Anasarca Edema with Amlodipine Treatment

Case Report

A 77-year-old previously healthy woman was admitted to the hospital for treatment of newly identified hypertension. She was 1.60 meters tall, weighed 79 kg, and her blood pressure was 150/90 mm Hg. She had no comorbid disease and was taking no medications. Her physical examination was completely normal, as were urine analysis, and biochemical parameters including plasma glucose, liver function tests, and kidney function tests. Cholesterol, high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, triglyceride, and albumin levels were also normal. There was no reason for secondary hypertension. Treatment with amlodipine 10 mg/day was started for essential hypertension, and the woman was discharged.

Seven days later, she returned to the hospital with newly and gradually developed generalized edema. She had no complaints other than generalized edema at the time of admission, and had no history of chest pain, dyspnea, or palpitations before anasarca edema occurred. Her blood pressure was 120/70 mm Hg, heart rate 84 beats/min, respiratory rate 20 breaths/min, and temperature 37°C. Perioral, periorbital, pretibial, pedal, and vulvar edema were detected, as well as bilateral rales on posterobasal segment of the lungs on chest auscultation. There was no erythematous area, rash, or sense of flare or itching. Her baseline blood urea nitrogen (BUN), creatinine, and creatinine clearance calculated according to the Cockcroft—Gault formulation were 19 mg/L, 0.7 mg/L, and 69 mL/min, respectively. Plasma sodium was 140 mEq/L, potassium 4.8 mEq/dL, and chloride 103 mEq/dL; liver function test results were normal. In urine analysis, density, and microscopy were normal and no proteinuria was detected.

After starting treatment with amlodipine 10 mg/day, laboratory reports revealed elevated blood levels of creatinine and BUN 34 mg/dL and 1.1 mg/dL. Estimated creatinine clearance decreased from 69 to 45 mL/min; however, these are estimates, since 24-hour urine creatinine clearance measurements were not done. Plasma sodium was 141 mEq/dL, potassium 4.5 mEq/dL, and chloride 108 mEq/dL. No decrease in urine output had been noted. Posteroanterior chest X-ray, urinary system ultrasound, and renal arterial Doppler ultrasound were normal. There was no QT wave or ST segment change, and no arrhythmias compared with the previous electrocardiogram. Plasma CK-MB, myoglobulin, and troponin-T levels were normal. Her ejection fraction was determined as 65% with echocardiogram; no other valve or systolic dysfunction was diagnosed. Having consulted with the nephrology department, the patient's amlodipine treatment was discontinued.

Consequently, the edema had completely resolved one week after discontinuation of the drug, and the patient's plasma BUN and creatinine levels returned to baseline values. Following this, angiotensin receptor blocker treatment with losartan 50 mg/day was started for essential hypertension. The woman's blood pressure fell to within normal levels with this drug, and no other clinically apparent adverse effects recurred.

Discussion

In this case, we considered amlodipine as the reason for anasarca edema. There was no evidence of heart failure, pericarditis, cirrhosis, protein-losing enteropathy, diarrhea, malnutrition, or acute or chronic renal insufficiency to cause generalized edema. The patient did not have a risk factor of coronary artery disease, history of an acute coronary syndrome, or heart failure. Systolic function, cardiac valve function, and plasma myocardial injury markers were normal, and there was no fluid between the pericardial leaves. Due to the physical examination findings, we did not consider this an allergic reaction. Cirrhosis and other chronic gastrointestinal disease causing malnutrition were eliminated based on her previous history. There was no increase in blood leukocyte count, fever, or infiltration on chest X-ray; pulmonary infection was therefore not considered. Using the Naranjo probability scale to assess causality, we consider this case of generalized edema associated with the use of amlodipine as probable. ⁴

There has been only one other case of generalized edema related to amlodipine in the Japanese literature, ³ and our report is the first in the English-language literature. In the Japanese case, there were important underlying factors that accelerated the dilation of the blood vessels, such as systemic lupus erythematosus and steroid treatment. Both candesartan and amlodipine seemed to be causative drugs. In our case, the patient was previously healthy except for essential hypertension and was taking only amlodipine for control of her blood pressure.

The mechanism of amlodipine-related edema is unclear. It may be related to a local phenomenon associated with relative differences in venous and arteriolar dilation. ⁵ According to several studies in the literature, none of the calcium-channel blockers produce changes in body weight, plasma volume, or extracellular volume. The edemas are related to the vascular effects of the calcium antagonist, and not to general fluid retention. ⁶ It is thought to be the result of uncompensated precapillary vasodilation causing increased intracapillary hydrostatic pressure. ⁷

Animal studies showed that calcium antagonists increase fluid filtration and albumin permeability through large arteries, and this changes the degree of permeability in different tissues, such as those of the lungs, testes, brain, and heart. ⁸ In our patient, lungs and capillaries could be affected primarily. Additionally, amlodipine may cause pulmonary edema, which has been reported as an amlodipine overdose. ⁹ The mechanism of this effect is likely multifactorial and related to vasodilation and ventilation—perfusion mismatch.^10,11 In our patient, the pulmonary rales without dyspnea, generalized edema, and even mild renal function impairment can be explained by this vascular effect and reversible redistribution of the fluids.

Possibly because of their reduced skin elasticity and altered skin mechanical properties, older patients appeared to be more susceptible to the development of pedal edema.^2,12 Pedal edema is the most expected and well-tolerated adverse effect of amlodipine, increasing with the dose dependently. Apart from this known adverse effect, edema in any part of the body, even generalized edema as in our case, may occur. Therefore, clinicians must monitor for this unexpected effect of amlodipine in elderly patients.

Conclusions

Generalized edema is a rare complication of treatment with amlodipine. The edema in our patient resolved without serious consequences; however, all patients should be monitored during therapy.