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, www.theannals.com, DOI 10.1345/aph.1E410

mlodipine is a dihydropyridine calcium-channel blocker
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
such as pedal, pretibial, and periorbital. Vasodilation and in-
tracapillary hypertension are the underlying mechanisms of
this effect.2 Theoretically, amlodipine can cause general-
ized edema; however, according to our knowledge, as of
February 3, 2005, there has been only one case reported
describing generalized edema.3 We report a 77-year-old
woman with amlodipine-induced anasarca edema, which
disappeared after discontinuation of the drug therapy.
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 examina-
tion was completely normal, as were urine analysis, and biochemical pa-
rameters including plasma glucose, liver function tests, and kidney func-
Author information provided at the end of the text.
tion tests. Cholesterol, high-density lipoprotein, low-density lipoprotein,
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 gradual-
ly developed generalized edema. She had no complaints other than gen-
eralized 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, pretib-
ial, 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 ac-
cording 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, potassi-
um 4.5 mEq/dL, and chloride 108 mEq/dL. No decrease in urine output
had been noted. Posteroanterior chest X-ray, urinary system ultrasound,

www.theannals.com The Annals of Pharmacotherapy ■ 2005 April, Volume 39 ■ 761

Downloaded from aop.sagepub.com at NANYANG TECH UNIV LIBRARY on June 3, 2015
D Şener et al.
and renal arterial Doppler ultrasound were normal. There was no QT
wave or ST segment change, and no arrhythmias compared with the pre-
vious 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 am-
lodipine treatment was discontinued.
Consequently, the edema had completely resolved one week after dis-
continuation 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 hy-
pertension. 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 coro-
nary syndrome, or heart failure. Systolic function, cardiac
valve function, and plasma myocardial injury markers
were normal, and there was no fluid between the pericar-
dial leaves. Due to the physical examination findings, we
did not consider this an allergic reaction. Cirrhosis and oth-
er 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 asso-
ciated with the use of amlodipine as probable.4
There has been only one other case of generalized ede-
ma 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 Ac-
cording to several studies in the literature, none of the cal-
cium-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 re-
sult of uncompensated precapillary vasodilation causing
increased intracapillary hydrostatic pressure.7
Animal studies showed that calcium antagonists in-
crease 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 af-
fected primarily. Additionally, amlodipine may cause pul-
762 ■ The Annals of Pharmacotherapy ■ 2005 April, Volume 39
Downloaded from aop.sagepub.com at NANYANG TECH UNIV LIBRARY on June 3, 2015
monary edema, which has been reported as an amlodipine
overdose.9 The mechanism of this effect is likely multifac-
torial 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 re-
versible redistribution of the fluids.
Possibly because of their reduced skin elasticity and al-
tered 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 ad-
verse effect of amlodipine, increasing with the dose depen-
dently. 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 un-
expected effect of amlodipine in elderly patients.
Conclusions
Generalized edema is a rare complication of treatment
with amlodipine. The edema in our patient resolved with-
out serious consequences; however, all patients should be
monitored during therapy.
Didem Şener MD, Internal Medicine Resident, Medical Faculty,
Department of Internal Medicine, Hacettepe University, Ankara,
Turkey
M Halil MD, Internal Medicine Specialist, Fellow of Geriatrics, Med-
ical Faculty, Department of Internal Medicine, Division of Geriatrics,
Hacettepe University
Burcu Balam Yavuz MD, Internal Medicine Resident, Medical Fac-
ulty, Department of Internal Medicine, Hacettepe University
Mustafa Cankurtaran MD, Internal Medicine Specialist, Fellow of
Geriatrics, Medical Faculty, Department of Internal Medicine, Divi-
sion of Geriatrics, Hacettepe University
Servet Arıoǧul MD, Professor of Internal Medicine, Medical Faculty,
Department of Internal Medicine, Division of Geriatrics, Hacettepe
University
Reprints: Dr. Cankurtaran, Hacettepe University Faculty of Medicine,
Department of Internal Medicine, Division of Geriatric Medicine,
06100 Sıhhiye, Ankara, Turkey, fax 90-312-72-08, mcankurt@
hacettepe.edu.ctr
References
1. Osterloh I. The safety of amlodipine. Am Heart J 1989;118(5 pt 2):1114-
20.
2. Messerli FH. Evolution of calcium antagonists: past, present, and future.
Clin Cardiol 2003;26(2 suppl 2):II12-6.
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
patient with systemic lupus erythematodes during long-term treatment
with anti-hypertensive drugs] Japanese. Nippon Ronen Igakkai Zasshi
2001;38:696-9.
4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239-45.
5. Vetrovec GW. Calcium antagonists and myocardial ischemia. In: Ebstien
M, ed. Calcium antagonists in clinical medicine. 2nd ed. Philadelphia:
Hanley and Belfus, 1998(vol. 2):106.
6. Johansen PL. Hemodynamic effect of calcium antagonists in hyperten-
sion. In: Ebstien M, ed. Calcium antagonists in clinical medicine. 2nd ed.
Philadelphia: Hanley and Belfus, 1998(vol. 2):188.
7. Weir MR. Clinical benefits of Ca antagonists in renal transplant recipi-
ents. In: Ebstien M, ed. Calcium antagonists in clinical medicine. Phila-
delphia: Hanley and Belfus, 1992:391.
www.theannals.com

8. Lacolley P, Poitevin P, Koen R, Levy BI. Different effects of calcium an-
tagonists on fluid filtration of large arteries and albumin permeability in
spontaneously hypertensive rats. J Hypertens 1998;16:349-55.
9. Stanek EJ, Nelson CE, DeNofrio D. Amlodipine overdose. Ann Pharma-
cother 1997;31:853-6.
10. Piper P, Vane J. Release of prostaglandins from lung and other tissues.
Ann N Y Acad Sci 1971;180:363-85.
11. Kennedy TP, Michael JR, Huang CK. Nifedipine inhibits hypoxic pul-
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
properties present adaptation to man’s upright position. In vivo studies of
young and aged individuals. Acta Derm Venereol 1994;74:188-90.
EXTRACTO
OBJETIVO: Notificar el caso de una paciente con edema masivo asociado
con el uso de amlodipina.
RESUMEN DEL CASO: A una mujer de 77 años con hipertensión esencial,
que no recibía tratamiento con ningún medicamento, se le prescribió
amlodipina para controlar la presión arterial. Desarrolló edema masivo
tan pronto como comenzó el tratamiento con la amlodipina. Los
resultados de las pruebas de laboratorio para diagnosticar otras posibles
etiologías fueron negativos. Se observó una mejoría espectacular al
suspender la amlodipina.
DISCUSIÓN: Hasta donde sabemos, en la literatura científica en inglés no
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
efecto secundario más común del tratamiento con amlodipina. Edema
www.theannals.com The Annals of Pharmacotherapy
Downloaded from aop.sagepub.com at NANYANG TECH UNIV LIBRARY on June 3, 2015
Anasarca Edema with Amlodipine
periocular y perioral son menos frecuentes, pero el edema masivo no ha
surgido como un problema. Una evaluación objetiva del caso mostró
una relación causal posible entre el uso de amlodipina y el edema
masivo, según la escala de probabilidad de Naranjo.
CONCLUSIONES: La amlodipina puede causar edema generalizado, que
desaparece al suspender el fármaco en raras ocasiones.
Rafaela Mena
RÉSUMÉ
OBJECTIF: Décrire le cas d’un patient qui a développé un œdème
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
après le début du traitement avec l’amlodipine. Les autres étiologies ont
été éliminées; les résultats des tests de laboratoire étant négatifs. Une
semaine suite à l’arrêt de l’amlodipine, l’œdème généralisé s’est résorbé.
DISCUSSION: Les auteurs mentionnent qu’un seul cas d’œdème généralisé
associé à l’amlodipine a été rapporté dans la littérature japonaise. Un
œdème prétibial est l’effet secondaire le plus souvent décrit avec
l’amlodipine. L’œdème périoculaire ou l’œdème périoral sont moins
fréquemment observés. En utilisant l’échelle de Naranjo, une association
probable entre la prise d’amlodipine et la présence d’une anasarque a été
observée.
CONCLUSIONS: L’amodipine peut causer un œdème généralisé qui
disparaît suite à l’arrêt du médicament.
Louise Mallet
■ 2005 April, Volume 39 ■ 763