A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

168 ANTI-INFLAMMATORY DRUGS AND THE TREATMENT OF ARTHRITIS
Phospholipid
Phospholipase A2
H
COOH
Arachidonic acid
Cyclo-oxygenase
Peroxidase
O
O
2O 2
PGG 2 OOH
COOH
PGH
synthases
2e
COOH
O
O
Synthases
PGH 2
OH
Prostacyclin
(PGI 2 )
Prostaglandins
Thromboxane A 2
Figure 26.1: The arachidonic acid
cascade.
Adverse effects of NSAID on the stomach are covered in
Chapter 25. They can be reduced by co-administration of a proton
pump inhibitor, such as omeprazole (Chapter 34).
The main prostaglandins produced in human kidneys are
prostacyclin (PGI 2 ) and prostaglandin E 2 . NSAIDs predictably
cause functional renal impairment in patients with pre-existing
glomerular disease (e.g. lupus nephritis), or with systemic diseases
in which renal blood flow is dependent on the kidneys’
ability to synthesize these vasodilator prostaglandins. These
include heart failure, salt and water depletion, cirrhosis and
nephrotic syndrome. The elderly, with their reduced glomerular
filtration rate and reduced capacity to eliminate NSAIDs, are
especially at risk. Renal impairment is reversible within a few
days if the NSAID is stopped promptly. All NSAIDs can cause
this effect, but it is less common with aspirin or low doses
of sulindac. This is because sulindac is a prodrug that acts
through an active sulphide metabolite; the kidney converts the
sulphide back into the inactive sulphone. Sulindac is therefore
relatively ‘renal sparing’, although, at higher doses, inhibition
of renal prostaglandin biosynthesis and consequent renal
impairment in susceptible patients do occur. For the same reason
(inhibition of renal prostaglandin biosynthesis), NSAIDs all
interact non-specifically with antihypertensive medication, rendering
them less effective. NSAIDs are a common cause of loss
of control of blood pressure in treated hypertensive patients.
Again and for the same reasons, aspirin and sulindac are less
likely to cause this problem.
PGE 2 and PGI 2 are natriuretic as well as vasodilators, and
NSAIDs consequently cause salt and water retention, antagonize
the effects of diuretics and exacerbate heart failure.
(Some of their interaction with diuretics also reflects competition
for the renal tubular weak acid secretory mechanism.) As
well as reducing sodium excretion, NSAIDs reduce lithium
ion clearance and plasma concentrations of lithium should be
closely monitored in patients on maintenance doses of lithium
in whom treatment with an NSAID is initiated. NSAIDs
increase plasma potassium ion concentration.
In addition to these predictable effects on the kidney,
NSAIDs can cause acute interstitial nephritis, presenting as
nephrotic syndrome or renal impairment that resolves after
withdrawing the drug. This is an idiosyncratic effect, unique
to a particular drug within one susceptible individual. NSAIDs
worsen bronchospasm in aspirin-sensitive asthmatics (who
sometimes have a history of nasal polyps and urticaria, see