Dr ANECITA GIGI LIM looks at how NSAIDs work and in particular how using NSAIDs can increase the risk of acute kidney injury.
NSAIDs (nonsteroidal anti-inflammatory drugs) are used to reduce inflammation. However, this is not the only indication for NSAIDs, as they can also be used for fever and or even in coagulation. Therefore, NSAIDs are a drug class that groups drugs providing pain relief, fever relief and, in higher doses, anti-inflammatory relief (see table 2 for list of common NSAIDs).
Medsafe (New Zealand Medicines and Medical Devices Safety Authority) reported in 2013 that not one but all NSAIDs have been associated with numerous adverse events, including the development of acute kidney injury (AKI).
Adverse effects associated with NSAIDs
The use of NSAIDs has long been linked to a number of adverse effects. Prolonged use of NSAIDs has been associated with increased risks of gastrointestinal problems, which can result in gastrointestinal bleeding. Long-term use of NSAIDs has also been associated with erectile dysfunction as shown in a Finnish study in 2005. NSAIDs are also classified as teratogenic as they have been associated with patent ductus arteriosus, premature birth and polyhydramnios, so are not recommended in pregnancy.
The drug class has also been linked to allergy and allergy-type hypersensitivity reactions, which can be idiosyncratic and at times life threatening. Apart from aspirin, both the newer selective COX-2 inhibitors and the traditional anti-inflammatory NSAIDs ibuprofen and diclofenac are known to increase the risk of myocardial infarction and stroke. Merck’s immediate withdrawal of rofecoxib (vioxx) worldwide in 2004 was particularly related to the likelihood of the drug causing serious cardiovascular events even at commonly used doses. Therefore, some NSAIDs are not recommended for people who have had a previous heart attack.
The most important adverse drug reaction associated with NSAIDs is renal adverse effects. In New Zealand acute renal injury was highlighted in a report by CARM (Centre for Adverse Reaction and Monitoring) in 2000. The report showed that 70 per cent of the 119 reports of renal adverse reactions associated with NSAIDs (including COX-2 inhibitors) were serious and resulted in four deaths and 12 reactions that were considered life threatening.
How can NSAIDs use cause acute kidney injury (AKI)?
The use of NSAIDs has increased worldwide. PHARMAC statistics show that ibuprofen is the most commonly prescribed drug in New Zealand followed by fellow NSAIDs diclofenac and naproxen.
To understand the mechanism of how NSAIDs work, it is important to look first at the physiology of pain and fever. In most cases, inflammation and fever are associated with the normal immune response. However, it is the pain associated with inflammation that causes discomfort for many people so this article will focus on the NSAIDs’ mechanisms for reducing inflammation.
Inflammation is a complex protective response to an infection – or other injury –and involves immune cells, blood vessels and molecular mediators. Through the release of different substances from the damaged tissue, inflammation directs the body’s defences to wall off the affected area, attack and kill any invaders, dispose of dead and damaged tissue, and initiate the process of repairing tissue. Some of the substances released in inflammation are chemical mediators. They are compounds released by cells to trigger signalling mechanisms from one cell to another.
Many mediators are released in tissue injury, and one particular one is called arachidonic acid. When arachidonic acid is metabolised by the enzyme cyclo-oxygenase 2 (COX2), it results in prostaglandins, which contribute to the classic inflammation symptoms of redness, heat, swelling and pain. It is both cyclo-oxygenase 1 (COX1) and COX2 that cause the production of inflammatory prostaglandins, but it is mainly COX2 that is associated with the pain and swelling of inflammation.
NSAIDs work by blocking the production of inflammatory prostaglandins. Paracetamol (acetaminophen) is not considered an NSAID as it has relatively little anti-inflammatory activity. Its mechanism of action is not completely understood but unlike NSAIDs, paracetamol’s anti-inflammatory action is concentrated on the central nervous system.
But when a drug inhibits the production of an enzyme like COX1 and COX 2 it impacts not only on the prostaglandin synthesis in the inflamed area, but also elsewhere in the body. Prostaglandin is synthesised in the walls of blood vessels and serves the physiological function of preventing needless clot formation, as well as regulating the contraction of smooth muscle tissues. Renal prostaglandin causes dilatation of the renal afferent arterioles, which helps maintain the kidney’s essential glomerular filtration process.
Glomerular filtration is the first step in urine formation. The kidney’s glomerulus network of capillaries receive blood through the afferent arterioles and filter out waste and excess fluid. Effective glomerular filtration is the sign of a healthy functioning kidney and is measured using the glomerular filtration rate (eGFR) value.
NSAIDs inhibit COX1 and COX2, so they also inhibit the synthesis of prostaglandin which is protective for the renal smooth muscle. Prostaglandin E2 is partly responsible for the vasodilatory effects on the afferent arteriole which increases blood flow to the glomerulus. This means the absence of prostaglandin E2 can lead to the constriction and dilatation of the renal afferent arterioles being compromised.
NSAIDs use on their own, and if used appropriately and in short term, is not harmful. However, there are situations when using NSAIDs can further compromise glomerular filtration causing AKI; that is, damage to the kidney tissue caused by decreased renal blood flow. People who develop AKI may have an increased risk of developing chronic kidney disease, therefore it is important to identify the underlying cause to reduce further harm. Medsafe lists the risk factors as shown in Table 1. When these risk factors are present, nurses must watch for potential effects and ensure that interventions are in place to minimise harm to the patient.
NSAIDs are commonly used for pain. NSAIDS are effective for inflammation and pain. However, NSAIDs can cause adverse renal effects. It is therefore important that nurses understand that certain populations, such as the elderly, may be more at risk to AKI when taking NSAIDs, and that some drugs may increase the risks of AKI when given together with NSAIDs.
Nurses must be vigilant around situations that can lead to AKI and ensure that they review medications regularly and advise patients to report any adverse effects. :
AUTHOR: Anecita Gigi Lim RN PhD is a senior lecturer at the University of Auckland’s School of Nursing and teaches in nurse prescribing and pharmacology.
NB: Full references for this article can be viewed in the online version at www.nursingreview.co.nz.
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