Calcium Channel Blocker-Related Peripheral Edema: Can It Be Resolved?

Domenic A. Sica, MD

Disclosures
In This Article

Pathophysiology of Edema

The pathophysiology of edema with CCB therapy has no relationship to salt and water retention. In fact, CCBs are intrinsically natriuretic -- a process related to a direct tubular effect of CCBs.[6,16] This latter phenomenon is the probable explanation for the occasional reports of polyuria in patients receiving CCB therapy.[17] However, CCB-related edema can occur with pre-existing volume expanded forms of edema, in which case the edema can be severe. CCB-related edema is caused by preferential arteriolar or precapillary dilation without commensurate dilation in the venous or postcapillary circulation.[18,19]

In addition, the reflex rise in precapillary resistance that ordinarily occurs with upright posture is effectively blocked by CCBs.[20,21] This further compounds the problem.

This discrepancy in resistance values increases pre-capillary pressures to a degree that plasma is literally forced from the intravascular compartment into the interstitium -- the origin of peripheral edema with CCB therapy. Under these circumstances the continuous nature of transcapillary fluid movement must exceed the capacity of the lymphatic system for edema to be clinically evident. The issue of CCBs specifically modifying capillary permeability as an additional cause of edema has been debated with no definitive conclusions.[22] In addition, if specific CCBs increase angiotensin-II concentrations it can be expected that venoconstriction might occur with the potential for worsening of the peripheral edema.[6,23]

Several factors will influence the onset and/or severity of peripheral edema with CCB therapy. The individual CCB classes have differing capacities to decrease vascular resistance, with dihydropyridine CCBs being more potent arteriolar dilators than the nondihydropyridine CCBs such as verapamil and diltiazem. Thus, dihydropyridine CCBs are more commonly associated with peripheral edema.[10,17] Peripheral edema rates increase in tandem with dose escalation for all CCBs but not necessarily in an exact, dose-proportional manner.[13,15] Modifiers of CCB-related edema are well characterized and include upright posture,[24] warmth,[24] older age,[25] and female gender. Although female gender is often cited as a risk for peripheral edema with CCBs[26,27] most studies fail to report edema rates on a gender-specific basis.[11,12,13,14,15]

Upright posture provides an additional gravitational contribution to the already increased hydrostatic forces in CCB-treated patients with peripheral edema.[24] On occasion, in an otherwise edema-free CCB-treated patient, peripheral edema can develop if there is a change in the daily postural pattern so that an upright posture is maintained for longer periods of time.

A common pattern with CCB-related peripheral edema is that edema is worse at the end of the day and improves and/or disappears after a patient has remained recumbent throughout the overnight hours. Warm conditions -- be they seasonal or work-related -- can independently vasodilate the arteriolar circulation and worsen edema. Age is an additional determinant of edema in that interstitial tissue typically serves a barrier role to hydrostatically driven edema formation and the counterbalancing nature (to prevent edema) of such tissue diminishes with age.[25]

Although the principle is sound to support the notion that edema formation with CCB therapy is more common in the elderly, not all reports break edema formation rates out based on age.[25] Finally, edema rates are suggested to be higher in women than men.[26,27] The basis for this has been suggested to relate to the lower threshold for women to report cosmetic changes (such as edema) that might go unrecognized by males.[27] This is a curious supposition and not one that has been formally evaluated. A more interesting possibility for this may be pharmakokinetic. For example, with equivalent doses of the CCB verapamil, women will attain much higher plasma levels for this compound than men.[26] Because peripheral vasodilation relates directly to plasma levels of CCBs, it can be inferred that the higher the plasma levels of verapamil, the greater the tendency to develop edema. The pharmacokinetics of other CCBs have not been determined on a gender basis to permit a generalization of this concept.

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