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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 9  |  Issue : 4  |  Page : 230-232

A rare case report on telmisartan-induced angioedema and mouth ulcers


1 Department of General Medicine, Bharati Vidyapeeth Medical College and Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
2 Department of Clinical Pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
3 Department of Pharmacology, Bharati Vidyapeeth Medical College and Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India

Date of Web Publication11-Mar-2020

Correspondence Address:
Mr. Bijoy Kumar Panda
Assistant Professor, Department of Clinical Pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JICC.JICC_44_19

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  Abstract 


A 67-year-old hypertensive female was hospitalized for painful, bleeding mouth ulcers, angioedema (lip swelling and glossitis), and dysphagia. A history reported by the patient and recent medication history revealed the onset of the symptoms on the initiation of telmisartan for hypertension. Telmisartan was discontinued, and the patient was managed symptomatically for pain, mouth ulcers, glossitis, and dysphagia. The symptoms completely resolved over 10 days of drug withdrawal. As per the World Health Organization and Naranjo adverse drug reaction assessment, telmisartan had a “Probable” association with the oral toxicity observed in this patient.

Keywords: Angioedema, mouth ulcers, telmisartan


How to cite this article:
Diwan A, Umarje SP, Dhande P, Panda BK. A rare case report on telmisartan-induced angioedema and mouth ulcers. J Indian coll cardiol 2019;9:230-2

How to cite this URL:
Diwan A, Umarje SP, Dhande P, Panda BK. A rare case report on telmisartan-induced angioedema and mouth ulcers. J Indian coll cardiol [serial online] 2019 [cited 2020 Mar 28];9:230-2. Available from: http://www.joicc.org/text.asp?2019/9/4/230/280348




  Introduction Top


Oral toxicities such as xerostomia, angioedema, oral lichen planus dysgeusia, gingival enlargement, scalded mouth syndrome, cheilitis or glossitis, and aphthous stomatitis are frequently observed with cardiovascular drugs such as beta-blockers or aspirin.[1] Angiotensin receptor blockers (ARBs) are widely used in hypertension and heart failure patients. The commonly associated adverse effects associated with the ARBs include upper respiratory tract infections, diarrhea, myalgia, sinusitis, or back pain. Telmisartan-induced allergic reactions involving the oral mucosa have not been widely reported. This case report is a rare finding in which the patient was hospitalized for angioedema with severe mouth ulcers due to telmisartan.


  Case Report Top


A 67-year-old female was hospitalized on February 04, 2018 with complaints of glossitis, severe mouth ulcers all over the oral mucosa (cheeks, tongue, gums, and palate), and lips associated with severe pain and bleeding. She also complained of severe throat pain with difficulty in swallowing (dysphagia) which restricted her food intake. The patient complained of having hypertension for 12 years and was on atenolol tablet 50 mg/day. On January 10, 2018, she visited a physician's clinic to check her fitness for bilateral cataract surgery. In view of poorly controlled hypertension (170/90 mmHg) along with Grade 1 chronic white matter ischemic changes in the brain, atenolol was changed to metoprolol 25 mg/day, chlorothiazide 12.5 mg/day, and aspirin 75 mg + clopidogrel 75 mg/day. On January 24, the patient visited a hospital for cataract surgery. Upon routine investigations, hypokalemia (3.0 mEq/L) was detected for which her physician changed chlorothiazide to telmisartan 40 mg/day and suggested to revisit after 3 days for further management of bilateral cataract. First dose of telmisartan was taken on January 26, 2018 and after 2 days of telmisartan administration (January 28, 2018), the patient reported to have one episode of high fever spike (102°F/38.88°C) and mild symptoms of angioedema such as lip swelling, heavy tongue, and throat congestion with mild difficulty in swallowing since morning. Fever was managed with paracetamol 650 mg at home. The symptoms of angioedema progressed intensively over 3 days and were followed by flare of mouth ulcers along with bleeding, severe pain, and dysphagia requiring immediate medical management. Therefore, she was admitted to our hospital for further management. On admission, the patient was vitally stable. However, she complained of severe pain associated with ulcers, continuous bleeding, and inability to swallow liquids, suggestive of severe dysphagia. She did not report to have a history of similar complaints or known food/drug allergies or use of tobacco products. The dermatologist reported the presence of multiple erosions over the buccal mucosa with fissuring over the angles of mouth and a bald, inflamed tongue suggestive of angular stomatitis and glossitis suspected to be secondary to drug use [Figure 1] and [Figure 2]. The patient was prescribed choline salicylate oral gel and triamcinolone acetonide paste for 2 days, which was changed to benzocaine (I.P.) 20% gel and clotrimazole mouth paint for topical application over the oral mucosa along with poviodine-iodine gargles (2–3 times/day), and multivitamin (biotin, calcium pantothenate, folic acid, niacinamide, Vitamin B1, Vitamin B12, Vitamin B2, Vitamin B6, and Vitamin C). The ear, nose, and throat specialist confirmed severe dysphagia (Grade III) and stomatitis. Laboratory investigations were suggestive of elevated C-reactive protein (CRP = 62.2 mg/L), mildly elevated liver enzymes (serum glutamic oxaloacetic transaminase = 43 IU/L and serum glutamic pyruvic transaminase 44 IU/L), hypoalbuminemia (2.6 g/dL; normal = 3.8–4.4 g/dL), elevated erythrocyte sedimentation rate (ESR) (32 mm/h; normal = 0–30 mm/h), and extremely high absolute eosinophil count (1806/mm3; normal = 40–400/mm3). Vitamin B12 levels were within the normal range (214 pg/mL, normal = 187–883 pg/mL). With 2 days of hospitalization, the patient showed mild pain relief with topical benzocaine. However, mouth ulcers, bleeding, and dysphagia did not show any significant prognosis. The patient complained of abdominal pain and dysphagia. The gastroenterologist reference was suggestive of atrophic gastritis requiring management with antacids. Considering the medication history, onset, and poor prognosis of symptoms, drug-induced stomatitis was considered differential diagnosis. An adverse reaction assessment was done for all the drugs. Considering the past history, the temporal association of telmisartan with angioedema and mouth ulcers was high. Thus, dechallenge strategy was implemented, and telmisartan was withdrawn on day 3 of hospitalization. All other drugs were continued, and benidipine (T-type calcium channel blocker) 4 mg was initiated. Dual antiplatelet (aspirin/clopidogrel) therapy was switched to single antiplatelet therapy with aspirin because of persistent bleeding mouth ulcers. The patient showed gradual improvement of pain and bleeding over 5 days and was discharged on request. She was continued on metoprolol 25 mg/day, benidipine 4 mg/day, pantoprazole 40 mg/day, clotrimazole mouth paint, multivitamins, and calcium supplements. The dual antiplatelet regimen was reinitiated in view of ischemic changes seen in brain. Ten days later, the patient came for a follow-up visit wherein her blood pressure was in control; all the symptoms of angioedema had resolved and the oral mucosa was normal. The patient could tolerate soft diet and reported to have a significant improvement in dysphagia. The adverse drug reaction can be labeled as “probable” as per the World Health Organization Uppsala monitoring center and NARANJO score of 7.[2]
Figure 1: Glossitis with ulceration on the lower lip

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Figure 2: Angular stomatitis with restricted mouth opening

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  Discussion Top


A comparative study on the relationship between angioedema and the drugs targeting the renin-angiotensin system suggested a low risk of angioedema with ARBs.[3] The observations reported in this case report can be considered as rare adverse effects of the ARB telmisartan. The subjective complaints of sudden onset of lip swelling, heaviness of tongue, throat congestion followed by severe mouth ulcers and dysphagia along with objective findings of elevated CRP, ESR, and extremely high absolute eosinophil count levels were suggestive of an allergic reaction. Apart from a recent change in her anti-hypertensive medications, there were no other offenders suspected to have caused the severe condition in this patient. Furthermore, the successful dechallenge strategy confirms the adverse effect. The complaints of abdominal pain and atrophic gastritis could be associated with a severe decrease in food intake due to mouth ulcers and dysphagia along with intake of multiple medications such as antihypertensives and anti-platelet agents. Persistent bleeding could be attributed to the soft-tissue damage combined with dual antiplatelet activity of aspirin and clopidogrel.

ARBs are related to cutaneous reactions such as angioedema, vasculitis, cutaneous lymphoid hyperplasia, and erythema multiforme.[4] Apthous mouth ulcers due to ARBs such as losartan, candesartan, and irbesartan have been reported previously. Mouth ulcers and angioedema are directly related to the accumulation of bradykinin, an inflammatory mediator and a peptide that causes blood vessels to dilate. Angiotensin-converting enzyme (ACE) inhibitors increase the bradykinin levels in tissue by inhibiting its degradation which may induce cough or angioedema. On the other hand, as ARBs do not have a direct inhibitory effect on ACE, the bradykinin levels do not increase and are less likely to induce angioedema. A randomized controlled trial reported a less incidence of angioedema associated with telmisartan as compared to that with ramipril.[5] However, a recent finding suggests that ARBs have a secondary stimulation effect of unblocked angiotensin II (AT2) receptors which increases and levels of bradykinin and risk of angioedema.[1] AT2 receptors increase the cyclic guanosine 3′5′ monophosphate (cGMP) and subsequently release nitric oxide. It is assumed that tissue bradykinin is an intermediary factor between cGMP and nitric oxide. Tissue bradykinin acts locally on the B2-subtype receptors of vascular endothelium to form and release nitric oxide. When AT2 is combined with ARB, it binds to AT2 receptors and triggers a cascade and releases bradykinin, increases synthesis of nitric oxide, and releases cGMP leading to vasodilation and reduction in blood pressure.[6] Few case reports on valsartan, candesartan, olmesartan, fixed-dose combination of telmisartan plus ramipril, losartan, and induced angioedema are available.[7],[8],[9],[10],[11],[12],[13] As per the FDA reports, 0.25% of telmisartan users had swallowing difficulty. Such rare adverse effect was found more in female population, those above the age of 60 years or those who were on telmisartan for <1 month. Fever and stomatitis was observed in 40% of the reported cases.[14] These evidence suggest the uncommon occurrence of telmisartan-induced angioedema and mouth ulcers.


  Conclusion Top


Oral toxicity can be considered an uncommon side effect of ARBs. However, previous evidence suggests it association with angioedema and mouth ulcers. Thus, a probable association of ARBs and oral toxicity should not be ruled out. The clinicians should be vigilant about the rare adverse effects of ARBs. ADR assessment and its management should be done promptly to identify the offending agent. Reporting of uncommon side effects develops future scope for research and prevention of serious ADRs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Balakumar P, Kavitha M, Nanditha S. Cardiovascular drugs-induced oral toxicities: A murky area to be revisited and illuminated. Pharmacol Res 2015;102:81-9.  Back to cited text no. 1
    
2.
Zaki SA. Adverse drug reaction and causality assessment scales. Lung India 2011;28:152-3.  Back to cited text no. 2
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3.
Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med 2012;172:1582-9.  Back to cited text no. 3
    
4.
Francesca M, Laura A, Luca P, Caterina F. Letter to Editor Global Dermatology Irbesartan-induced aphthous stomatitis. Global Dermatology 2015;2:62-63.   Back to cited text no. 4
    
5.
ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.  Back to cited text no. 5
    
6.
Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A 1999;96:6506-10.  Back to cited text no. 6
    
7.
Irons BK, Kumar A. Valsartan-induced angioedema. Ann Pharmacother 2003;37:1024-7.  Back to cited text no. 7
    
8.
Lo KS. Angioedema associated with candesartan. Pharmacotherapy 2002;22:1176-9.  Back to cited text no. 8
    
9.
Nykamp D, Winter EE. Olmesartan medoxomil-induced angioedema. Ann Pharmacother 2007;41:518-20.  Back to cited text no. 9
    
10.
Tandon VR, Mahajan A, Khajuria V, Gillani ZH. Angioedema due to fixed dose combination of telmisartan plus ramipril. J Pharmacol Pharmacother 2014;5:214-6.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Shino M, Takahashi K, Murata T, Iida H, Yasuoka Y, Furuya N. Angiotensin II receptor blocker-induced angioedema in the oral floor and epiglottis. Am J Otolaryngol 2011;32:624-6.  Back to cited text no. 11
    
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Borazan A, Ustün H, Yilmaz A. Angioedema induced by angiotensin II blocker telmisartan. Allergy 2003;58:454.  Back to cited text no. 12
    
13.
Nair C. A case of losartan induced angioedema. Indian J Med Sci 2010;64:81-4.  Back to cited text no. 13
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14.
Will you have Swallowing Difficulty with Telmisartan – From FDA Reports – eHealthMe; 2018. Available from: https://www.ehealthme.com/ds/telmisartan/swallowing-difficulty/. [Last accessed on 2018 Mar 08].  Back to cited text no. 14
    


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