ORAL MEDICINEíiit Ltiim iiiiiílûnn

SLENTINÜIhG EDUCATION

Üsinopril-induced Angioedema of the LipRonald 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-Amer-

ican female who presented with a swollen lower lip

that had developed overnight. A review of her medi-

cal history revealed that she was being treated for hy-

pertension with a combination product containing

lisinopril and hydrocholorothiazide. A diagnosis of

lisinopril-induced angioedema was made. Her physi-

cian was consulted and her medications were discon-

tinued. The lip swelling resolved without incident.

Angiotensin-converting enzyme inhibitors (ACE inhibitors) arecommonly used in the management of hypertension, either aloneor in combination with other antihypertensive agents. They arealso utilized as adjunctive therapy in the treatment of congestiveheart failure and in the treatment of acute myocardial infarctionin hemodynamically stable patients.^'^

Known side effects of ACE inhibitors include those commonto antihypertensives, such as hypotension and hyperkalemia, aswell as unique side effects, such as a dry cough unrelated to arespiratory infection and angioedema. ACE inhibitors act by com-

petitively inhibiting angiotensin-converting enzyme, effectivelyinterfering with the renin-angiotension-aldosterone pathway.^

The renin-angiotensin-aldosterone pathway is a primarymetabolic mechanism to regulate systemic blood pressure, flu-id volume and sodium balance. When renal cell blood perfu-sion pressure decreases, the juxtaglomerular cells of the kidneynephrons produce renin. Hepatically produced angiotensinogenis transformed by renin to angiotensin I. Angiotensin-convert-ing enzyme metabolizes the weak vasoconstrictor angiotensin Ito angiotensin II, a potent vasoconstrictor. Norepinephrine isthen released, resulting in peripheral and renal vasoconstriction.Angiotensin II also promotes the release of aldosterone from theadrenal cortex, with subsequent sodium retention, potassiumdepletion and systemic volume expansion. The net effect of theseactions is an increase in systemic blood pressure.^'*

Angiotensin-converting enzyme, or kininase II, is also in-volved in the catabolism of bradykinin, a potent mediator of va-sodilation and vascular permeability. With ACE inhibitor therapy,bradykinin catabolism is blocked and systemic bradykinin levelsincrease, along with an increase in substance p. This results invasodilation, increased vascular permeability, increased prosta-glandin synthesis and interstitial fluid build-up.^''

Angioedema is a diffuse edematous swelling of the skin, mu-cosa and/or gastrointestinal tract. It has been associated with avariety of causes, including a hereditary angioedema resultingfrom a deficiency of the enzyme complement 1 inhibitor, an ac-quired angioedema related to several lymphoproliferative, neo-plastic and autoimmune disorders, and as an adverse drug reac-tion.^'^ While most cases of angioedema are localized and respond

The New York State Dental Journal • APRIL 2 O 1 3 2 5

well to symptomatic treatment, edema of the mucous membranesof the tongue or pharyngeal/laryngeal regions may lead to a life-threatening airway compromise.'''^

Angioedema is a known side effect of angiotensin-convertingenzyme inhibitors, with a reported incidence of 0.1% to 0.7% oftreated patients.' The majority of cases involve the head, neck,lips, tongue and larynx, although, in some cases, the gastrointes-tinal tissues may be affected.̂ '̂ "̂ "̂ ^ In most cases, the angioedemais self-limited and responds to cessation of ACE inhibitor therapy,although life-threatening airway compromise has been reportedin 25% to 67% of cases.^*''" Fatal reactions related to airway com-promise have been reported.^''""

There have been a very limited number of cases of ACE inhib-itor-induced angioedema published in the dental literature.̂ ""^"*The following is a case of a non-life-threatening angioedema in apatient who had been taking lisinopril for many years.

Case ReportA 69-year-old African-American female presented with a com-plaint of a swollen lower lip that had developed the night before.Clinical examination did not reveal any evidence of lip biting oran insect bite. She did not appear to be in acute distress and de-nied difficulty breathing or swallowing. Intraoral examination didnot reveal any tongue or throat swelling. The oral soft tissues ap-peared dry. There was no dermatologie evidence of a rash. Thepatient denied any history of food or drug allergy.

A review of the patient's medical history revealed that shewas being treated for hypertension for several years with a combi-nation drug product containing lisinopril 20 mg and hydrochlo-rothiazide 12.5 mg, and had last seen her primary care physicianeight months earlier. It was noted that she appeared thinner thanat her previous periodontal appointments. Upon questioning, thepatient reported she had been dieting and had lost 32 poundsover the previous six months. It was hypothesized that the pa-tient's significant decrease in body mass, combined with a relativedehydration related to diuretic use during an ongoing Northeast-ern heat wave, had created a situation in which her previouslytherapeutic, appropriate medication dosages were now suprath-erapeutic and inappropriate.

A diagnosis of lisinopril-induced angioedema of the lip wasmade. The patient's physician was consulted by telephone and ar-rangements were made for her to be examined by him that day.

After reviewing the pertinent medical history and performinga clinical examination, the patient's physician concurred with thediagnosis of lisinopril-induced angioedema of the lip. The lisino-pril/hydrochlorothiazide combination product was discontin-ued and a calcium channel blocker, amlodipine 10 mg, was pre-scribed. Two weeks later, the patient developed edema in her legsand hydrochlorothiazide 25mg was added to her drug regimen.She is currently adequately maintained on amlodipine 10 mg andhydrochlorothiazide 25 mg without any adverse effects.

Figure 1 . Angioedema of lip.

DiscussionAngioedema is a known adverse reaction to ACE inhibitors. Whilethe exact mechanism by which ACE inhibitors induce angioedemaremains unclear, the inhibition of bradykinin metabolism and subse-quent increase in bradykinin and substance p levels is suspected. ACEinhibitor-induced angioedema usually manifests during the first weekof therapy, but may occur at any üme.̂ * It has been reported that Afri-can Americans, individuals over the age of 65 and patients with a his-tory of seasonal allergies are at increased risk of ACE inhibitor-inducedangioedema.^'"^' Concurrent use of NSAIDs may precipitate thedevelopment of angioedema in patients taking ACE inhibitors.̂ °"^^

A patient presenting with medication-induced angioedemamay present a diagnostic challenge. Oral and perioral angioede-ma may be misdiagnosed as a dental infection,^* with subsequentinappropriate dental therapy or antibiotic prescribing. Gastro-intestinal angioedema may be misdiagnosed as Crohn's disease,ulcerative colitis, malignancy or gastroenteritis, with subsequenthospitalization and unnecessary imaging and invasive proce-dures.̂ °"^^ Misdiagnosis of an allergic reaction or a misunder-standing of the pathophysiology of angioedema have led to empir-ical therapy with antihistamines, subcutaneous epinephrine andcorticosteroids, which are of limited value, as angioedema doesnot appear to be mediated by an antibody-antigen reaction.^^

Patients may suffer recurrent bouts of angioedema over sev-eral months, with repeated medical evaluations and inappropriatetherapies, before an accurate diagnosis is made and medicationcessation is attempted. A careful medical history is mandatoryin making this diagnosis and avoiding unnecessary suffering andinappropriate therapies.

ConclusionAngiotensin-converting enzjones are commonly used in the man-agement of h3^ertension. Angioedema is a well-known adverse

2 6 APRIL 2 O 1 3 • The New York State Dental Journal

TABLE T

ACE Inhibitors

Drug

Ca potril

Lisinopril

Enalapril

Benazepril

Fosinopril

Ramipril

Quinapril

Trandolapril

Perindopril

Moexipril

Brand Name

Capoten

Prinivil, Zestril

Vastotec

Lotensin

Monopril

Altace

Accupril

Mavik

Aceon

Univasc

TABLE 2ACE Inhibitor Combination Products

Drug Brand Name

ACE Inhibitor and Diuretic Combinations

Captopril and hydrachlarothiazide

Liosinapril and hydrochlorothiazide

Enalapril and hydrochlorathiazide

Benazepril and hydrochlorothiazide

Fasinopril and hydrochlorothiazide

Quinapril and hydrochlorothiazide

Perinodopril and indapamide

Moexipril and hydrochlorothiazide

Capozide

Prinzide, Zestoretic

Vaseretic

Lotensin HCT

Monopril HCT

Accuretic

Aceon Plus

Uniretic

ACE Inhibitor and Calcium Channel Blocker Combinations

Benazepril and amiodipine

Enalaprii and diltiazem

Enalapril and felodipine

Ramipril and felodipine

Trandolapril and verapamil

Lotrel

Teczem

Lexxel

Unimax

Torka

drug reaction associated v«th ACE inhibitors. The diagnosis ofmedication-induced angioedema can be a diagnostic challenge.Awareness of a patient's medical status and an accurate updatingof changes in medical and social histories may aid in the earlyidentification of an adverse drug reaction.

In the current case, awareness of the patient's medical histo-ry and familiarity with the signs and symptoms of the side effectsassociated with lisinopril led to a diagnosis of angioedema and anappropriate medical referral. Rapid cessation of lisinopril therapyallowed for resolution without further incident, Á

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

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