Why are NSAID's the villain?

As clinicians, prescribers and pharmacists we have been cautioned time and time again on the use Non - SteroidalAnti inflammatory drugs(NSAID’s). You pick up a pack from local convenience store of Ibuprofen or take aprescription to your chemist you will find a long list of cautions and contraindications. As a prescriber you think at-least twice whilst prescribing NSAIDs, especially if it is on a repeat prescription.

We all have heard or read the bigger print regarding gastric bleed, kidney damage, cardio-vascular issues andexacerbation of asthma as far as NSAIDs are concerned. Here we shall revisit the reasons behind such cautions.

There are two types of anti-inflammatory drugs namely; Steroids and Non-Steroidal (NSAIDs). The process of inflammation is mediated via various prostaglandins and it all starts with the phospholipids of the cellmembrane. The first step of Prostaglandin production is derivation of Arachidonic acid from Phospholipids withthe help of Phospholipase A2. This is blocked by steroids and hence puts an end to any subsequent cascade.Arachidonic acid has two products guided by two different enzymes. One of them is Cyclo-oxygenase ( has twosubsets COX-1 and COX-2) and the other one is Lypo-Oxygenase. Of these two pathways, the COX pathway primarily deals with inflammation, platelets and vascular permeability etc, whereas LOX pathway is more specificto the respiratory system.

COX-1 pathway produces prostaglandins (PGI-2, PGE2 and TXA-2) which exert the below effects:

  • Reduces gastric acid secretion (via PGI-2) → Gastro-protective

  • Stimulates GI mucous (Via PGI-2 and PGE-2) → Gastro-protective

  • Maintains renal blood flow (afferent arterioles dilation hence increases GFR via PGE-2 and PGI-2) → renal protective

  • Enhances platelet aggregation and vasoconstriction (via TXA-2)

Therefore its inhibition will lead to gastric irritation/haemorrhaging/bleed, reduced GFR and reduced plateletaggregation at platelet level.

COX-2 pathway also produces prostaglandin mainly PGE-2 and PGI-2, which exert the following effects:

  • Inflammation (PGE-2)

  • Endothelial vasodilation and inhibit platelet aggregation (PGI-2)

LOX pathway produces Leukotrienes (LTC-4 and LTD4)

These leukotrienes cause bronchoconstriction,oedema and mucous secretion in respiratory organs.

Now let’s see if COX (both COX-1 and COX-2) is inhibited by non-selective NSAIDs there is likely shift of balanceto LOX pathway. This explains why people with Asthma/respiratory problems are cautioned regarding use ofNSAIDs.

There are non-selective NSAIDs (such as Ibuprofen, Naproxen), preferentially COX-2 inhibiting NSAIDs ( such asMeloxicam, Nimesulide, Etodolac) and selective COX-2 inhibitors (Etoricoxib and Celecoxib). This is based on a ratio of theability of the drug to inhibit COX-1/COX2 at the therapeutic dose. The closer the ratio to 1, the more non-selective the NSAIDis. As the ratio increases the selectivity towards COX-2 increase. The figure indicates that Ibuprofen and Naproxen have gotalmost no preference of inhibition, whereas Rofecoxib is a strong COX-2 inhibitor. Diclofenac and celecoxib have almostsuperimposable profiles in their COX inhibiting abilities.own in the table (1) above.

In the physiologically healthy state there is minimal COX-2 in body (2). However in response to pro- inflammatorystimuli COX-2 expression increases and this calls for appropriate intervention to inhibit the COX-2 pathwaymediated pro-inflammatory prostaglandins.

Let’s explore current cautions and contraindications in light of the brief introduction to COX and LOX pathway.

Gastro-intestinal toxicity:

This is mainly due to COX-1 inhibition. COX-1 inhibition leads to loss of gastro-protective action of prostaglandins.Although the advice to avoid NSAID would only seem rationale for Non-selective NSAIDs, but actually all NSAIDsinhibit COX-1 to a variable extent. Even highly specific COX-2 inhibiting NSAID also inhibit COX-1, when given inhigher doses. Therefore, it is sensible to avoid if patient has an active disease or history of GI bleed.

Cardiovascular disease:

This came to light after a COX-2 inhibitor was marketed in 1999; VIOXX (Rofecoxib). In 2004 the drug was withdrawn after a significant rise in cardiovascular disease following use of the drug. The withdrawal of Vioxxraised questions on safety of NSAIDs as a whole and COX-2 inhibitors in particular.

In a nutshell inhibition of Prostacycline (also known as PGI-2) via COX-2 pathway throws production ofThromboxane-A2 (via COX-1) out of balance. TXA-2 is responsible for platelet aggregation and vasoconstriction. This is termed as pro-thrombotic effect. There is also a linear relationship between the dose ofNSAID’s and risk of acute Myocardial Infarction (3). Interestingly longer duration of NSAID use does not increasethe risk of MI when less than 30 days’ use was compared to more than this duration (3). Cardiotoxicity ismultifactorial and the pro-thrombotic effect is only a part of the story.Other aspects include a raise in BP, fluid retention and exacerbation of heart failure.

When COX2 mediated vasodilation is inhibited, it reduces renal blood flow, which in turn reduces GFR andincreased proximal tubular reabsorption. This translates into fluid and sodium retention. A reduction in renal flow also triggers Antidiuretic Hormone which causes further fluid and salt retention. Fluid retention not onlycontributes to raised BP but also exacerbate heart failure in susceptible individuals. Another effect of reducedrenal blood flow is increased release of renin.Renin-Angiotensin mediated raise in BP is one other reason for avoiding NSAIDs in hypertensive individuals.

Risk of Asthma exacerbation:

This mechanism is shared by NSAID and Aspirin. Aspirin and other NSAIDs that block COX 1 pathway inadvertently lead to higher levels of pro-inflammatory Leukotrienes in respiratory tree. These Leukotrienes cause bronchoconstriction, mucous production and oedema in lungs. A study (4)suggests that between8%-20% adults experience bronchospasm following ingestion of Aspirin or other NSAIDs. Therefore caution needs to be exercised.

Acute Kidney Injury:

Acute Kidney injury is one of the top 5 avoidable drug related harm. Avoidable adverse drug events claimapproximately 712 deaths across England (6). During just one quarter of 2017/2018 8.2 million people over theage of 18 were prescribed a NSAID, Diuretic or a Renin Angiotensin System drug (6). Please note that all three categories individually pose a risk of acute kidney injury (AKI). Therefore, when given in combination the risk increases several folds. Co-administration of NSAID + Diuretic + Renin Angiotensin system drug is also wellknown as a triple WHAMMY.

There is less blood volume with a narrow entry and wide exit. Glomerulus apparatus struggles to maintain ahealthy GFR. If patient only had NSAID, the glomerulus will trigger Renin system as soon as NSAID mediatedafferent arterioles constriction reduces renal blood flow. However, in the presence of Renin Angiotensininhibitors this protection is lost. A patient does not have to be on a diuretic to be at risk of an acute kidney injury (AKI), asdehydration brought on by other illnesses is all that’s needed to complete the triangle of AKI injury. All patients onNSAID’s and Renin angiotensin should be made aware of sick-day rules. This will help patients avoid AKI inevent of dehydration from either less oral fluid intake or higher loss such as in diarrhoea, vomiting, shock.

To sum up we need to follow evidence based advice from NICE and BNF whilst considering NSAID prescribingfor the first time or repeat issue. Patient specific factors can change over time, therefore, regular reviews andappropriate over the counter advice is essential.

  1. hhttps://www.ajmc.com/journals/supplement/2015/a518_apr15_nsaid_pharmacology/a518

_ apr15_nsaid_hunter

  1. h ttps://www.jimmunol.org/content/jimmunol/167/5/2831.full.pdf

  2. h ttps://www.bmj.com/content/357/bmj.j1909

  3. h ttps://www.ncbi.nlm.nih.gov/pubmed/10561993

  4. hhttps://www.pharmaceutical-journal.com/news-and-analysis/target-six-high-risk-drugs- d uring-medication-reviews-say-researchers

  5. hhttps://www.pharmaceutical-journal.com/news-and-analysis/news/almost-200000- p atients-at-risk-from-nsaid-prescribing-nhs-data-show/20204829.article