Currently available calcium channels blockers are divided into two categories based upon their effect: the dihydropyridines, which cause arterial vasodilation but do not influence heart contractility and conduction, and the nondihydropyridines, which do not cause vasodilation but have negative effect upon heart conduction and contractility [1, 2]. The most commonly reported adverse events noted with dihydropyridines are peripheral oedema and flushing that occur in 10–20% of the patients, both children and adults. These adverse events do not occur with nondihydropyridines. The tendency to oedema is directly linked to the extent of arterial vasodilation that redistributes fluid from the vascular space into the interstitium and is not dependent on the type of the dihydropyridine [3, 4].
The nephrotoxicity of cyclosporin may be in part counterbalanced by calcium channel blockers [5]. On the other side, treatment with certain calcium channel blockers increases cyclosporin blood levels. The effect of the dihydropyridine amlodipine on cyclosporin metabolism is not as great as that seen with other calcium channel blockers. Consequently amlodipine is frequently prescribed in hypertensive patients on cyclosporin [6, 7].
Between 1994 and 2001 we treated at least 54 hypertensive patients (31 male and 23 female subjects, aged between 1.1 and 20, median 13 years) with amlodipine. Ten of the patients were on treatment with cyclosporin. Nine patients (four boys and five girls, aged 3.2–19, median 11 years) withdrew from amlodipine because of oedema, flushing or headache. They were 4 of the 10 patients (40%) with and 5 of the 44 patients (11%) without cyclosporin (P < 0.02, χ2-test). The dosage of amlodipine was similar in the patients who developed oedema (from 0.10 to 0.36, median 0.26 mg kg−1 body weight once a day) and in those who failed to develop this complication (from 0.11 to 0.34, median 0.22 mg kg−1 body weight).
It has been stated that oedema and flushing are less common when calcium channel blockers are given with a converting enzyme inhibitor [3]. Thirteen of our 54 patients given amlodipine were on treatment with a converting enzyme inhibitor (enalapril, n = 6; ramipril, n = 3; captopril, n = 3; perindopril, n = 1). In our experience the tendency to develop oedema was not different in patients with (2 out of 13 patients; namely 15%) and in patients without (7 out of 41 patients; namely 17%) converting enzyme inhibitors.
The potential of calcium channel blockers to aggravate the gum enlargement caused by cyclosporin is well recognized [8]. The present data suggest the existence of a further unpleasant interaction between calcium channel blockers and cyclosporin: oedema and flushing are more common when the dihydropyridine amlodipine is given with cyclosporin. On the other hand, our experience with a limited number of patients does not corroborate data from the literature suggesting that oedema and flushing are less common when a dihydropyridine is given with a converting enzyme inhibitor [4].
In conclusion, peripheral oedema and flushing, the most commonly adverse events noted on treatment with dihydropyridine calcium channel blockers, occur more frequently in patients concomitantly treated with cyclosporin and amlodipine. Our data do not provide any explanation for this association.
We kindly acknowledge the support of the Associazione Bambino Nefropatico.
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