How do NSAIDs block COX?
The classic non-aspirin NSAIDs block both COX-1 and COX-2 isozymes to varying degrees, by binding an arginine molecule at position 120 halfway up their channel, thereby inhibiting access of arachidonic acid to the catalytic site and thus ultimately inhibiting the synthesis of prostaglandins, PGI2, and thromboxanes [22.
Can ibuprofen cause metabolic acidosis?
There have been reports of metabolic acidosis after an acute overdose of ibuprofen and other NSAIDs, which may be explained by the accumulation of acidic metabolites in the blood.
How are NSAIDs cardiotoxic?
The cardiotoxicity associated with use of NSAIDs might be due to inhibition of prostacyclin synthesis, oxidative stress, increase in blood pressure and impaired endothelial function.
What pathway does NSAIDs affect?
Although NSAIDs exert their effects on COX pathways, there are many studies about their effects on more complicated mechanisms. The first evidence about these mechanisms emanating from acetylsalicylic acid reported nuclear factor-kappa beta (NF-κB) inhibition [11, 12].
How are NSAIDs nephrotoxic?
The nephrotoxic effects of NSAIDs arise mainly from two pathological mechanisms: (1) acute tubulo-interstitial nephritis (ATIN) following immune reaction and (2) prerenal failure because of reduced renal plasma flow. Histological examinations are required to confirm the pathomechanism of AKI after NSAID exposure.
How does ibuprofen inhibit the COX enzyme?
Ibuprofen (IBP) has classically fallen into the time-independent class of COX inhibitors as it binds rapidly and reversibly to COX and acts as a competitive inhibitor of arachidonic acid (AA) oxygenation (Gierse et al., 1999; Prusakiewicz et al., 2009).
What happens when COX-2 is inhibited?
COX-2 inhibitors are NSAIDs that selectively block the COX-2 enzyme and not the COX-1 enzyme. Blocking this enzyme impedes the production of prostaglandins by the COX-2 which is more often the cause the pain and swelling of inflammation and other painful conditions.
How NSAIDs cause metabolic acidosis?
High anion gap metabolic acidosis is recognized following large overdoses of NSAIDs and occurs due to the accumulation of acidic metabolites. Acidosis may also be exacerbated by vomiting and alcohol ingestion. Inhibition of COX-1 also affects platelet aggregation, due to reduced formation of thromboxane-A2.
Are NSAIDs nephrotoxic?
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity.
Why do NSAIDs increase risk of MI?
Interference with the cyclooxygenase enzyme is thought to be the primary mechanism by which NSAIDs exert their pharmacologic action. NSAIDs, as a class, have a broad range of CV effects that may play a role in causing myocardial infarction (MI) and sudden cardiac death (SCD).