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Anasarca Edema with Amlodipine Treatment

Didem Şener, M Halil, Burcu Balam Yavuz, Mustafa Cankurtaran, and Servet Arıoǧul

OBJECTIVE: To report a case of anasarca edema associated with amlodipine use.

CASE SUMMARY: A 77-year-old woman with essential hypertension who had not been treated with any other drug was prescribed
amlodipine 10 mg/day to control her blood pressure. She developed anasarca edema soon after amlodipine treatment was initiated.
Laboratory test results for possible etiologies were negative. Discontinuation of amlodipine resulted in dramatic improvement.
DISCUSSION: To our knowledge, as of February 3, 2005, there have been no other reports of amlodipine-related anasarca edema in
the English literature, and only one case was described in the Japanese literature. Pretibial edema is the most common adverse
effect of amlodipine. Periocular and perioral edema have occurred less frequently, but anasarca edema has not emerged as a
problem. An objective causality assessment revealed amlodipine to be a probable cause of anasarca edema.
CONCLUSIONS: In rare instances, amlodipine may cause generalized edema, which will resolve upon discontinuation of the drug.

KEY WORDS: amlodipine, anasarca edema.

Ann Pharmacother 2005;39:761-3.

Published Online, 22 Feb 2005,, DOI 10.1345/aph.1E410

mlodipine is a dihydropyridine calcium-channel blocker tion tests. Cholesterol, high-density lipoprotein, low-density lipoprotein,
A that is usually safe and well tolerated by elderly patients.
The most common adverse effect of amlodipine is edema,
1 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
such as pedal, pretibial, and periorbital. Vasodilation and in- the woman was discharged.
tracapillary hypertension are the underlying mechanisms of Seven days later, she returned to the hospital with newly and gradual-
ly developed generalized edema. She had no complaints other than gen-
this effect.2 Theoretically, amlodipine can cause general- eralized edema at the time of admission, and had no history of chest
ized edema; however, according to our knowledge, as of pain, dyspnea, or palpitations before anasarca edema occurred. Her
February 3, 2005, there has been only one case reported blood pressure was 120/70 mm Hg, heart rate 84 beats/min, respiratory
describing generalized edema.3 We report a 77-year-old rate 20 breaths/min, and temperature 37 ˚C. Perioral, periorbital, pretib-
ial, pedal, and vulvar edema were detected, as well as bilateral rales on
woman with amlodipine-induced anasarca edema, which posterobasal segment of the lungs on chest auscultation. There was no
disappeared after discontinuation of the drug therapy. erythematous area, rash, or sense of flare or itching. Her baseline blood
urea nitrogen (BUN), creatinine, and creatinine clearance calculated ac-
cording to the Cockcroft–Gault formulation were 19 mg/L, 0.7 mg/L,
Case Report 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
A 77-year-old previously healthy woman was admitted to the hospital
normal. In urine analysis, density, and microscopy were normal and no
for treatment of newly identified hypertension. She was 1.60 meters tall,
proteinuria was detected.
weighed 79 kg, and her blood pressure was 150/90 mm Hg. She had no
After starting treatment with amlodipine 10 mg/day, laboratory reports
comorbid disease and was taking no medications. Her physical examina-
revealed elevated blood levels of creatinine and BUN 34 mg/dL and 1.1
tion was completely normal, as were urine analysis, and biochemical pa-
mg/dL. Estimated creatinine clearance decreased from 69 to 45 mL/min;
rameters including plasma glucose, liver function tests, and kidney func-
however, these are estimates, since 24-hour urine creatinine clearance
measurements were not done. Plasma sodium was 141 mEq/dL, potassi-
um 4.5 mEq/dL, and chloride 108 mEq/dL. No decrease in urine output
Author information provided at the end of the text. had been noted. Posteroanterior chest X-ray, urinary system ultrasound, The Annals of Pharmacotherapy ■ 2005 April, Volume 39 ■ 761

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D Şener et al.

and renal arterial Doppler ultrasound were normal. There was no QT monary edema, which has been reported as an amlodipine
wave or ST segment change, and no arrhythmias compared with the pre- overdose.9 The mechanism of this effect is likely multifac-
vious electrocardiogram. Plasma CK-MB, myoglobulin, and troponin-T
levels were normal. Her ejection fraction was determined as 65% with torial and related to vasodilation and ventilation–perfusion
echocardiogram; no other valve or systolic dysfunction was diagnosed. mismatch.10,11 In our patient, the pulmonary rales without
Having consulted with the nephrology department, the patient’s am- dyspnea, generalized edema, and even mild renal function
lodipine treatment was discontinued.
Consequently, the edema had completely resolved one week after dis-
impairment can be explained by this vascular effect and re-
continuation of the drug, and the patient’s plasma BUN and creatinine versible redistribution of the fluids.
levels returned to baseline values. Following this, angiotensin receptor Possibly because of their reduced skin elasticity and al-
blocker treatment with losartan 50 mg/day was started for essential hy- tered skin mechanical properties, older patients appeared to
pertension. The woman’s blood pressure fell to within normal levels
with this drug, and no other clinically apparent adverse effects recurred.
be more susceptible to the development of pedal edema.2,12
Pedal edema is the most expected and well-tolerated ad-
verse effect of amlodipine, increasing with the dose depen-
Discussion dently. Apart from this known adverse effect, edema in any
In this case, we considered amlodipine as the reason for part of the body, even generalized edema as in our case,
anasarca edema. There was no evidence of heart failure, may occur. Therefore, clinicians must monitor for this un-
pericarditis, cirrhosis, protein-losing enteropathy, diarrhea, expected effect of amlodipine in elderly patients.
malnutrition, or acute or chronic renal insufficiency to
cause generalized edema. The patient did not have a risk Conclusions
factor of coronary artery disease, history of an acute coro-
Generalized edema is a rare complication of treatment
nary syndrome, or heart failure. Systolic function, cardiac
with amlodipine. The edema in our patient resolved with-
valve function, and plasma myocardial injury markers
out serious consequences; however, all patients should be
were normal, and there was no fluid between the pericar-
monitored during therapy.
dial leaves. Due to the physical examination findings, we
did not consider this an allergic reaction. Cirrhosis and oth-
Didem Şener MD, Internal Medicine Resident, Medical Faculty,
er chronic gastrointestinal disease causing malnutrition Department of Internal Medicine, Hacettepe University, Ankara,
were eliminated based on her previous history. There was Turkey
no increase in blood leukocyte count, fever, or infiltration M Halil MD, Internal Medicine Specialist, Fellow of Geriatrics, Med-
on chest X-ray; pulmonary infection was therefore not ical Faculty, Department of Internal Medicine, Division of Geriatrics,
Hacettepe University
considered. Using the Naranjo probability scale to assess Burcu Balam Yavuz MD, Internal Medicine Resident, Medical Fac-
causality, we consider this case of generalized edema asso- ulty, Department of Internal Medicine, Hacettepe University
ciated with the use of amlodipine as probable.4 Mustafa Cankurtaran MD, Internal Medicine Specialist, Fellow of
There has been only one other case of generalized ede- Geriatrics, Medical Faculty, Department of Internal Medicine, Divi-
sion of Geriatrics, Hacettepe University
ma related to amlodipine in the Japanese literature,3 and Servet Arıoǧul MD, Professor of Internal Medicine, Medical Faculty,
our report is the first in the English-language literature. In Department of Internal Medicine, Division of Geriatrics, Hacettepe
the Japanese case, there were important underlying factors University
that accelerated the dilation of the blood vessels, such as Reprints: Dr. Cankurtaran, Hacettepe University Faculty of Medicine,
Department of Internal Medicine, Division of Geriatric Medicine,
systemic lupus erythematosus and steroid treatment. Both 06100 Sıhhiye, Ankara, Turkey, fax 90-312-72-08, mcankurt@
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 References
control of her blood pressure.
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The mechanism of amlodipine-related edema is unclear. 20.
It may be related to a local phenomenon associated with 2. Messerli FH. Evolution of calcium antagonists: past, present, and future.
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cording to several studies in the literature, none of the cal- 3. Maekawa Y, Sugimoto K, Ohishi M, Moriguchi A, Rakugi H, Iegushi
OH, et al. [A case of severe systemic edema in an elderly hypertensive
cium-channel blockers produce changes in body weight, patient with systemic lupus erythematodes during long-term treatment
plasma volume, or extracellular volume. The edemas are with anti-hypertensive drugs] Japanese. Nippon Ronen Igakkai Zasshi
related to the vascular effects of the calcium antagonist, 2001;38:696-9.
4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
and not to general fluid retention.6 It is thought to be the re- method for estimating the probability of adverse drug reactions. Clin
sult of uncompensated precapillary vasodilation causing Pharmacol Ther 1981;30:239-45.
increased intracapillary hydrostatic pressure.7 5. Vetrovec GW. Calcium antagonists and myocardial ischemia. In: Ebstien
M, ed. Calcium antagonists in clinical medicine. 2nd ed. Philadelphia:
Animal studies showed that calcium antagonists in- Hanley and Belfus, 1998(vol. 2):106.
crease fluid filtration and albumin permeability through 6. Johansen PL. Hemodynamic effect of calcium antagonists in hyperten-
large arteries, and this changes the degree of permeability sion. In: Ebstien M, ed. Calcium antagonists in clinical medicine. 2nd ed.
in different tissues, such as those of the lungs, testes, brain, Philadelphia: Hanley and Belfus, 1998(vol. 2):188.
7. Weir MR. Clinical benefits of Ca antagonists in renal transplant recipi-
and heart.8 In our patient, lungs and capillaries could be af- ents. In: Ebstien M, ed. Calcium antagonists in clinical medicine. Phila-
fected primarily. Additionally, amlodipine may cause pul- delphia: Hanley and Belfus, 1992:391.

762 ■ The Annals of Pharmacotherapy ■ 2005 April, Volume 39

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Anasarca Edema with Amlodipine

8. Lacolley P, Poitevin P, Koen R, Levy BI. Different effects of calcium an- periocular y perioral son menos frecuentes, pero el edema masivo no ha
tagonists on fluid filtration of large arteries and albumin permeability in surgido como un problema. Una evaluación objetiva del caso mostró
spontaneously hypertensive rats. J Hypertens 1998;16:349-55. una relación causal posible entre el uso de amlodipina y el edema
9. Stanek EJ, Nelson CE, DeNofrio D. Amlodipine overdose. Ann Pharma- masivo, según la escala de probabilidad de Naranjo.
cother 1997;31:853-6.
CONCLUSIONES: La amlodipina puede causar edema generalizado, que
10. Piper P, Vane J. Release of prostaglandins from lung and other tissues. desaparece al suspender el fármaco en raras ocasiones.
Ann N Y Acad Sci 1971;180:363-85.
11. Kennedy TP, Michael JR, Huang CK. Nifedipine inhibits hypoxic pul- Rafaela Mena
monary vasoconstriction during rest and exercise in patients with COPD.
Am Rev Respir Dis 1984;129:544-51.
12. Gniadecka M, Gniadecka R, Serup J, Sondergaard J. Skin mechanical RÉSUMÉ
properties present adaptation to man’s upright position. In vivo studies of OBJECTIF: Décrire le cas d’un patient qui a développé un œdème
young and aged individuals. Acta Derm Venereol 1994;74:188-90. généralisé (anasarque) suite à la prise de l’amlodipine.
RÉSUMÉ DU CAS: Il s’agit d’une femme de 77 ans présentant un nouveau
diagnostic d’hypertension artérielle. De l’amlodipine a été prescrit pour
contrôler sa tension artérielle. Elle a présenté une anasarque une semaine
EXTRACTO après le début du traitement avec l’amlodipine. Les autres étiologies ont
été éliminées; les résultats des tests de laboratoire étant négatifs. Une
OBJETIVO: Notificar el caso de una paciente con edema masivo asociado
semaine suite à l’arrêt de l’amlodipine, l’œdème généralisé s’est résorbé.
con el uso de amlodipina.
DISCUSSION: Les auteurs mentionnent qu’un seul cas d’œdème généralisé
RESUMEN DEL CASO: A una mujer de 77 años con hipertensión esencial,
associé à l’amlodipine a été rapporté dans la littérature japonaise. Un
que no recibía tratamiento con ningún medicamento, se le prescribió œdème prétibial est l’effet secondaire le plus souvent décrit avec
amlodipina para controlar la presión arterial. Desarrolló edema masivo l’amlodipine. L’œdème périoculaire ou l’œdème périoral sont moins
tan pronto como comenzó el tratamiento con la amlodipina. Los fréquemment observés. En utilisant l’échelle de Naranjo, une association
resultados de las pruebas de laboratorio para diagnosticar otras posibles probable entre la prise d’amlodipine et la présence d’une anasarque a été
etiologías fueron negativos. Se observó una mejoría espectacular al observée.
suspender la amlodipina.
CONCLUSIONS: L’amodipine peut causer un œdème généralisé qui
DISCUSIÓN: Hasta donde sabemos, en la literatura científica en inglés no
disparaît suite à l’arrêt du médicament.
se ha publicado ningún caso de edema masivo, y sólo hay uno publicado
en la literatura científica escrita en japonés. El edema pretibial es el Louise Mallet
efecto secundario más común del tratamiento con amlodipina. Edema The Annals of Pharmacotherapy ■ 2005 April, Volume 39 ■ 763

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