibitor of
coagulation. Its main action is to inhibit thrombin and activated factor X.

Metabolism:
Heparin is degraded by enzymes called "heparinases" and it has a half life of approximately
2- hours

Uses:
Heparin is given intravenously (for the treatment of thromboembolic disease) or
subcutaneously (for prophylaxis). Intravenous heparin therapy should be monitored by
regular measurement of the activated partial thromboplastin time (APTT). When it is used
subcutaneously for the prevention of thromboembolic disease there is no prolongation of the
APTT so there is no point in monitoring this measure.
Side effects:
The main side effect is bleeding. Heparin induced thrombocytopaenic syndrome (HITS) can
also occur.

LMWH increases the action of antithrombin III in binding factor Xa but there is little activity
against thrombin. Thus, the APTT is of no use in monitoring their activity. Measures of factor
Xa are necessary. The LMWH have similar efficacy to heparin. LMWH can be given
subcutaneously and they are excreted mainly by the kidney. Dose reduction may be
necessary in patients with significant renal impairment.

WARFARIN

Class:
Warfarin is the most commonly used oral anticoagulant.

Mechanism of action:
It is a vitamin K analogue and it interferes with the carboxylation step in the synthesis of
clotting factors II, VII, IX and X. The onset of anticoagulant action of warfarin will depend
upon the time it takes for clotting factors to be depleted, and this usually requires some days.

Effects: The peak pharmacological effect after a given dose occurs at about 48 hours and it
can last up to four or five days. Its efficacy is monitored by measuring the International
Normalised Ratio (INR). Depending upon the clinical indication, the INR is normally
maintained in the range of 2 to 3.

Metabolism:
It is metabolised by cytochrome P450 in the liver and this is the basis of potential drug
interactions

Side effects :
The main side effect is bleeding and great care must be taken with concurrent admission of
other drugs, which may increase the likelihood of bleeding, either because of a
pharmacodynamic interaction (e.g. aspirin), or a pharmacokinetic interaction (such as co-
administration of imidazole), which inhibits hepatic metabolism of warfarin.

Further reading:
Cardiovascular safety of rofecoxib (Vioxx) : lessons learned and unanswered questions. Med J
Aust (2004) 181, 524

Author: Paul Seale