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WAYS TO PREVENT SIDE EFFECTS OF NONSTEROIDAL DRUGS
Sobirjonov Islombek Tavakkaljon ugli
Andijan State Medical Institute
https://doi.org/10.5281/zenodo.14752771
Abstract.
Adverse effects of medications, particularly those affecting the kidneys and
cardiovascular system, represent a significant global medical concern. Non-steroidal anti-
inflammatory drugs (NSAIDs) are among the primary contributors to these complications, as
they are one of the most widely used drug classes. The pharmacological action of NSAIDs
involves inhibiting the synthesis of vasodilatory renal prostaglandins by deactivating the
cyclooxygenase enzyme. This inhibition can result in vasomotor acute kidney injury, acute
tubulointerstitial nephritis, chronic kidney disease, and other renal complications.
Kеywоrds:
kidneys, nonsteroidal anti-inflammatory drugs, glomerular filtration rate.
INTRОDUСTIОN
Side effects of various drugs have become a serious medical and social problem today,
which is explained by [1]:
• their often unjustified prescription, inadequate dosages and unjustified duration of
use;
• interactions between different classes of drugs;
• insufficient understanding of the pharmacodynamic and pharmacokinetic
characteristics of drugs;
• insufficient knowledge of the features of side effects of different classes of drugs;
• lack of proper monitoring of patients during drug therapy;
• late diagnosis of side effects that have developed, which makes it difficult to eliminate
them and increases the unfavorable prognosis;
• an increase in the frequency of hospitalizations and deaths due to side effects of drugs;
• high financial costs aimed at eliminating side effects.
MАTЕRIАLS АND MЕTHОDS
The high frequency (often unjustified) of prescribing NSAIDs and a wide range of side
effects (including life-threatening ones), including complications from the gastrointestinal
tract (dyspepsia, ulcers, bleeding and perforation of the upper and lower gastrointestinal
tract), cardiovascular system (destabilization of blood pressure and heart failure, increased
risk of cardiovascular catastrophes), liver and kidneys, confirm the complexity and
importance of studying this problem. This review examines the renal and cardiovascular side
effects of NSAIDs. Discussion of other complications developing with the use of NSAIDs is not
the purpose of our report.
RЕSULTS АND DISСUSSIОN
Most reports note a relatively low frequency of renal side effects, amounting to 1–4% in
individuals taking NSAIDs for a long time. However, due to their widespread use, the
frequency of adverse events caused by NSAIDs in the structure of all drugs used is 25% in the
USA and 21% in the UK. Serious side effects of NSAIDs requiring hospitalization have a high
proportion [2]. L.A. Dudareva and M.M. Batyushin consider the side effects of NSAIDs
(including renal ones) as a “national tragedy” [3]. Many studies and their meta-analyses have
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demonstrated a link between the development of acute kidney injury (AKI) and the use of
NSAIDs. Thus, C. Huerta, J. Castellsaque et al. [4] studied the risk of developing AKI in 386,916
patients (aged 50–84 years). During the observation period, 103 cases of AKI were diagnosed.
In patients receiving NSAIDs, the risk was 3 times higher compared to the control (odds ratio -
OR 3.2, 95% confidence interval - CI 1.8–5.8). The increased risk was associated with an
increased duration of therapy and high doses of NSAIDs (OR 3.4, 95% CI 1.6–7.0). The meta-
analysis presented by P. Ungprasert et al. [2] showed a statistically significant increase in the
risk of developing AKI with the use of NSAIDs (OR from 1.58 to 2.11). At the same time, there
were no differences between individual representatives of NSAIDs. The risk was somewhat
lower, but statistically insignificant (p≥0.19) for cyclooxygenase (COX)-2-selective drugs.
NSAIDs inhibit COX, which catalyzes the process of PG synthesis. Under the influence of
COX, cyclic endoperoxide PgG2 is formed from arachidonic acid, which is then converted into
PgH2 by peroxidation with the simultaneous production of unstable toxic oxygen radicals.
PgH2, in turn, is converted into PgE2, PgI2, PgF2 and thromboxane. PG synthesis is activated
by vasoactive hormones and cytokines, as well as hypoxia, ischemia and cellular mechanical
disorders [4]. The formation and localization of different PGs are determined by the features
of the expression of isoenzymes - COX-1 and COX-2. Expression of COX-1 occurs in arteriolar
smooth muscle, in mesangial and endothelial cells, parietal epithelial cells of the
Shumlyansky-Bowman capsule, in cells of the cortical and medullary collecting ducts.
Expression of COX-2 occurs in cells of the macula densa, in epithelial cells of the ascending
thick limb of the loop of Henle, as well as in podocytes and arteriolar smooth muscle, in
medullary interstitial cells and in cells of the cortical part of the collecting ducts and proximal
tubules [1].
NSAIDs (including gels) are the most common cause of vasomotor (hemodynamic) AKI.
This complication is caused by blockade of vasodilator PG synthesis, leading to decreased
blood flow in afferent arterioles, glomerular hydrostatic pressure and SCF.
Vasomotor (hemodynamic) AKI is often caused by risk factors, including:
• hypovolemia;
• congestive heart failure;
• nephrotic syndrome;
• diabetes mellitus;
• decompensated liver cirrhosis;
• CKD (regardless of cause, especially stages III–IV);
• infections;
• combination of NSAIDs with diuretics, angiotensin-converting enzyme inhibitors
(ACEI), angiotensin II receptor blockers (ARB);
• old age.
Features of the pharmacokinetics of NSAIDs may contribute to the risk of nephrotoxic
effects. NSAID metabolites and the drug itself are excreted mainly by the kidneys due to
glomerular filtration and proximal tubular secretion. With a decrease in renal function, serum
levels of NSAIDs and their metabolites increase, and therefore the risk of developing side
effects.
СОNСLUSIОN
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The use of NSAIDs is steadily increasing in various areas of medicine, and therefore it is
important to raise awareness among physicians and pharmacists regarding the risk of
developing NSAID-associated renal side effects. It should be taken into account that even
short-term use of NSAIDs can cause not only AKI with a possible favorable outcome, but also a
permanent decrease in renal function, up to the development of ESRD, requiring
hemodialysis. Given the inconsistency of retrospective studies on the effect of NSAIDs on the
development and progression of CKD, it is necessary to conduct large CRIs.
References:
1.
Musu M et al. Acute nephrotoxіcіty of NSAІD from the fetus to the adult. Eur Rev Med
Pharmacol Scі 2011; 15 (12): 1461–72.
2.
Davіs A, Regіstrar G. The dangers of NSAІDs: look both ways. Br J Gen Pract 2016; 66
(645): 172–3. DOІ: 10.3399/bjgp16X684433
3.
Paі A. Keepіng kіdneys safe: the pharmacіst`s role іn NSAІD avoіdance іn hіgh-rіsk
patіents. Pharmacy Today 2014; 20 (12): 54–64.
4.
Hörl W et al. Nonsteroіdal Antі-Іnflammatory Drugs and the Kіdney. Pharmaceutіcals
(Basel) 2010; 3 (7): 2291–321.
