Int J Colorectal Dis DOI 10.1007/s00384-015-2139-4
LETTER TO THE EDITOR
Nicorandil, an unusual ulcer etiology Isa Santos & Paulo Fernandes & Fernando Aldeia & José Mendes Almeida
Accepted: 21 January 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor: Nicorandil is a nicotinamide ester that acts as an adenosine triphosphate (ATP)-dependent potassium channel activator, causing a sustained dilation of both peripheral and coronary arteries, reducing cardiac afterload. On the other end, its’ nitrate component causes venodilatation, reducing cardiac preload. Although not a first-line agent, it is mainly prescribed for refractory stable and unstable angina and ischaemic heart disease. Nicorandil is usually well tolerated, but the most common adverse effect is transient headache, common on the first days of treatment, usually weans with continued use. Other side effects include anorexia, nausea and vomiting, dyspepsia, diarrhea, abdominal pain, constipation, dizziness, myalgia, cutaneous vasodilatation, and rashes, or, less frequently, thrombocytopenia and ulcers [1]. We hereby present the case of a 74-year-old male, with previous medical history of arterial hypertension, ischaemic heart disease with diastolic dysfunction, diabetes mellitus, and hypercholesterolemia, treated with aspirin 100 mg id, clopidogrel 75 mg id, nicorandil 20 mg 2id, isosorbide mononitrate 50 mg id, trimetazidine dichlorhydrate 35 mg 2id, amlodipine 5 mg id, carvedilol 3125 mg 2id, simvastatin 20 mg id, and lisinopril 20 mg id, since 2010. The patient was admitted to the emergency department in November 2011, with an acute abdominal pain due to colonic obstruction with necrosis, perforation, and fecal peritonitis. He was submitted to a total colectomy with terminal ileostomy and treated with I. Santos (*) : P. Fernandes : F. Aldeia : J. M. Almeida Serviço de Cirurgia, Centro Hospitalar Lisboa Norte - Hospital de Santa Maria, EPE, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal e-mail: [email protected]
broad-spectrum antibiotics i.v. No post-operative course was recorded, and the patient was discharged 6 days after surgery. The specimen pathology report revealed a chronic diverticulosis mass with stenosis and lesions of ischaemic necrosis of the colon. No evidence of malignancy or inflammatory bowel disease was detected. After discharge, an endoscopic appraisal showed no lesions of the rectal stump. Six months later, intestinal continuity was reestablished. The post-operative course was complicated by a severe wound dehiscence with abdominal skin necrosis on the immediate post-operative period. Eight weeks later after discharge, considering that abdominal wound healing failed, the patient was assessed by plastic surgery for cutaneous engraftment on the abdominal wound, but surgery was denied given the high cardiovascular risk. During the next 6 months, he developed multiple painful oral ulcers, predominantly in the tongue and soft palate. The presence of a bloody and mucous discharge per annum led to the detection of an anal ulcer. Even though on symptomatic local and systemic medications with oral elixirs, nystatin suspension, and several courses of topical corticosteroids, analgesics, and antibiotics, no improvement whatsoever was recorded. Endoscopic examination was repeated, and a normal mucosa was found with no evidence of endo-luminal lesions. After reassessment of all medical history, and considering the absence of signs of chronic inflammatory intestinal disease, infectious disease, or trauma, the suspicion of a nicorandil-induced ulceration arose, leading to the suspension of nicorandil. A cardiology assessment considered this approach as safe. To monitor outcome, the patient was assessed every 4 weeks. One month later, a clear improvement was noted. Oral ulcerations disappeared completely, and perianal ulcer became
Int J Colorectal Dis
superficial and much less painful. Within 4 months of stopping nicorandil, he had an almost complete healing of abdominal wound and complete closure of the perianal ulcer. Oral ulcers did not recur. Magnetic resonance (MR) of the pelvis showed an intersphincteric fistula tract without evidence of pelvic sepsis or other lesions. At 6 months, and without any plastic surgery techniques, a complete closure of the abdominal wound was evident. Oral ulcers and perianal ulcers healed completely. Nicorandil is an anti-anginous drug, part of the cardiology armamentarium. Associated with other adverse events, it has been reported to cause ulceration of the ears, mouth, eyes, small and large bowel, anus, foreskin, penis, vulva, vagina, and lower limbs. This drug has also been related with nonhealing wounds after elective surgery, such as peristomal ulceration and chronic wounds [2]. Nicorandil is an important but poorly recognized cause of ulceration, which can lead to considerable morbidity and unnecessary major surgery. The incidence of such ulcers is likely to be more prevalent than suggested by the paucity of reports in the literature [3]. The pathogenesis of these ulcers is not clear but several hypothesis arise: 1) BVascular Steal^ phenomenon, in which dilatation of one vascular network Bsteals^ blood from another, leading to uneven redistribution of blood flow, potentially leading to focal ischemia and ulceration; 2) Nicorandil is considerably metabolized in the liver and generates nicotinamide and nicotinic acid, accumulating exogenously outside the endogenous pool of nicotinamide adenine dinucleotide/phosphate. This excessive systemic distribution makes the mucous membrane more susceptible to physical aggression or to the local flora, leading to ulcer formation; 3) Direct toxic effect on mucosal cells; 4) Hypersensitivity reaction [4]. Although these hypothesis try to explain the causal mechanism, some inconsistencies remain. The metabolites have mainly renal excretion, and the steal phenomenon cannot explain the fact that ulcer sites are in mucosa interfaces, typically well vascularized. Ulcers associated with systemic disorders, malignancy, infection, trauma, or induced by other drugs should always be investigated and excluded [3, 4].
After starting nicorandil, the natural history of ulcer formation can vary from several weeks to months or it may show a sudden onset after long-term therapy. Several authors suggest that the ulcerative effects of nicorandil could be dose dependent and consider that ulcers occurred at high doses with a required minimum dose of 30 mg/day. Nevertheless, ulceration can occur with doses as low as 5 mg/day [4]. Dose increment, old age, presence of concomitant disease, and drug interaction may lower the toxicity threshold. Ulcer healing upon drug withdrawal is characteristic of nicorandil-induced ulceration, usually occurring 12 weeks after suspension. Given the possibility of a dose-effect threshold, reducing the dose, instead of altogether stopping the drug, might allow healing and prevent recurrence. Given the cardiac risk of these patients, all adjustments in anti-anginous drugs must be done under strict supervision of a cardiologist [1]. Surgical intervention is unnecessary and inappropriate. Not only ineffective, it usually exacerbates morbidity, compromising peripheral perfusion, and tissue integrity [2]. Despite all reports in the literature, nicorandil-induced ulceration is still underdiagnosed and widely underestimated. In this paper, the authors present the particular case of a patient presenting with ulcers in three different locations (oral, perianal, and abdominal wound), all refractory to different therapeutic approaches until improved with nicorandil suspension. Surgeons facing gastrointestinal ulceration in patients on regular nicorandil medication should be aware of this serious side effect and of the need to consider alternative anti-anginal therapy. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Bhatti I, Cohen SN, Bleiker T, Lund J, Tierney G (2009) Nicorandilinduced foreskin ulceration. Color Dis 11:424–425 2. Donaldson JF, Flohr C, English JS (2009) Peri-stomal ulceration with nicorandil. Color Dis 11:426–427 3. Akbar F, Maw A, Bhowmick A (2007) Anal ulceration induced by nicorandil. BMJ 2007(335):936–937 4. Yamamoto K, Matsusue Y, Horita S et al (2011) Nicorandil-induced oral ulceration: report of 3 cases and review of the Japanese literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:754–759
LETTER TO THE EDITOR
Nicorandil, an unusual ulcer etiology Isa Santos & Paulo Fernandes & Fernando Aldeia & José Mendes Almeida
Accepted: 21 January 2015 # Springer-Verlag Berlin Heidelberg 2015
Dear Editor: Nicorandil is a nicotinamide ester that acts as an adenosine triphosphate (ATP)-dependent potassium channel activator, causing a sustained dilation of both peripheral and coronary arteries, reducing cardiac afterload. On the other end, its’ nitrate component causes venodilatation, reducing cardiac preload. Although not a first-line agent, it is mainly prescribed for refractory stable and unstable angina and ischaemic heart disease. Nicorandil is usually well tolerated, but the most common adverse effect is transient headache, common on the first days of treatment, usually weans with continued use. Other side effects include anorexia, nausea and vomiting, dyspepsia, diarrhea, abdominal pain, constipation, dizziness, myalgia, cutaneous vasodilatation, and rashes, or, less frequently, thrombocytopenia and ulcers [1]. We hereby present the case of a 74-year-old male, with previous medical history of arterial hypertension, ischaemic heart disease with diastolic dysfunction, diabetes mellitus, and hypercholesterolemia, treated with aspirin 100 mg id, clopidogrel 75 mg id, nicorandil 20 mg 2id, isosorbide mononitrate 50 mg id, trimetazidine dichlorhydrate 35 mg 2id, amlodipine 5 mg id, carvedilol 3125 mg 2id, simvastatin 20 mg id, and lisinopril 20 mg id, since 2010. The patient was admitted to the emergency department in November 2011, with an acute abdominal pain due to colonic obstruction with necrosis, perforation, and fecal peritonitis. He was submitted to a total colectomy with terminal ileostomy and treated with I. Santos (*) : P. Fernandes : F. Aldeia : J. M. Almeida Serviço de Cirurgia, Centro Hospitalar Lisboa Norte - Hospital de Santa Maria, EPE, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal e-mail: [email protected]
broad-spectrum antibiotics i.v. No post-operative course was recorded, and the patient was discharged 6 days after surgery. The specimen pathology report revealed a chronic diverticulosis mass with stenosis and lesions of ischaemic necrosis of the colon. No evidence of malignancy or inflammatory bowel disease was detected. After discharge, an endoscopic appraisal showed no lesions of the rectal stump. Six months later, intestinal continuity was reestablished. The post-operative course was complicated by a severe wound dehiscence with abdominal skin necrosis on the immediate post-operative period. Eight weeks later after discharge, considering that abdominal wound healing failed, the patient was assessed by plastic surgery for cutaneous engraftment on the abdominal wound, but surgery was denied given the high cardiovascular risk. During the next 6 months, he developed multiple painful oral ulcers, predominantly in the tongue and soft palate. The presence of a bloody and mucous discharge per annum led to the detection of an anal ulcer. Even though on symptomatic local and systemic medications with oral elixirs, nystatin suspension, and several courses of topical corticosteroids, analgesics, and antibiotics, no improvement whatsoever was recorded. Endoscopic examination was repeated, and a normal mucosa was found with no evidence of endo-luminal lesions. After reassessment of all medical history, and considering the absence of signs of chronic inflammatory intestinal disease, infectious disease, or trauma, the suspicion of a nicorandil-induced ulceration arose, leading to the suspension of nicorandil. A cardiology assessment considered this approach as safe. To monitor outcome, the patient was assessed every 4 weeks. One month later, a clear improvement was noted. Oral ulcerations disappeared completely, and perianal ulcer became
Int J Colorectal Dis
superficial and much less painful. Within 4 months of stopping nicorandil, he had an almost complete healing of abdominal wound and complete closure of the perianal ulcer. Oral ulcers did not recur. Magnetic resonance (MR) of the pelvis showed an intersphincteric fistula tract without evidence of pelvic sepsis or other lesions. At 6 months, and without any plastic surgery techniques, a complete closure of the abdominal wound was evident. Oral ulcers and perianal ulcers healed completely. Nicorandil is an anti-anginous drug, part of the cardiology armamentarium. Associated with other adverse events, it has been reported to cause ulceration of the ears, mouth, eyes, small and large bowel, anus, foreskin, penis, vulva, vagina, and lower limbs. This drug has also been related with nonhealing wounds after elective surgery, such as peristomal ulceration and chronic wounds [2]. Nicorandil is an important but poorly recognized cause of ulceration, which can lead to considerable morbidity and unnecessary major surgery. The incidence of such ulcers is likely to be more prevalent than suggested by the paucity of reports in the literature [3]. The pathogenesis of these ulcers is not clear but several hypothesis arise: 1) BVascular Steal^ phenomenon, in which dilatation of one vascular network Bsteals^ blood from another, leading to uneven redistribution of blood flow, potentially leading to focal ischemia and ulceration; 2) Nicorandil is considerably metabolized in the liver and generates nicotinamide and nicotinic acid, accumulating exogenously outside the endogenous pool of nicotinamide adenine dinucleotide/phosphate. This excessive systemic distribution makes the mucous membrane more susceptible to physical aggression or to the local flora, leading to ulcer formation; 3) Direct toxic effect on mucosal cells; 4) Hypersensitivity reaction [4]. Although these hypothesis try to explain the causal mechanism, some inconsistencies remain. The metabolites have mainly renal excretion, and the steal phenomenon cannot explain the fact that ulcer sites are in mucosa interfaces, typically well vascularized. Ulcers associated with systemic disorders, malignancy, infection, trauma, or induced by other drugs should always be investigated and excluded [3, 4].
After starting nicorandil, the natural history of ulcer formation can vary from several weeks to months or it may show a sudden onset after long-term therapy. Several authors suggest that the ulcerative effects of nicorandil could be dose dependent and consider that ulcers occurred at high doses with a required minimum dose of 30 mg/day. Nevertheless, ulceration can occur with doses as low as 5 mg/day [4]. Dose increment, old age, presence of concomitant disease, and drug interaction may lower the toxicity threshold. Ulcer healing upon drug withdrawal is characteristic of nicorandil-induced ulceration, usually occurring 12 weeks after suspension. Given the possibility of a dose-effect threshold, reducing the dose, instead of altogether stopping the drug, might allow healing and prevent recurrence. Given the cardiac risk of these patients, all adjustments in anti-anginous drugs must be done under strict supervision of a cardiologist [1]. Surgical intervention is unnecessary and inappropriate. Not only ineffective, it usually exacerbates morbidity, compromising peripheral perfusion, and tissue integrity [2]. Despite all reports in the literature, nicorandil-induced ulceration is still underdiagnosed and widely underestimated. In this paper, the authors present the particular case of a patient presenting with ulcers in three different locations (oral, perianal, and abdominal wound), all refractory to different therapeutic approaches until improved with nicorandil suspension. Surgeons facing gastrointestinal ulceration in patients on regular nicorandil medication should be aware of this serious side effect and of the need to consider alternative anti-anginal therapy. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Bhatti I, Cohen SN, Bleiker T, Lund J, Tierney G (2009) Nicorandilinduced foreskin ulceration. Color Dis 11:424–425 2. Donaldson JF, Flohr C, English JS (2009) Peri-stomal ulceration with nicorandil. Color Dis 11:426–427 3. Akbar F, Maw A, Bhowmick A (2007) Anal ulceration induced by nicorandil. BMJ 2007(335):936–937 4. Yamamoto K, Matsusue Y, Horita S et al (2011) Nicorandil-induced oral ulceration: report of 3 cases and review of the Japanese literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:754–759
