Swollen ankles and calcium antagonists

Peripheral oedema, including ankle oedema

• a recognised adverse effect of the calcium channel blocking agents (CCBs) which may limit their usefulness
  • particularly in an aging population who are more likely to have co-morbidities
• ankle oedema can range from being mild and unnoticed to severely affecting quality of life
• risk of developing ankle oedema whilst using CCB therapy appears to be higher in:
  • women, older patients,
  • those with heart failure,
  • upright postures, and
  • those in warm environments (1)

Mechanism of ankle oedema

• mechanisms by which CCBs give rise to ankle oedema are not currently understood
  • proposed mechanisms include an increase in capillary pressure, resulting in fluid loss from the capillaries, or by interference with local vascular control
  • unlike peripheral oedema caused by fluid retention, CCB-induced oedema appears to be due to redistribution of fluid from capillaries to interstitial spaces
    • oedema caused by CCBs seems unaffected by diuretic treatment, suggesting it may be due to fluid pooling rather than fluid retention
    • oedema occurs despite CCBs possessing inherent diuretic effects
    • as well as these possible mechanisms, CCB therapy blocks reflex increases in precapillary resistance which occur on standing, further compounding the problem of oedema formation
    • evidence suggests that ankle oedema may have a delayed onset, with its incidence increasing gradually as treatment continues, meaning it is not likely to be a transient, self-limiting effect (2)
      

Difference in chemical class

• CCBs are generally classified into dihydropyridines (DHP) and non-dihydropyridines (diltiazem, verapamil) based on their chemical structure (DHP) (amlodipine, nifedipine, felodipine, nimodipine, nicardipine, lercanidipine, lacidipine)
  • with oedema being more likely with the dihydropyridine agents
    • incidence of ankle oedema has been reported as ranging from 1-15% in patients treated with DHP agents
    • within the DHP group, it is thought that those which are more lipophilic, thus stay at the site of action for longer (such as lercanidipine and lacidipine), may be associated with a lower incidence of ankle oedema
    • ankle oedema incidence appears to be dose related
    • ankle oedema seems to be associated with both long and short acting DHP agent use
  • non DHP agents
    • rate of ankle oedema occurring with verapamil therapy is variable
      • increases plasma volume whilst also reducing vasoconstriction in the lower extremities, similar to amlodipine and nifedipine
      • suggested that reduced incidence of ankle oedema in patients treated with diltiazem compared to other CCB agents (3)

Management of ankle oedema with CCBs

Ankle oedema is sually refractory to diuretic treatment as it is due to changes in capillary pressure leading to leakage into interstitial areas, rather than due to water retention.

Treatment strategies include (4):

• Non-pharmacological interventions - these interventions include elevation of legs when in a prone position, or graduated compression stockings, may be an option in some patients with mild oedema
  • little evidence to suggest these methods may be effective in reducing oedema
• Dosage adjustments - however note that the relationship with ankle oedema and CCB use may not occur in an exact dose-proportional relationship (1)
  • as dose related side effect - reduction of dose may lead to resolution/improvement
• Switching to an alternative CCB
  • switching between classes e.g DHP to non DHP CCB; or within the same class e.g. a third generation DHP, such a lercanidipine, with a lower reported incidence of ankle oedema may also be an option
• Adding an ACEi or ARB
  • evidence that adding an ACEi to a CCB reduces the incidence of ankle oedema. The mechanism by which this occurs is not currently known (4)
  • mechanisms by which ARBs reduce incidence of CCB induced ankle oedema remains unknown, but are likely to be similar to that involved when an ACEi is added to CCB therapy
• Adding a nitrate
  • due to their venodilating action, may be offer some useful effects in treating CCB induced ankle oedema, but their use are limited by the practical considerations of having a stop-start regimen so tolerance does not develop (4)
• Discontinuation of CCB

Reference:

• NHS Specialist Pharmacy Service (March 2020). What are the reported incidences of ankle oedema with different calcium channel blockers?
• Zanchetti A. Emerging data on calcium channel blockers: The COHORT study. Clinical Cardiology. 2003; 26(sII): II-17- II-20.
• Sirker A, Missouris CG, and Macgregor G. Dihydropyridine calcium channel blockers and peripheral side effects. Journal of Human Hypertension. 2001: 15; 745-746.
• NHS Specialist Pharmacy Service (March 2020). How should ankle oedema caused by calcium channel blockers be treated?