A Textbook of Clinical Pharmacology and Therapeutics

Adverse effects of NSAID on the stomach are covered in
Chapter 25. They can be reduced by co-administration of a pro-
ton 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 dis-
eases 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 glomeru-
lar 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 aspirinor low doses
ofsulindac. This is because sulindacis a prodrug that acts
through an active sulphide metabolite; the kidney converts the
sulphide back into the inactive sulphone. Sulindacis 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 rea-
son (inhibition of renal prostaglandin biosynthesis), NSAIDs all

interact non-specifically with antihypertensive medication, ren-

dering 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, aspirinandsulindacare 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, antag-

onize the effects of diuretics and exacerbate heart failure.

(Some of their interaction with diuretics also reflects competi-

tion 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

168 ANTI-INFLAMMATORY DRUGS AND THE TREATMENT OF ARTHRITIS

H

COOH

COOH

PGG (^2) OOH
2O 2
O
O
COOH
PGH 2 OH
2e
O
O
Phospholipid
Arachidonic acid
Phospholipase A2
Cyclo-oxygenase
Peroxidase
Synthases
Prostacyclin Prostaglandins
(PGI 2 )
Thromboxane A 2
PGH
synthases
Figure 26.1:The arachidonic acid
cascade.