Foot volume increase on nifedipine is not prevented by pretreatment with diuretics.
OBJECTIVE
Despite their natriuretic effects, dihydropyridine calcium-channel blockers (CCBs) often induce ankle oedema, probably due to vasodilation in the dependent legs. Since concomitant administration of frusemide does not prevent the acute increase in foot volume on nifedipine, we investigated whether diuretic pretreatment attenuates foot swelling on CCBs.


METHODS
In four separate experiments, 10 healthy volunteers received: (i) 20 mg of nifedipine without active pretreatment (pretreatment with placebo only); (ii) 20 mg of nifedipine after 5 days' treatment with amiloride 5 mg twice daily; (iii) 20 mg of nifedipine after 5 days' treatment with chlorthalidone 50 mg once daily; and (iv) no active drugs (pretreatment with placebo and placebo in place of nifedipine) as the control. Foot volumes were measured using an accurate water displacement technique (intra-individual coefficient of variance 0.27%).


RESULTS
Amiloride and chlorthalidone pretreatment induced marked volume depletion, with a 2-3% reduction in body weight, a 5-10% increase in haematocrit and a 14-23% increase in plasma colloid osmotic pressure. In addition, the mean +/- SEM foot volume after both chlorthalidone (1282 +/- 37 ml) and amiloride (1289 +/- 40 ml) was lower than without pretreatment (1315 +/- 38 ml) (P < 0.05). Neither amiloride nor chlorthalidone significantly influenced the acute increase in foot volume on nifedipine. However, due to pretreatment effects, the foot volume after nifedipine was higher (P < 0.05) without pretreatment (1356 +/- 36 ml) than after amiloride (1318 +/- 38 ml) or chlorthalidone (1319 +/- 37 ml). Amiloride significantly attenuated the natriuretic effect of nifedipine, whereas chlorthalidone prevented the nifedipine-induced rise in colloid osmotic pressure and haematocrit.


CONCLUSIONS
Diuretic pretreatment and the concomitant volume depletion did not prevent acute foot swelling on nifedipine, although the absolute foot volume remained lower after such pretreatment. Therefore diuretics mitigate the oedema of CCBs, but do not directly interfere with oedema formation.
van der Heijden
Antoine G
AG
Department of Medicine, University Medical Centre, Nijmegen, The Netherlands. T.vanderheijden@uro.umcn.nl
Huysmans
Frans Th M
FT
van Hamersvelt
Henk W
HW
D000328:Adult; D000584:Amiloride / Q000627:therapeutic use; D000842:Ankle; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D002752:Chlorthalidone / Q000627:therapeutic use; D004232:Diuretics / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D005534:Foot Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006400:Hematocrit; D006801:Humans; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009543:Nifedipine / Q000009:adverse effects*; D009997:Osmotic Pressure / Q000187:drug effects; D011292:Premedication
D002121:Calcium Channel Blockers; D004232:Diuretics; D000584:Amiloride; D009543:Nifedipine; D002752:Chlorthalidone