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ORAL MEDICINE

SLE

NTINIhG EDUCATION

sinopril-induced Angioedema of the Lip

Ronald J. Lehane, D.D.S., M.S.

ABSTRACT
Angiotensin-converting enzyme (ACE) inhibitors are
commonly used in the treatment of hypertension.
Angioedema is a known side effect of ACE inhibitors.
Awareness of the clinical presentation of angioedema
can allow for appropriate medical referral. The case
presented here describes a 69-year-old African-American female who presented with a swollen lower lip
that had developed overnight. A review of her medical history revealed that she was being treated for hypertension with a combination product containing
lisinopril and hydrocholorothiazide. A diagnosis of
lisinopril-induced angioedema was made. Her physician was consulted and her medications were discontinued. The lip swelling resolved without incident.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) are
commonly used in the management of hypertension, either alone
or in combination with other antihypertensive agents. They are
also utilized as adjunctive therapy in the treatment of congestive
heart failure and in the treatment of acute myocardial infarction
in hemodynamically stable patients.^'^
Known side effects of ACE inhibitors include those common
to antihypertensives, such as hypotension and hyperkalemia, as
well as unique side effects, such as a dry cough unrelated to a
respiratory infection and angioedema. ACE inhibitors act by com-

petitively inhibiting angiotensin-converting enzyme, effectively

interfering with the renin-angiotension-aldosterone pathway.^
The renin-angiotensin-aldosterone pathway is a primary
metabolic mechanism to regulate systemic blood pressure, fluid volume and sodium balance. When renal cell blood perfusion pressure decreases, the juxtaglomerular cells of the kidney
nephrons produce renin. Hepatically produced angiotensinogen
is transformed by renin to angiotensin I. Angiotensin-converting enzyme metabolizes the weak vasoconstrictor angiotensin I
to angiotensin II, a potent vasoconstrictor. Norepinephrine is
then released, resulting in peripheral and renal vasoconstriction.
Angiotensin II also promotes the release of aldosterone from the
adrenal cortex, with subsequent sodium retention, potassium
depletion and systemic volume expansion. The net effect of these
actions is an increase in systemic blood pressure.^'*
Angiotensin-converting enzyme, or kininase II, is also involved in the catabolism of bradykinin, a potent mediator of vasodilation and vascular permeability. With ACE inhibitor therapy,
bradykinin catabolism is blocked and systemic bradykinin levels
increase, along with an increase in substance p. This results in
vasodilation, increased vascular permeability, increased prostaglandin synthesis and interstitial fluid build-up.^''
Angioedema is a diffuse edematous swelling of the skin, mucosa and/or gastrointestinal tract. It has been associated with a
variety of causes, including a hereditary angioedema resulting
from a deficiency of the enzyme complement 1 inhibitor, an acquired angioedema related to several lymphoproliferative, neoplastic and autoimmune disorders, and as an adverse drug reaction.^'^ While most cases of angioedema are localized and respond

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25

well to symptomatic treatment, edema of the mucous membranes

of the tongue or pharyngeal/laryngeal regions may lead to a lifethreatening airway compromise.'''^
Angioedema is a known side effect of angiotensin-converting
enzyme inhibitors, with a reported incidence of 0.1% to 0.7% of
treated patients.' The majority of cases involve the head, neck,
lips, tongue and larynx, although, in some cases, the gastrointestinal tissues may be affected.^'^"^"^^ In most cases, the angioedema
is self-limited and responds to cessation of ACE inhibitor therapy,
although life-threatening airway compromise has been reported
in 25% to 67% of cases.^*''" Fatal reactions related to airway compromise have been reported.^''""
There have been a very limited number of cases of ACE inhibitor-induced angioedema published in the dental literature.^""^"*
The following is a case of a non-life-threatening angioedema in a
patient who had been taking lisinopril for many years.
Figure 1. Angioedema of lip.

Case Report
A 69-year-old African-American female presented with a complaint of a swollen lower lip that had developed the night before.
Clinical examination did not reveal any evidence of lip biting or
an insect bite. She did not appear to be in acute distress and denied difficulty breathing or swallowing. Intraoral examination did
not reveal any tongue or throat swelling. The oral soft tissues appeared dry. There was no dermatologie evidence of a rash. The
patient denied any history of food or drug allergy.
A review of the patient's medical history revealed that she
was being treated for hypertension for several years with a combination drug product containing lisinopril 20 mg and hydrochlorothiazide 12.5 mg, and had last seen her primary care physician
eight months earlier. It was noted that she appeared thinner than
at her previous periodontal appointments. Upon questioning, the
patient reported she had been dieting and had lost 32 pounds
over the previous six months. It was hypothesized that the patient's significant decrease in body mass, combined with a relative
dehydration related to diuretic use during an ongoing Northeastern heat wave, had created a situation in which her previously
therapeutic, appropriate medication dosages were now supratherapeutic and inappropriate.
A diagnosis of lisinopril-induced angioedema of the lip was
made. The patient's physician was consulted by telephone and arrangements were made for her to be examined by him that day.
After reviewing the pertinent medical history and performing
a clinical examination, the patient's physician concurred with the
diagnosis of lisinopril-induced angioedema of the lip. The lisinopril/hydrochlorothiazide combination product was discontinued and a calcium channel blocker, amlodipine 10 mg, was prescribed. Two weeks later, the patient developed edema in her legs
and hydrochlorothiazide 25mg was added to her drug regimen.
She is currently adequately maintained on amlodipine 10 mg and
hydrochlorothiazide 25 mg without any adverse effects.

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A P R I L 2 O 1 3 The New York State Dental Journal

Discussion
Angioedema is a known adverse reaction to ACE inhibitors. While
the exact mechanism by which ACE inhibitors induce angioedema
remains unclear, the inhibition of bradykinin metabolism and subsequent increase in bradykinin and substance p levels is suspected. ACE
inhibitor-induced angioedema usually manifests during thefirstweek
of therapy, but may occur at any me.^* It has been reported that African Americans, individuals over the age of 65 and patients with a history of seasonal allergies are at increased risk of ACE inhibitor-induced
angioedema.^'"^' Concurrent use of NSAIDs may precipitate the
development of angioedema in patients taking ACE inhibitors.^"^^
A patient presenting with medication-induced angioedema
may present a diagnostic challenge. Oral and perioral angioedema may be misdiagnosed as a dental infection,^* with subsequent
inappropriate dental therapy or antibiotic prescribing. Gastrointestinal angioedema may be misdiagnosed as Crohn's disease,
ulcerative colitis, malignancy or gastroenteritis, with subsequent
hospitalization and unnecessary imaging and invasive procedures.^"^^ Misdiagnosis of an allergic reaction or a misunderstanding of the pathophysiology of angioedema have led to empirical therapy with antihistamines, subcutaneous epinephrine and
corticosteroids, which are of limited value, as angioedema does
not appear to be mediated by an antibody-antigen reaction.^^
Patients may suffer recurrent bouts of angioedema over several months, with repeated medical evaluations and inappropriate
therapies, before an accurate diagnosis is made and medication
cessation is attempted. A careful medical history is mandatory
in making this diagnosis and avoiding unnecessary suffering and
inappropriate therapies.

Conclusion
Angiotensin-converting enzjones are commonly used in the management of h3^ertension. Angioedema is a well-known adverse

TABLE T
ACE Inhibitors

REFERENCES
1.

Drug

Brand Name

2.

Ca potril

Capoten

3.

Lisinopril

Prinivil, Zestril

Enalapril

Vastotec

4.

Benazepril

Lotensin

5.

Fosinopril

Monopril

Ramipril

Altace

Quinapril

Accupril

Trandolapril

Mavik

Perindopril

Aceon

Moexipril

Univasc

6.
7.
8.
9.

10.
n.

TABLE 2
ACE Inhibitor Combination Products
Drug

12.
13.

Brand Name

14.

ACE Inhibitor and Diuretic Combinations

Captopril and hydrachlarothiazide

Capozide

15.
16.

Liosinapril and hydrochlorothiazide

Prinzide, Zestoretic

Enalapril and hydrochlorathiazide

Vaseretic

Benazepril and hydrochlorothiazide

Lotensin HCT

Fasinopril and hydrochlorothiazide

Monopril HCT

Quinapril and hydrochlorothiazide

Accuretic

Perinodopril and indapamide

Aceon Plus

Moexipril and hydrochlorothiazide

Uniretic

ACE Inhibitor and Calcium Channel Blocker Combinations

Benazepril and amiodipine

Lotrel

Enalaprii and diltiazem

Teczem

Enalapril and felodipine

Lexxel

Ramipril and felodipine

Unimax

Trandolapril and verapamil

Torka

17.
18.

19.
20.
21.
22.

23.
24.
25.

drug reaction associated vth ACE inhibitors. The diagnosis of

medication-induced angioedema can be a diagnostic challenge.
Awareness of a patient's medical status and an accurate updating
of changes in medical and social histories may aid in the early
identification of an adverse drug reaction.
In the current case, awareness of the patient's medical history and familiarity with the signs and symptoms of the side effects
associated with lisinopril led to a diagnosis of angioedema and an
appropriate medical referral. Rapid cessation of lisinopril therapy
allowed for resolution without further incident,

26.
17.

28.

29.
30.
31.

32.

Queries about this article can be sent to Dr. Lehane at rjl8@nyu.edu.

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