Cilnidipine induced ankle edema.

Cilnidipine is a 4(th) generation dihydropyridine calcium channel blocker approved recently for the treatment of essential hypertension. It is not known to present with ankle edema like amlodipine. Moreover, it has been proposed as an alternative anti-hypertensive for patients with amlodipine-induced edema. We report a case of cilnidipine induced ankle edema.

Introduction

Ankle edema, is a common adverse effect of L-type calcium channel blocker (CCB) and can sometime progress to anasarca.[1] CCB commonly known to cause ankle edema are amlodipine, nifedipine, diltiazem, felodipine, isradipine, lacidipine, lercanidipine, nisoldipine and manidipine.[12]

Cilnidipine is a 4th generation dihydropyridine CCB approved for the treatment of hypertension with efficacy and safety that is comparable to amlodipine. It is a unique L-type Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ channels. It has a slow-onset but the long-lasting action.[3] It was introduced in the market, with a claimed superiority over amlodipine. In a study by Shetty et al.,[4] therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia and thus it has been suggested as an alternative antihypertensive for patients with amlodipine-induced edema.

We report an isolated case of cilnidipine induced ankle edema. Although, it was a relatively mild and non-serious adverse effect, it can lead to reduced drug compliance or complete discontinuation of therapy.

Case Report

This was a case report of a 40-year-old male patient, weighing 64 kg was recently diagnosed as a case of uncomplicated hypertension (stage 1) as per JNC 7 guidelines. He was advised to start cilnidipine 5 mg once daily with salt restriction and lifestyle management. He had no history of smoking and alcohol consumption. There was no associated pathology or any history of concurrent drug intake. He presented with bilateral pitting ankle edema after the 6th week of the drug therapy [Figure 1]. There was no history of such an episode in the recent past. Clinical examination revealed no symptoms and signs of liver, pulmonary, renal, cardiac and rheumatological disease. Investigations revealed a normal X-ray chest. All basic investigations such as complete blood count, total lecucocyte count, differential lecucocyte count, erythrocyte sedimentation rate, platelet count, routine urine and stool examination, blood sugar, blood urea, creatinine, liver function test, lipid profile, hr-C-reactive protein, T3, T4 and thyroid stimulating hormone and serum uric acid were normal. Electrocardiography (ECG) and echocardiography were normal. Ultrasonography abdomen and pelvic organs and color Doppler of lower extremities were also normal. The patient was advised to stop the suspected drug cilnidipine. The patient was changed over to telmisartan with hydrochlorothiazide (40 + 12.5 mg) once day. The edema disappeared completely on the 14th day after stopping cilnidipine with achievement of normotension. Further re-challenge was not carried out in the interest of the patient. Thus, the appearance of ankle edema in a patient taking cilndipine could not be explained by a concurrent disease, drug or chemicals while dechallenge improved the condition. The current case was reported to ADRM Centre GMC/Jammu, vide no. 2916/010713/ADRM/Pharma/GMC/JMU.

Figure 1

Cilnidipine Induced Pedal/Ankle Edema

Discussion

Common adverse effects reported with cilnidipine are nausea, vomiting, abdominal pain, constipation, dry mouth, gingival hypertrophy, heartburn, headache, dizziness, light headedness and insomnia. Rarely, hot flushes, palpitations, ECG abnormalities, chest pain, atrioventricular block, hypersensitivity reactions, photosensitivity, frequent urination and elevated liver enzyme.[4] Cilnidipine has been recently suggested to result in complete resolution of amlodipine-induced edema and has been recommended as an alternative antihypertensive for patients with amlodipine-induced edema. However, on the contrary our case presented with bilateral ankle pitting edema with cilnidipine therapy. One report of clinidipine induced ankle edema has been published in the literature.[5]

The mechanism of this adverse effect is unknown. However, number of mechanisms has been postulated for CCB-induced edema including inhibition of pre-capillary vasoconstriction through arteriolar dilatation and thus, promoting interstitial edema. CCBs are known to cause ankle edema. The structural similarity of clinidipine with other dihydropyridines is hypothesized to be the probable reason for this adverse drug reaction (ADR). This ADR has “probable” causal relationship with clinidipine as assessed by Naranjo score (Score = 6)[6] and with World Health Organization-Uppsala Monitoring Centre scale for causality assessment. The present ADR was not studied for dose dependent response and was unpredictable/unusual. Thus it is difficult to label it as Type-A or B class of ADR.[7]

The usual approach to patients with CCB-induced edema involves cessation of therapy and substitution with an alternative antihypertensive, typically as a thiazide diuretic or angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARBs) as was carried out in our case. A combination therapy of ARBs, diuretic CCB are usual in clinical practice in such cases.[8]

The current case report is in contradiction to study of Shetty et al. In 27 patients with essential hypertension with amlodipine-induced edema cannot become the basis for recommendation of cilnidipine in these patients. However, it is in accordance to the study of Narita et al., 2011[5] which documented leg edema in 16% of patients, receiving cilnidipine. Moreover, the present case report leaves another important message for the practicing physicians, that never be first and last to prescribe any new drug.

Conclusion

In this case report, the conventional practice to prescribe thiazide diuretic or ACEI or ARBs should be carried until larger clinical trial supports the role of clindipine in such conditions.