Nicorandil: from ulcer to fistula into adjacent organs

Abstract

Nicorandil is an original vasodilatator used to control angina by decreasing cardiac preload and afterload. Since 1997, many reports of single or multiple nicorandil-induced ulcerations have been published. To date, eight cases of nicorandil-induced fistula into adjacent organs have been described. The pathogeneses of nicorandil-induced ulceration and fistula into adjacent organs are not yet elucidated. The two main hepatic biotransformation pathways of nicorandil are denitration and reduction of the alkyl chain leading to nicotinamide and niconitic acid which merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate. This merging which is known as saturable, may contribute to a slow and abnormal distribution of nicotinamide and nicotinic acid out of the endogenous pool. Under these special conditions, providing these two molecules in situ, nicotinic acid associated with nicotinamide may ulcerate rather recent or maintained trauma. Ulcers and fistulae induced by nicorandil heal after withdrawal. Surgical intervention is unnecessary and inappropriate as it is ineffective and exacerbates morbidity. All practitioners should be correctly informed about these serious but preventable nicorandil side effects, which mostly occur in the elderly and fragile population. In the absence of corrective measures, withdrawal of this original and active drug should be considered.

Role of nicotinic acid and nicotinamide in nicorandil‐induced ulcerations: from hypothesis to demonstration

“…It is critical to rapidly reassess the risk-benefit ratio of this drug for any patient, and not only for those with diverticular diseases (24,25).…”

Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review

“…Although this is not in keeping with the hypothesis above [158][159][160][161], the accumulation of the allegedly ulcerogenic molecule would take place at the tissue level, likely without high serum concentrations observed in patients under niacin therapy.…”

“…Trechot et al [158][159][160][161] analysed an ulcerated skin biopsy from a patient exposed to nicorandil via mass spectrometry: they found high concentration of nicotinic acid (38g/mg of dried skin biopsy) and nicotinamide (11g/mg) in the cutaneous ulcer, as opposed to 21 and 4g/mg of nicotinic acid and nicotinamide from a random non-ulcerated skin sample from the same patient. Nicotinic acid and nicotinamide were estimated as <1g/mg of dried skin biopsy in a control, not exposed to nicorandil (one of the authors) [21].…”

Is research declining amongst gastroenterology trainees in the United Kingdom?

“…2 In more serious cases, ulcers progress to fistulae into adjacent organs. 3 The mechanism is, as yet, unclear but may involve the effects of nicotinic acid on causing ulceration in the epithelium of healing wounds. 4 With calcium antagonists, an underappreciated problem is reflux cough 5 due to attenuation of the lower oesophageal sphincter and reduced oesophageal clearance.…”