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.