Review Article

The Pharmacological Causes of Colon Ischaemia

Ziga Vodusek; Paul Feuerstadt; Lawrence J. Brandt

Disclosures

Aliment Pharmacol Ther. 2019;49(1):51-63. 

In This Article

Pharmacologic Agents Moderately Associated With Colon Ischaemia

Antimicrobials

Colonic injury following antimicrobial use was first described when clindamycin treatment was associated with Clostridioides difficile infection and colonoscopically identified pseudomembranes.[90] It has been hypothesised that ischaemia plays a role in pseudomembrane formation in C. difficile infection as well as in antibiotic-associated haemorrhagic colitis, a theory supported by histological and pathological evidence.[91]

Several case reports have clarified the course of antibiotic-associated haemorrhagic colitis as an acute onset of abdominal pain with loose stools followed by diarrhoea and haematochezia 4–6 hours later.[92] Usually antibiotic-associated haemorrhagic colitis symptoms resolve within 3 days of antibiotic treatment cessation with some reports noting that diarrhoea can persist for a week following termination of therapy.[92–94] Given the similarities between the presentation of colonic ischaemia and antibiotic associated haemorrhagic colitis with antibiotic associated haemorrhagic colitis having pathologic evidence of an ischaemic insult to the colon, it is believed that antimicrobials may cause colon ischaemia and result in antibiotic-associated haemorrhagic colitis.

The precise mechanism for antibiotic-associated haemorrhagic colitis associated with antimicrobial therapy remains a topic of debate. Klebsiella oxytoca originally was believed to be a commensal bacterium of the human gut, but it seems more likely that following the administration of microbiota-altering antibiotics, K. oxytoca can proliferate, with over production of a bacterial toxin, tilivalline, which causes intestinal apoptosis resulting in bacterial infiltration of the epithelium and intestinal inflammation, consistent with an ischaemic insult.[95] Further research is needed to confirm the exact mechanisms for ischaemic aetiologies associated with tilivalline and the clinical presentation but pathologic evidence of resultant ischaemia from this toxin has been recorded.[93] There have been several case reports in recent years linking penicillins, fluoroquinolones, and cephalosporins with K. oxytoca proliferation and a resultant episode of antibiotic-associated haemorrhagic colitis.[96–99] Antibiotic-associated haemorrhagic colitis is believed to be an ischaemic process that should be identified quickly based upon symptomatic presentation. Treatment is usually conservative with discontinuance of the offending antimicrobial and provision of supportive care. It is important to note that affected patients should not receive the culprit antimicrobial again in the future and that alternative antimicrobials should be sought to treat any active infection susceptible to the offending agent.

Appetite Suppressants

Appetite suppressants have been associated with colon ischaemia. Phentermine is one amphetamine-derived sympathomimetic drug used to assist with short-term weight loss. This drug has been associated with cerebral and spinal ischaemic events in patients with vascular risk factors, the hypothesised cause being decreased vascular perfusion from vasospasm.[100,101] The colon also has had documented ischaemic events associated with phentermine. Two recent case reports of woman taking this longer than prescribed have resulted in biopsy-proven colon ischaemia.[102,103]

While amphetamine-derived sympathomimetic drugs are believed to pose the greatest risk for colon ischaemia of all appetite suppressants, other weight-loss interventions have been associated with. In one case, a 39-year-old woman presented with symptoms of colon ischaemia after mesotherapy (a procedure whereby tiny medicinal injections of homeopathic medicines, vitamins, minerals, and amino acids are injected into the mesoderm to minimise cellulite) in combination with an oral weight-loss regimen that included fluoxetine, ephedrine hydrochloride, anhydrous caffeine, and green tea powder;[104] which of these agents, alone or in combination, was the culprit remains unproven. Other weight loss treatments including bitter orange-containing supplements and herbal supplements like ma huang, which contains ephedrine, have also been associated with colon ischaemia.[105,106]

Careful dosage and duration surveillance of amphetamine-containing sympathomimetic drugs together with monitoring for abdominal pain and rectal bleeding are important for prevention and early detection of colon ischaemia in any patient taking these medications.

Chemotherapeutic Agents

Certain chemotherapeutic agents are known to be associated with colon ischaemia including taxane-based chemotherapy, vinca alkaloids, and platinum-based chemotherapies.

Taxanes are hypothesised to induce colon ischaemia through several mechanisms including local inhibition of angiogenesis and mitotic arrest in the cells of the gastrointestinal tract.[107] In one case series of six patients with metastatic breast cancer treated with docetaxel (taxane-based medication) in combination with vinorelbine (a vinca alkaloid) who presented with abdominal pain, bloody diarrhoea and colitis, four had pathologically-proven colonic ischaemia; docetaxel was thought to be the culprit.[108] Two other case reports showed similar pathologic evidence of ischaemic and inflammatory intestinal changes in patients taking docetaxel for prostate, pancreatic, lung, and breast cancer treatment.[109,110] Paclitaxel, another taxane-based therapy, also has been associated with pathologically-proven colon ischaemia.[111,112]

Colon ischaemia can also be seen in patients taking vinorelibine, a vinca alkaloid-based chemotherapy, for small-cell lung cancer. One patient presented with abdominal pain and bloody diarrhoea one day after the sixth cycle of treatment, after which colonoscopy showed colitis from the descending colon to the mid-sigmoid colon with rectal sparing. Biopsies were consistent with colon ischaemia.[113]

Platinum-based chemotherapies are also associated with colon ischaemia. One case study described a patient with metastatic bile-duct cancer who was treated with gemcitabine and cisplatin, and developed severe abdominal pain. The patient underwent a colonoscopy which revealed necrosis that required emergent total colectomy 9 hours after the onset of symptoms. Pathology was consistent with colon ischaemia although the mechanism of this drug-induced process remained unclear.[114]

Chemotherapeutic agents are the most frequently reported class of medications associated with colon ischaemia according to a study from the Federal Adverse Event Reporting System.5 Despite the frequency with which these treatments are associated with colonic ischaemia, there is little insight into the pathophysiologic mechanisms to explain this complication; most are believed to result from direct toxicity to the colonic epithelium or anti-angiogenic toxicities. Presentation is usually with mild symptoms and outcome is favourable with just conservative management. In patients receiving treatment with these chemotherapeutic agents, one should always be mindful of colonic ischaemia and if the presentation is severe, as with all colon ischaemia regardless of aetiology, there should be a low threshold for aggressive workup and management including involving interventional radiologists and surgeons early in the presentation to minimise the risks for poor-outcomes, colectomy and mortality.

Decongestants

Nasal decongestants are over the counter medications used to reduce copious nasal discharge resulting from seasonal allergies or upper respiratory tract infections. The active ingredients in most of these products function by stimulating vasoconstriction. Prior to 2005, pseudoephedrine was the most common active ingredient, whereas after 2005, phenylephrine has become more popular. In several case reports, pseudoephedrine, a strong alpha-adrenergic agonist, was associated with colonic ischaemia and presentations with abdominal pain with or without bloody diarrhoea.[115–120] Such splanchnic vasoconstriction-induced colon ischaemia can affect those as young as their fourth decade of life with a range of associated dosing regimens of 60–300 mg/d taken for at least 5 days.[115–120]

Pseudoephedrine usage decreased after the 2005 introduction of the "Combat Methamphetamine Act." This Act resulted in the introduction of phenylephrine as a replacement for pseudoephedrine because pseudoephedrine can be chemically altered at home to create recreational amphetamines.[121] Phenylephrine, however, also acts on alpha-adrenergic receptors and also may lead to systemic vasoconstriction and colonic ischaemia.[121]

The use of such compounds as treatment for the common cold underlines the importance of identifying any over-the-counter cold medications in the history of patients presenting with a clinical picture consistent with colon ischaemia.

Diuretics

Diuretics, such as frusemide, have been linked to the development of non-occlusive mesenteric ischaemia and colon ischaemia. Initial evidence of this association found that patients on frusemide and a cardiac glycoside were at increased risk of non-occlusive mesenteric ischaemia. This increased risk was believed to result from the frusemide's decreasing peripheral vascular resistance, thereby shunting blood to the limbs away from splanchnic circulation and further exacerbated by vasoconstriction from the cardiac glycoside.[122] Colon ischaemia resulting directly from diuretic use alone is difficult to identify. In one case, a 49-year-old man presented with the acute onset of fatigue, weight loss, and bloody stools. Colonoscopic examination showed a stricture with pathologic biopsies revealing dysplastic tissue without malignancy, but consistent with an ischaemic origin.[123] Although the patient's symptoms resolved following the stoppage of the diuretic, favouring the diuretic as a cause, this is not a general rule in medication-induced colon ischaemia as other medications (eg, oral contraceptive pills) can be continued during which time symptoms typically resolve.[123]

Ergot Alkaloids

Ergotamine is an alkaloid derivative from the ergot plant that is used to treat migraine headaches by acting as a 5-HT1D receptor agonist causing vasoconstriction.[124] Its vasoactive properties have been associated with cardiac, cerebral, and colonic ischaemic events especially when taken in larger quantities than therapeutically indicated.[125–131]

Patients taking any ergotamine medication should have a careful and precise dosing regimen and if they present with symptoms of colonic ischaemia, the drug should be stopped along with any other medications associated with colon ischaemia. Conservative measures will typically yield positive outcomes.[124]

Serotonin Agents

"Serotonin agents" are medications that either agonise or antagonise serotonin (5-hydroxytryptamine, 5-HT) receptors within the neurotransmitter system of both the central and enteric nervous system. This class of agents has been widely associated with colonic ischaemia through a variety of hypothesised mechanisms.

Alosetron, a 5-hydroxytryptamine-3 antagonist indicated for the treatment of severe irritable bowel syndrome with diarrhoea (IBS-D) in women, is probably the most studied drug associated with colon ischaemia. Following a brief time on the market in the United States, this medication was removed in November 2000 due to its severe gastrointestinal side-effect profile including 84 instances of ischaemic colitis, 113 episodes of severe constipation, 143 admissions to the hospital, and seven deaths.[132] Alosetron was reintroduced in 2002 under a Risk Management Plan, including a more restricted indication and a prescribing program. Since its reintroduction, a review showed that from 2002 to 2007, 0.2% of patients taking alosetron developed colon ischaemia.[133] The mechanism of the disease remains unclear as 5-hydroxytryptamine-3 receptors are not present in the colonic vasculature.[134] One study hypothesised that alosetron might be responsible for decreased activity of intrinsic enteric sensory neurons thereby decreasing motility and secretion in the colon.[135] It is essential to note that following the temporary removal of alosetron from the market, there was significant interest in the incidence of colonic ischaemia in patients with and without irritable bowel syndrome. It was subsequently shown that patients with irritable bowel syndrome, independent of alosetron usage, are approximately 3.4-fold more likely to have an episode of colon ischaemia.[6] The mechanisms behind this increased risk are unclear; some believe the irritable bowel syndrome itself is a risk factor while others hypothesise that the chronic constipation, diarrhoea or chronic usage of anti-diarrhoeal agents or laxatives play a role as each are risk factors for colonic ischaemia. The mechanism of this increased risk is likely multifactorial. Alosetron remains a seldom used but effective treatment for irritable bowel syndrome with diarrhoea predominance in women, but it needs to be used carefully and with appropriate patient education to minimise the risks of colonic ischaemia.

Considering that many psychotropic agents act on serotonergic and cholinergic pathways, it is expected that they may affect the blood supply to the colon. One such medication is quetiapine, a dopamine and 5-hydroxytryptamine-2 antagonist with limited anticholinergic effects. When quetiapine is taken in combination with tropatepine, colon ischaemia has been associated with severe outcomes, including death in one 34-year-old man.[136,137] The aetiology for this severe outcome is unclear but it is speculated that the anticholinergic medication decreased peristalsis, which could lead to the ischaemic injury. Less severe presentations of colonic ischaemia, improving with conservative measures have been documented when quetiapine was taken in combination with other medications including the anti-convulsant oxcarbazepine, olanzapine and other psychotropics.[19,138,139]

Clozapine is an atypical antipsychotic agent, which acts as an antagonist to 5-hydroxytryptamine and has anticholinergic activity.[140] It too, has been associated with colon ischaemia with a mechanism thought to be linked to its anticholinergic activity and altered colonic motility.[141] Clozapine-induced colon ischaemia has been associated with severe outcomes requiring surgical intervention.[16,140,142] The question of whether the clozapine itself is causing the colonic ischaemia or whether clozapine is causing severe constipation resulting in colon ischaemia remains unclear. One study compared the median colonic transit time in patients taking clozapine with controls, and found that in those on clozapine the transit time was over 100 hours compared with 23 hours in those not on this medication. These data would favour clozapine-induced constipation-induced colon ischaemia as the basic mechanism.[141] Clozapine is used as a second or third-line treatment for diseases like schizophrenia and its usage should be carefully monitored for symptoms of colonic ischaemia and potential precursors to colonic ischaemia including severe constipation. It probably should not be used in patients who are severely constipated without prior attention to a careful laxative regimen.

Sumatriptan, a 5-hydroxytryptamine-1 receptor agonist used for the treatment of migraine headache, has been shown to be associated with colon ischaemia. Sumatriptan-induced colon ischaemia is dose dependent, and seems to have a female predominance, although migraines are seen in a female predominant population; it most commonly presents with abdominal pain, hypotension, or haematochezia.[143–147] The mechanism of the disease is believed to result from sumatriptan-induced vasoconstriction of the splanchnic circulation and seems to most frequently have a benign disease course.[147]

Patients taking anticholinergic medications and combinations of psychotropic medications need to be carefully monitored. Some may present with severe symptoms and will require aggressive management with surgical intervention. It remains most important to identify these patients early in their disease course, use combination therapy only when absolutely necessary and stop the combination therapy with the first sign of colon ischaemia.[11]

Statins

Statin medications are widely used for their lipid-lowering capabilities via inhibition of 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Both rosuvastatin and simvastatin have been associated with mild episodes of colon ischaemia.[148,149] While no exact mechanism for statin-induced colon ischaemia has been described, it is believed that this class of drugs has no direct vasoactive properties, but patients on statins do have increased lipid levels and likely have peripheral vascular disease. Also, statin treatment has been shown to increase reactive hyperaemia in the peripheral circulation.[150] It is hypothesised that the combination of peripheral vascular disease and the possible "steal" phenomena favouring peripheral over the splanchnic circulation may play a role in statin-induced colon ischaemia.[148] The patients reported in the literature improved with cessation of the statin medication and conservative therapy.

Vasopressor Agents

Vasopressors such as vasopressin and its analogue glypressin have been used for treatment of bleeding oesophageal varices as they selectively decrease splanchnic blood flow. This mechanism, although helpful to the patient with severe hypotension, is also the explanation for the associated colonic ischaemia.[151,152] Vasopressin is also administered after cardiopulmonary bypass surgery and has been shown to be a risk factor for developing colonic ischaemia in those patients as well.[153] In one study of pigs undergoing cardiopulmonary bypass, vasopressin was shown to decrease rectosigmoid perfusion compared with a sham infusion.[154] Glypressin (ie, terlipressin) has fewer side effects, but also has been associated with colon ischaemia.[155] In patients with hypotension and cardiopulmonary bypass, it is unclear if hypotension, the medication, or the combination of the two causes the ischaemic episode. Regardless, these patients are clearly at risk for colonic ischaemia and should be monitored for signs of this disease.[153]

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