2.2.2 Non-steroidal anti-inflammatory drugs
Peripheral edema is not uncommon as it occurs in 2–5% of non-steroidal anti-inflammatory drugs (NSAIDs) users (C. Walker & Biasucci, 2018), especially when patients are at risk of increasing susceptibility to clinical effect of NSAID-induced vasoconstriction (e.g., absolute volume depletion, old age) (Whelton, 1995, 2000). NSAID-induced peripheral edema has both direct and indirect mechanisms that are independent to RAAS; they otherwise inhibit (Beck et al., 2020; Cabassi et al., 2020; Frishman, 2002). Disruption of renal homeostasis induced by the inhibition of cyclooxygenase (COX)-dependent generation of prostaglandins (PG) is the primary mechanism. The COX isoforms (i.e., COX-1 and COX-2) are expressed at different levels by each nephron component. They synthesize several PG (Cabassi et al., 2020) including PGE2 and PGI2 which are both involved in NSAID-associated peripheral edema. Firstly, NSAID-induced PGE2 lowering decrease both natriuresis in the thick ascending loop of Henle (Frishman, 2002) and aquaresis through facilitation of arginine vasopressin activity in the collecting duct (Cabassi et al., 2020). Secondly, NSAIDs inhibit PGI2-related afferent arteriole vasodilatation, reducing glomerular filtration rate and thus promote proximal tubular reabsorption (Frishman, 2002). Nonselective and COX-2 selective NSAIDs have similar incidence of peripheral edema (Frishman, 2002; C. Walker & Biasucci, 2018), supporting that fluid retention is mostly COX-2 mediated (Cabassi et al., 2020; Frishman, 2002). Edema, which is usually mild and subclinical (typical weight gain 1 to 2 kg), exhibits early onset such as within the first week of NSAID use, and is reversible on discontinuation of the drug (Whelton, 2000).