Angiotensin Converting Enzyme Inhibitors and Delayed Onset

Home , Adverse effect, Angioedema

Angiotensin converting enzyme IN BRIEF • This paper highlights a possible serious cause of facial swelling presenting in a PRACTICE dental context. inhibitors and delayed onset, • Increases the reader’s knowledge of an important side-effect of a common medication. recurrent angioedema of the • Informs the reader of the causes and head and neck treatment of angioedema.

Y. S. Wakeﬁ eld,1 E. D. Theaker2 and M. N. Pemberton3

VERIFIABLE CPD PAPER

Angiotensin converting enzyme (ACE) inhibitors are a commonly prescribed, effective medication in the treatment of hypertension and heart failure. Several side-effects of dental relevance can occur including angioedema of the lips, mouth and throat. This adverse effect is well reported and can be fatal, but it is not always recognised by clinicians, as the angioedema does not always have a clear relationship with the commencement of the medication. The cases of angioedema reported here all presented in a dental setting and highlight both the delayed onset and the chronic recurrent nature of ACE inhibitor induced angioedema.

INTRODUCTION publication of NICE Clinical Guideline patient gave a 20 year history of recal- Angioedema describes a well-defi ned 34, which recommends that this group citrant lichen planus affecting both his non-pitting oedema of the subcutaneous of drugs should be the fi rst choice initial skin and mouth and was currently expe- tissues which can affect any area of the pharmacological intervention for hyper- riencing ulceration of his right buccal body but frequently presents as a tran- tension in patients under 55 years of age mucosa and lips, fi nding that topical sient swelling of the face and mucous (excluding patients of African and Car- steroids were of little help. The patient membranes.1-3 The swelling is usually of ibbean descent).10 Where angioedema also complained of frequent attacks acute onset and subsides after a couple secondary to ACE inhibitors occurs, in of spontaneously swollen lips occur- of days. The clinical picture can vary approximately 25% of patients the fi rst ring over the previous two years. These and ranges from mild localised symp- episode of angioedema will occur within attacks were of sudden onset with an toms to extensive upper airway obstruc- one month of the commencement of tak- increase in size over minutes subsid- tion, which can be fatal.4-6 Although ing the ACE inhibitor.11 However, it is ing over the next two days. The swell- allergy is sometimes the cause, many not uncommon for a patient to be taking ings were painless but of concern. The patients develop the problem for non- ACE inhibitors for many years before patient had sought the opinion of a der- allergic reasons and it is a well described any side-effects become apparent.4,5,12 matologist without success. He had a complication of angiotensin converting Because of this frequent lack of tempo- medical history of hypertension, hyper- enzyme (ACE) inhibitors.1-6 ral association between commencing the cholesterolaemia, angina, gout, oste- It is estimated that 35-40 million ACE inhibitor and angioedema occur- oarthritis, gastric ulcer, petit mal and patients worldwide are currently pre- ring, many clinicians are unaware of the impaired renal function. He had previ- scribed ACE inhibitors for treatment of causative relationship. ously suffered a myocardial infarction hypertension, heart failure and post- We here report fi ve cases of delayed and pulmonary embolism. In addition myocardial infarction.7 In this popu- onset angioedema that have presented a carcinoma had been excised from his lation group 0.1-0.2% are affected by to us in a dental setting over the last right ethmoid sinus. He had no known angioedema.8,9 The use of ACE inhibitors few years, to help raise awareness of allergies. The patient’s medication was in the UK is set to increase following the both this relationship and the chronic lamotrigine, clopidogrel, levetiracetam, recurrent nature of ACE inhibitor atenolol, co-proxamol, frusemide, prav- induced angioedema. astatin and ramipril. The patient had 1*Clinical Fellow, 2Lecturer, 3Consultant, Oral Medicine, been taking the ACE inhibitor ramipril University Dental Hospital of Manchester, Higher CASE REPORTS Cambridge Street, Manchester, M15 6FH 5 mg once a day for fi ve years. *Correspondence to: Mrs Yasha S. Wakefi eld Case 1 The patient was diagnosed with Email: yasha.wakefi [email protected] angioedema secondary to ACE inhibi- Refereed Paper An 81-year-old Caucasian male patient tors and ulcerative lichen planus. With Accepted 20 August 2008 DOI: 10.1038/sj.bdj.2008.982 was referred by his general dental prac- respect to the angioedema, his general ©British Dental Journal 2008; 205: 553-556 titioner (GDP) with a sore mouth. The medical practitioner (GMP) was contacted

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with a view to changing his ACE inhibitor to an alternative class of medication. For the treatment of his ulcerative lichen planus the patient was prescribed topical tacrolimus in orabase 0.1% and advised to apply sparingly to the affected areas of oral mucosa twice daily. At the review appointments the patient had not experienced any further episodes of angioedema following a change of his ramipril to an angiotensin II receptor antagonist. The patient also reported that his lichen planus had dramatically cleared up following use of tacrolimus.

Case 2 A 64-year-old Caucasian male was referred by his GDP with recurrent episodes of facial swelling. The patient gave a two year history of frequent recurrent transient swelling of the right side of Fig. 1 Swelling of upper lip due to angioedema his tongue, lips and face. The swellings were painless, appeared over 3-4 hrs each episode the patient had needed A diagnosis of angioedema secondary and lasted for 6-24 hrs. The patient had to attend an accident and emergency to ACE inhibitors was made and his GMP spent several thousand pounds on pri- department and was treated with ster- informed. After changing his lisinopril vate consultations with various medi- oids and antihistamines. The swelling to an angiotensin II receptor antago- cal specialists in an attempt to identify had decreased over a period of several nist no further episodes of angioedema the cause without success. He had no hours each time. The patient’s medical were reported. known allergies, although an allergic history consisted of angina, a previous cause to his swelling had been postu- myocardial infarction and bronchiecta- Case 5 lated. He had been prescribed an anti- sis. He had no known allergies. The An 86-year-old Afro-Caribbean male histamine for the episodes of swelling, patient was taking aspirin, lisinopril (an was referred by his GDP with a 21 month which had made very little difference. ACE inhibitor), bisoprolol, frusemide and history of intermittent episodes of swell- The patient’s medical history consisted isosorbide mononitrate. ing affecting his upper and lower lips. of hypertension, type II diabetes and The patient was diagnosed with These painless swellings occurred once mild asthma for which he was taking angioedema secondary to ACE inhibi- or twice each month, taking about an glibenclamide, aspirin, enalapril and a tors. The patient subsequently had his hour to develop fully and resolving salbutamol inhaler to use when needed. lisinopril changed to an angiotensin II slowly over the following two days. The The patient had been taking the ACE receptor antagonist and at his review patient’s medical history revealed that inhibitor enalapril 10 mg once a day for appointment reported no further he suffered from hypertension and had fi ve years. episodes of angioedema. undergone resection of an abdominal A diagnosis of angioedema second- tumour some fi ve years ago. He had no ary to ACE inhibitors was made. The Case 4 known allergies. His medication com- GMP was informed of the diagnosis, A 77-year-old Caucasian male was prised amlodipine, bendrofl umethiazide, and changed the patient’s enalapril to referred on an urgent basis by his GDP doxazosin, aspirin and enalapril. an angiotensin II receptor antagonist. At with a swollen upper lip (Fig. 1). He A diagnosis of angioedema second- review the patient reported a sustained gave a history of recurrent swelling ary to ACE inhibitors was made and the resolution in symptoms following his of his lips. The swellings were pain- patient’s GMP informed. The GMP was medication change. less, of rapid onset and usually resolved initially reluctant to change the patient’s within a day. The patient’s medical his- medication until the potential serious Case 3 tory consisted of asthma, hypertension consequences of upper aero-digestive A 78-year-old Caucasian male was and mitral valve prolapse for which he tract angioedema were emphasised in a referred by his GDP with a three month was taking bendrofl uazide, lisinopril further letter, following which the patient history of recurrent episodes of acute and a fl ixotide inhaler. He had been was commenced on the angiotensin II swellings of his tongue and throat. The taking the ACE inhibitor lisinopril 10 receptor antagonist losartan. At review swellings had a rapid onset and reached mg once daily for six years. He had no fi ve months later there had been no recur- a maximum in size after an hour. On known allergies. rence of the patient’s angioedema.

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DISCUSSION of bradykinin, which would predispose and acquired angioedema are caused Since ACE inhibitors were fi rst intro- the patient to episodes of angioedema by C1 esterase inhibitor defi ciency or duced, the most common reported side- as the effect of the ACE inhibitor would dysfunction.20,21 Angioedema in these effect is a non-productive cough which is further raise the levels of bradykinin. cases is frequently precipitated by thought to occur in 5-25% of patients.13 This could explain why only a propor- trauma or surgical procedures, but Other frequently reported side-effects tion of patients taking ACE inhibitors patients may give a history of spon- are angioedema and dizziness.13 There are affected by angioedema. taneous abdominal pain or pharyn- are several less common side-effects Black patients of African origin may geal swelling for no reason. Hereditary reported that affect the oral cavity, be at greater risk than other patients. angioedema is usually due to an auto- including dysgeusia, scalded mouth Patients in this ethnic group who somal dominant condition, whereas syndrome and oral ulceration.8 are taking ACE inhibitors have been acquired angioedema may be the result of Angioedema secondary to ACE inhibi- found to have an increased incidence lymphoproliferative disease. tors is frequently recurrent, its severity of angioedema.5,15,16 There is some evi- The management of acute episodes of is variable and may fl uctuate. Deaths dence that there is a racial difference angioedema is partly dependent on the have been reported.6 ACE inhibitor in the kallikrein-kinin system which underlying cause. In all cases, should the induced angioedema has a predilection leaves patients of African origin with patient’s breathing be compromised, then for the head and neck. It is reported an increased sensitivity to bradykinin, transfer to hospital to allow securing of to be responsible for 25-35% of cases thereby offering an explanation to this the airway should be arranged as soon of angioedema in these sites2 with the apparent racial difference.15,16 as possible. For hereditary and acquired tongue and lips being most commonly The recommended management for angioedema, an infusion of C1 esterase involved.11 While the prevalence of ACE patients who experience angioedema inhibitor will be the hospital treatment inhibitor induced angioedema is highest secondary to ACE inhibitors is to change of choice. For ACE inhibitor associated in the head and neck, other parts of the medication to an alternative class of angioedema, there is no standardised 7,9 body can be affected. Recurrent gastro- drug. Angiotensin II receptor antago- treatment for the acute attack other than intestinal angioedema is not uncommon nists are a popular choice as they are discontinuation of the ACE inhibitor.22 and in these cases patients present with well tolerated and decrease cardiovas- Other emergency procedures are essen- abdominal pain, nausea and vomiting.14 cular mortality and morbidity.17 As tially the same as would be clinically Such patients often undergo multiple angiotensin II receptor antagonists do warranted for an attack of acute aller- unnecessary investigations in an attempt not block bradykinin metabolism, it gic angioedema, including epinephrine, to fi nd the cause for their symptoms was thought that the unwanted side- antihistamines and systemic steroids. before the correct diagnosis is made. effect of increased bradykinin would be There is, however, little evidence of The pathophysiology of angioedema avoided. However, it has been reported their effectiveness in this situation and secondary to ACE inhibitors is unclear, that angioedema can also be associated recent interest has centred on treat- however it is thought to be a biochemical with this medication.11,18 The pathophys- ment with C1 esterase inhibitor concen- rather than an immunological response. iology of angiotensin II receptor antago- trate infusion. Preliminary reports have The principle cause is thought to be nists causing angioedema is unclear but been encouraging.23,24 related to bradykinin. In addition to may relate to angiotensin II receptors Angioedema of the head and neck is blocking the conversion of angiotensin being stimulated by increased levels of a serious and potentially fatal medical I to angiotensin II, ACE inhibitors also angiotensin II, which may activate the problem for which patients may initially block the metabolism of bradykinin, bradykinin-prostaglandin-nitric oxide present to their dental practitioner. Den- therefore increasing its levels within cascade leading to bradykinin mediated tists should be aware of the potential tissues.1 Bradykinin is an important adverse effects.17 Unfortunately it has causes of angioedema, including the infl ammatory mediator and increased been reported that all classes of anti- causative relationship of angioedema tissue levels result in vasodilatation, hypertensives can be associated with with ACE inhibitors. Dentists should increased vascular permeability and angioedema to some extent and hence ensure that the patient’s GMP is alerted interstitial oedema, thereby leading arrangements should be made for the should a patient on ACE inhibitors to angioedema.1 patient’s treatment for hypertension or present with a history of angioedema of Angioedema is usually reported in heart failure to be reviewed by their the head and neck. patients on standard doses of ACE inhib- physician when angioedema is thought itors and there is no clear evidence of a to be ACE inhibitor related.19 1. O’Ryan F, Poor D B, Hattori M. Intraoperative angioedema induced by angiotensin-converting dose-response relationship. It has been Angioedema in the head and neck enzyme inhibitors: overview and case report. suggested that individuals susceptible can occur for other non-allergic rea- J Oral Maxillofac Surg 2005; 63: 551-556. 2. Agar R, Bandi V, Guntupalli K K. Angioedema: the to developing angioedema secondary sons as well as being ACE inhibitor role of ACE inhibitors and factors associated with to ACE inhibitors may have a genetic induced. Other non-allergic causes poor clinical outcome. Intensive Care Med 1997; 23: 793-796. defi ciency of other bradykinin metabo- include pressure urticaria, hereditary 3. Stevenson H A, Steele J C, Field E A, Darroch C J. lising enzymes.12 These patients would angioedema, acquired angioedema and Angioedema of the lips and tongue induced by angiotensin-converting enzyme inhibitor: a report therefore naturally have a raised level idiopathic angioedema. Both hereditary of two cases. Prim Dent Care 2004; 11: 17-19.

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