2. DRUG-INDUCED PERIPHERAL EDEMA
Various drugs can induce or worsen peripheral edema by disrupting the delicate homeostasis between transcapillary flow, edema safety factors and lymphatic drainage capacity (Figure 2 ). Although most often pitting and bilateral, some drugs are involved in the development of peripheral edema that is readily erythematous (e.g., dopaminergic agonists (Wood, 2010), pemetrexed (D’Angelo, Kris, Pietanza, Rizvi, & Azzoli, 2011)) or unilateral (e.g., sirolimus (Rashid-Farokhi & Afshar, 2017)). In addition to aggressive fluid resuscitation and preparation providing a significant amount of sodium, drug-induced edema entails four mechanisms, namely precapillary arteriolar vasodilation (vasodilatory edema), sodium and water retention (renal edema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability edema). In most situations, several mechanisms occur and contribute synergistically to edema genesis. The underlying mechanism directly affects treatment efficacy.
The aim of this review is to raise awareness on the mechanisms involved in drug-induced peripheral edema. Each of these mechanisms is illustrated through an example of the most notable drug. Drug-induced angioedema, whether mediated by bradykinin (e.g., angiotensin-converting enzyme inhibitors), histamine (e.g., beta-lactams) or leukotrienes (e.g., non-steroidal anti-inflammatory drugs), is regarded as permeability edema. However, given its predominantly non-peripheral location (e.g., facial, laryngeal or gastrointestinal involvement), it will not be discussed in this review. This review does not cover drugs that may cause edema by a primary indirect mechanism, such as heart failure (Page et al., 2016) or hypoalbuminemia as in glomerular injury (Markowitz, Bomback, & Perazella, 2015) and liver injury (European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, Clinical Practice Guideline Panel: Chair:, Panel members, & EASL Governing Board representative:, 2019).