2.1.2 Calcium channel blockers
A classical pharmacodynamic effect of calcium channel blockers is to induce diffuse and bilateral swelling of the feet, ankles, and sometimes lower legs that worsen throughout the day and improve overnight (Sica, 2003). This effect is a local effect and not the consequence of water and/or sodium retention (van Hamersvelt, Kloke, de Jong, Koene, & Huysmans, 1996). While calcium channel blockers increase the subcutaneous tissue pressure (Messing, Van Essen, Smith, Smits, & Struyker-Boudier, 1991), the prevalence of peripheral edema is lower with lipophilic dihydropyridines (DHPs) such as manidipine or lercanidipine (de la Sierra, 2009; Makani, Bangalore, Romero, Htyte, et al., 2011; Messerli, 2002). The mechanism explaining this effect is more complex than routinely described. First, calcium channel blockers vasodilate arterioles but not venules (Messing et al., 1991). This selective arteriolar vasodilatation is often described as the main cause for the increased capillary pressure observed under calcium channel blockers. However, this cannot account for the whole effect, as venules are capacitance vessels exerting only a weak resistance to the blood flow. The second mechanism linked to the voltage operated channel blockade itself is the alteration of blood flow autoregulation (Gustafsson, Länne, Bjerkhoel, Johansson, & Lundvall, 1989) in addition to the abolition of the spontaneous vasomotion. Indeed, the target of calcium channels blockers, the channel pore of Cav1.2 subtype, is involved in the myogenic response (Retailleau et al., 2016; Tykocki, Boerman, & Jackson, 2017). The third mechanism is the alteration of the venoarteriolar reflex, as calcium channel blockers inhibit postural skin vasoconstriction at the dorsum of the foot (Iabichella, Dell’Omo, Melillo, & Pedrinelli, 1997; Pedrinelli, Dell’Omo, & Mariani, 2001) explaining the upright posture predominance and further compounds the problem.
Vasodilatory edema occurs in 12 to 16% of patients on DHP (Makani, Bangalore, Romero, Htyte, et al., 2011; Vukadinović et al., 2019). It is dose-dependent (Makani, Bangalore, Romero, Htyte, et al., 2011; Messerli, 2002), and varies according to the time of intake (lower frequency with bedtime ingestion (Hermida, Ayala, Mojón, & Fernández, 2008)) and age (Messerli, 2002). Age is an important determinant insofar as tissue wasting reduces interstitial hydrostatic pressure, acting as the main counterforce in hydrostatic-driven edema (Sica, 2003), in addition to functional venous insufficiency due to valve dysfunction. It may become more severe during long-term therapy (Makani, Bangalore, Romero, Htyte, et al., 2011; Messerli, 2002). Faced with these edema, many pharmacoepidemiologic studies have shown that a very frequent therapeutic reflex consists in initiating diuretics (Savage et al., 2020; Vouri et al., 2019). Indeed, 2.3% of patients over 65 years of age newly treated with DHP experience this prescription cascade within one year of initiation (Vouri et al., 2019). Compared to renin angiotensin aldosterone system (RAAS) inhibitor prescription, this risk is significantly increased by 2.4 after a 3-month treatment (Savage et al., 2020). Unfortunately, given that calcium channel blockers are intrinsically natriuretic and DHP-induced edema results from preferential arteriolar vasodilatation combined with autoregulation disruption; DHP-related edema has no relationship with sodium and/or water overload and is therefore diuretic-resistant (Messerli, 2002). A greater reduction of vasodilatory edema is achieved with the addition of a RAAS inhibitor to DHP, strategy that significantly reduces the risk of withdrawal due to peripheral edema by 62% (relative risk 0.38; 95% confidence interval, 0.22-0.66) (Makani, Bangalore, Romero, Wever-Pinzon, & Messerli, 2011). This elegant pathophysiologic observation is explained by the ability of RAAS inhibitors to decrease postcapillary resistance (i.e., venous dilatation), thus normalizing hydrostatic pressure within the capillary bed, thereby reducing fluid extravasation (de la Sierra, 2009; Makani, Bangalore, Romero, Wever-Pinzon, et al., 2011). Depending on the clinical context, several strategies may be considered as dosage reduction, DHP cessation, switch to another DHP or combination therapy with a RAAS inhibitor (de la Sierra, 2009; Makani, Bangalore, Romero, Wever-Pinzon, et al., 2011). Traditional measures such as limiting the amount of time that a patient is upright and/or considering the use of graduated compression stockings are useful adjunctive therapies (Sica, 2003). Furthermore, experimental data have shown off-target inhibitory effect of gabapentinoids (i.e., gabapentin, pregabalin) on the Cav1.2 channel pore of arterial myocytes (Bannister et al., 2009, 2012; Behuliak et al., 2018), suggesting that gabapentinoid-related edema (Freynhagen et al., 2015; Wiffen et al., 2017) may exhibit the same characteristics as induced by cardiovascular calcium channel blockers.