Journal of Human Hypertension (2001) 15, 745–746  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh CASE REPORT Dihydropyridine calcium channel blockers and peripheral side effects

A Sirker, CG Missouris and GA MacGregor Blood Pressure Unit, Department of Medicine, St Georges Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK

Keywords: dihydropyridine; calcium channel blockers

Case report Discussion A 56 year old Caucasian man was referred to our Non-pitting peripheral oedema is one of the most unit in 1994 with a 3-year history of elevated blood commonly described adverse effects of calcium pressure. Six months previously he had been treated channel blocking drugs. It has been described with by his general practitioner with nifedipine tablets all the available dihydropyridine agents and may (Adalat Retard) 10 mg t.d.s. On examination, the occur with diltiazem. An early study suggested that mean supine blood pressure was 135/77 mm Hg. He the incidence of oedema with nifedipine was 11.6% had marked bilateral ankle swelling, hyperpigment- in those treated for 6 months or longer.1 In the more ation of the legs with a petechial, non-blanching recent MATH2 and EXACT3 trials, involving nifedi- rash and areas of erythema which had developed pine in the extended-release formulation (Adalat since starting nifedipine (Figure 1). Nifedipine was XL) for treatment of hypertension, the incidence of discontinued and when he was reviewed in the oedema was 7.7% and 8.1% in those treated for over Blood Pressure Unit 6 weeks later the oedema and 18 and 20 weeks respectively. With amlodipine, an the macular rash had completely resolved; the blood early analysis of pooled data on 581 treated patients pressure was 143/72 mm Hg on non-pharmacologi- found that the incidence of oedema was 11.6% in cal therapy. younger patients and 16.4% in older patients.4 Pre- scription-Event Monitoring (PEM), a national scheme for postmarketing surveillance, has reported that the incidence of peripheral oedema was less with diltiazem than with amlodipine use.5 The peripheral oedema caused by calcium chan- nel blockers is dose dependent3 and is increased by prolonged dependency. The oedema is caused by the inhibition of the pre-capillary reflex6 on standing upright, which increases the hydrostatic pressure on the arteriolar side of the capillary bed leading to an increase in capillary filtration pressure. The oedema is not associated with salt and water retention, indeed the dihydropyridines are natriuretic, and does not improve with diuretic therapy.7 Mild oedema which is not troublesome to the patient does not require specific treatment and may Figure 1 Marked bilateral ankle swelling, associated with a pet- improve with time. In more severe cases, dose 8 echial non-blanching rash and areas of erythema in a patient on reduction or drug withdrawal may be necessary. If treatment with nifedipine tablets (Adalat Retard). continued use of the drug is necessary, for example because of intolerance of other classes of antihyper- tensive, problematic oedema may also be helped by Correspondence: Dr CG Missouris, Blood Pressure Unit, Depart- ment of Medicine, St Georges Hospital Medical School, Cranmer simple measures such as elevation of the legs when Terrace, London SW17 ORE, UK. Fax: 0208 725 2959 seated or lying flat and by wearing graduated com- Received and accepted 27 December 2000 pression stockings. Dihydropyridine calcium channel blockers A Sirker et al 746 A much less recognised but in our experience a 3 Toal CB et al. Nifedipine gastrointestinal therapeutic common associated feature is lower limb petechial, system for hypertensive patients in a primary care set- non-blanching rash. This is believed to result from ting: results of Extended Release Adalat Canadian Trial leakage of red blood cells from capillaries into the (EXACT). Clin Ther 1997; 19: 924–935. interstitium and can cause a long lasting discolour- 4 Osterloh I. The safety of amlodipine. Am Heart J 1989; ation. Our experience, as in this patient, is that with- 118: 1114–1120. 5 Kubota K, Pearce GL, Inman WHW. Vasodilation- drawal of drug results eventually in resolution of related adverse events in diltiazem and dihydropyrid- the rash. ine calcium antagonsists studied by prescription-event monitoring. Eur J Clin Pharmacol 1995; 48:1–7. References 6 Salmasi A-M, Belcaro G, Nicolaides AN. Impaired 1 Terry RW. Nifedipine and therapy in angina pectoris: venoarteriolar reflex as a possible cause for nifedipine- evaluation of safety and side-effects. Am Heart J 1982; induced ankle oedema. Int J Cardiol 1991; 30: 303– 104: 681–689. 307. 2 Krakoff LR, Bravo EL, Tuck ML and the Modern 7 Opie LH. Fluid retention with nifedipine in antihyper- Approach to the Treatment of Hypertension (MATH) tensive therapy. Lancet 1986; 2: 1456. Study Group. Nifedipine gastrointestinal therapeutic 8 Maclean D, MacConnachie AM. Selected side-effects: system in the treatment of hypertension: results of a 1. peripheral oedema with dihyfropyridine calcium multicentre trial. Am J Hypertens 1990; 3: 3185–3255. antagonists. Presc J 1991; 31:4–6.

Journal of Human Hypertension