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).