Pharmacologic Agents Strongly Associated With Colon Ischaemia
Constipation is a common side effect of many different classes of medications including antipsychotics (discussed in the "Serotonin Agent" section of the manuscript), mu-opioid agonists, and muscarinic antagonists. Any medication that causes constipation may produce colonic ischaemia as a direct result of the constipation. One potential mechanism for colon ischaemia caused by constipation-inducing agents is extrapolated from the observation that patients with idiopathic colonic slow transit have reduced baseline global colonic mucosal blood flow, possibly as a result of impaired efferent vagal cholinergic activity. Impaired cholinergic innervation is a side effect of many constipation-inducing medications, and the resultant unopposed sympathetic input leaves the colon susceptible to ischaemic injury. Another mechanism of constipation-associated colon ischaemia involves an increase in intracolonic luminal pressure which diminishes colon blood flow and causes mucosal-to-serosal shunting of blood with consequent reduction of the arteriovenous oxygen difference.
Loperamide is an over-the-counter mu-opioid agonist commonly used to decrease colonic motility and thereby reduce the frequency of bowel movements in patients with diarrhoea. It has been associated with severe colon ischaemia. One hypothesised mechanism for loperamide-induced colonic ischaemia involves vasospasm of the splanchnic vessels, either the superior mesenteric or inferior mesenteric artery. This theory stems from observations of coronary artery vasospasm observed in a patient on loperamide.
Drugs with anti-muscarinic effects such as clozapine have been linked with gastrointestinal side effects including colonic ischaemia.[11,16–19] This association is discussed in detail in the "Serotonin Agent" section of the manuscript.[11,17]
By altering transit time, cholinergic activity, or the serotonin system, many medications can cause constipation-induced colon ischaemia. It remains essential to consider colon ischaemia in patients receiving these classes of medications and to recognise and evaluate these patients rapidly. Most will have a benign course and clinically improve with conservative measures, but, rarely, some will experience severe disease requiring colectomy.
Many medications designed to treat diarrhoea are associated with colon ischaemia because of constipation, and, conversely, certain medications used to facilitate a bowel movement may help to heal ischaemic insults to the colon. Prostaglandin E2 has been shown to stimulate repair following ischaemic injury via chloride secretion and reductions in paracellular permeability. Given this, and the known mechanism of lubiprostone being a chloride channel agonist indicated for the treatment of irritable bowel syndrome with constipation predominance in women, one study applying lubiprostone to ischaemic porcine ileal mucosa showed that this medication increased transepithelial resistance and restored occlusion through enhanced tight junction function. This observation supported the possibility that lubiprostone might promote intestinal barrier repair following ischaemic injury.[20,21] This exciting potential intervention warrants further investigation to clarify the role, if any, in healing otherwise irreversible injury in colon ischaemia.
Digoxin is a cardiac glycoside previously commonly used to treat heart failure and cardiac arrhythmias. Digoxin increases intracellular sodium levels by Na+/K+ATPase inhibition, thereby improving cardiac function. Digoxin increases cardiac contractility and vagal tone but also decreases blood flow to the splanchnic circulation via smooth muscle contraction. Digoxin is a relatively specific splanchnic vasoconstrictor. Many dozens of case reports have presented patients with therapeutic as well as toxic levels of digoxin who developed colon ischaemia during the course of digitalisation, but especially upon rapid digitalisation.[23–25] One retrospective case-control study from Spain considered risk factors for colon ischaemia in a cohort of patients with biopsy-proven colon ischaemia and identified digoxin as an independent risk factor. Digoxin-induced colon ischaemia differs from some of the other pharmacologically-mediated colon ischaemia, since splanchnic vasoconstriction can be reversed with diltiazem. Therefore, in patients with digoxin-induced colon ischaemia, diltiazem should be considered as the treatment.
Colon ischaemia is most commonly seen in an older-age populations, but one cohort of susceptible younger patients are woman on oral contraceptive pills.[9,28–31] It is believed that oral contraceptive pills increase the risk of hypercoagulability and ischaemia by causing resistance to activated protein C, increases in levels of factors VII, VIII, X, prothrombin, and fibrinogen and decreased levels of anti-thrombin III, proteins C and S.[7,32] Colon ischaemia can occur in patients for whom the oral contraceptive pills are the only risk factor, but in younger patients, a second risk factor is usually present, such as a co-morbid medical condition or another medication associated with colon ischaemia, increasing their risk. The mode by which oral contraceptive pills are administered seems not as important as the agent itself; vaginal rings have also been reported to be associated with colon ischaemia.
Medical conditions that affect the young such as obesity or irritable bowel syndrome are associated with colon ischaemia, and when combined with an oral contraceptive pill can precipitate this disease.[7–9] As one would expect, oral contraceptive pills in combination with other medications associated with colonic ischaemia also increase patients' risk of ischaemic disease.
In patients with oral contraceptive pills as the sole risk factor for colonic ischaemia, continued use can lead to recurrence either in the short-term or sometimes several years later with no symptoms during the intervening time period. Stopping the oral contraceptive pill and finding an alternative method of birth control or therapy is a prudent option to minimise the risk of recurrence and its potential complications including stricture, chronic colitis and gangrene. Symptoms typically improve after conservative treatment with intravenous fluids, and discontinuing the oral contraceptive pill although some patients with more severe disease require antimicrobial therapy.[3,7–9,32,34]
As with all patients who have colon ischaemia, those who present with colon ischaemia associated with oral contraceptive pills can be challenging if other risk factors are present including medical co-morbidities, other medications, and potentially illicit drug use. In addition, oral contraceptive use is sometimes under-reported by patients for a variety of reasons. This sometimes makes identifying the cause of colon ischaemia, if it is an oral contraceptive pill, challenging and can lead to continued risks for recurrence. Therefore, when a female patient presents with symptoms consistent with colon ischaemia, it is important to directly ask if she is actively taking oral contraceptive pills.
Controlled/Illicit Pharmacologic Agents
Another group of pharmaceuticals that associates colon ischaemia with a younger population is controlled and illicit drugs. Cocaine is a recreational drug thought to induce colon ischaemia by inhibiting the reuptake of norepinephrine at presynaptic terminals, increasing calcium influx in muscle cells, interfering with platelet aggregation, and inducing vasospasm. There have been over 30 cases of cocaine-induced colon ischaemia reported in the literature with the mean age at diagnosis of 32.6 years and a slight male predominance.[36–43] Symptoms of cocaine-induced colon ischaemia most commonly develop within 48 hours of drug intake and include the acute onset abdominal pain, vomiting, melena, and/or diarrhoea.[35,39,44] Cocaine-induced colon ischaemia does not typically affect one segment of the bowel over another and inflammation of the distal ileum, caecum, ascending, transverse, and sigmoid colon all have been reported.[35,44–46] It is important to note that cocaine-induced colonic ischaemia sometimes presents with vomiting, reflecting small bowel involvement, which is uncommon with other pharmacologically mediated episodes of colon ischaemia and could also explain the increased mortality.
Given that so few things cause colon ischaemia in a young population, if a young patient presents with symptoms and imaging consistent with this disease, it is important to directly inquire about recent illicit drug use including cocaine; in fact, these inquiries should be made in any age group. If this key history is missed, patients might continue using the cocaine recreationally without realising the propensity to develop further bowel injury, myocardial infarction, and other complications from its usage. Cocaine use also can result in intestinal mucosal fibrosis and stenosis either from recurrent or severe ischaemic episodes of colon ischaemia. It has been hypothesised that small amounts of residual cocaine might deposit in the mucosa thus contributing to these clinical phenomena, but this has never been pathologically proven.[47,48] While drug cessation and conservative management can improve the patient's condition, it is the physician's duty to identify this potential trigger and strongly advise the patient to stop using cocaine. Cocaine-induced colonic ischaemia is associated with more severe disease and worse outcomes compared with other aetiologies.
Amphetamines are another illicit drug class that has been associated with colon ischaemia, although less so than cocaine.[49–53] Similar to cocaine, its main mechanisms of ischaemic injury involve splanchnic vasoconstriction secondary to its sympathomimetic actions.[54–56] As was the case with cocaine, amphetamine-induced colon ischaemia seems to be somewhat heterogeneous in its severity and distribution but the classic symptoms, signs, and colonoscopic findings of colon ischaemia are consistent regardless of the cause. As with all of the medication-induced aetiologies for colon ischaemia, a good history identifying this risk factor and advising against repeat use of the offending agent is essential.
Immunomodulator agents suppress the immune system and have been used in the treatment of a variety of diseases including inflammatory bowel disease, rheumatologic disease, and malignancy. One murine study of immunomodulator effects showed that a combination of methylprednisolone and azathioprine was associated with an increased risk of ischaemic injury to the colon compared with a placebo-treated cohort. In humans, a recent study using the FDA's Federal Adverse Event Reporting System showed that almost 6% of cases of colon ischaemia that had a medication as the identified source were attributable to the use of immunosuppressive agents.5 Therefore, immunosuppressive agents are now recognised to be associated with colon ischaemia and seem to be a common medical iatrogenic cause of this disease.
One immunomodulator associated with colonic ischaemia is Lenalidomide, a derivative of thalidomide used to treat multiple myeloma and myelodysplastic syndrome. Recent experimental models indicate Lenalidomide might also be effective in rheumatoid arthritis and inflammatory bowel disease. In one case report of a patient with multiple myeloma treated with Lenalidomide, colon ischaemia was identified and responded to conservative therapy.
Corticosteroids are immunosuppressive agents that also have been associated with colon ischaemia. The association of corticosteroids with colon ischaemia is not simple, since many of the disease states treated with steroids, are also associated with colon ischaemia (eg, rheumatologic disease, inflammatory bowel disease, and chronic obstructive pulmonary disease).[3,61,62] Whether the corticosteroids alone are responsible, or a combination of the steroids and the underlying disease state, remains to be clarified. However, patients who receive corticosteroids are at risk for colonic ischaemia and the diagnosis should be considered when patients on these agents present with typical symptoms.
Sodium polystyrene sulfonate (SPS, Kayexelate; Sanofi-Aventis, Bridgewater, NJ, USA) is a cation-exchange resin indicated for individuals with hyperkalaemia. Sodium polystyrene sulfonate has been associated with colonic ischaemia and rare instances of colonic necrosis with most reported patients having uraemia.[63–65] Sodium polystyrene sulfonate-induced colonic ischaemia is easier to diagnose than most other medication-induced colonic ischaemia since biopsy with haematoxylin and eosin staining typically shows basophilic kayexalate crystals forming a crystalline mosaic, either adherent to the epithelium or mixed with inflammatory cells. The resultant inflammation results in reduced vascular flow to the colonic mucosa. In addition, patients with uraemia and hypotension are at increased risk of colonic ischaemia due to increased angiotensin levels causing vasoconstriction with resultant decrease in splanchnic circulation. The mechanical effects of the crystal deposition and the physiological effects from uraemia act synergistically to render patients susceptible to colonic ischaemia. The colon is not the only region susceptible to ischaemic insult and there have been reports of ischaemic damage to the oesophagus, stomach, and small intestine.
Colon ischaemia from sodium polystyrene sulfonate does not necessarily occur immediately after administration.[67–69] Subacute presentations occur within a week to 10 days and are associated with favourable outcome. Delayed presentations occur weeks-to-months after the initial exposure and are associated with more severe outcomes.[67,68]
Sevelamer is an ion exchange resin used to lower phosphate levels in patients with chronic kidney disease. Colonic ischaemia can develop in patients receiving this drug through similar mechanisms as sodium polystyrene sulfonate and including the presence of histologically identified crystals that appear broad and curved in shape. In both sodium polystyrene sulfonate- and sevelamer-induced colon ischaemia, common findings are isolated ulcers and localised segmental ischaemia and the presence of characteristic crystals points towards causality.
Laxation is universally used to cleanse the colon prior to colonoscopy. Development of colonic ischaemia following colonoscopy is rare and believed to be associated with haemodynamic instability from volume depletion after bowel preparation, gaseous distension of the bowel from insufflation causing decreased colonic blood flow, and/or the preparation itself.[71–73] Bowel preparations have been observed to leave patients prone to colon ischaemia, with oral sulfate solution being the most common culprit, although the mechanism has not been studied in detail. It is likely that the volume depletion associated with bowel cleansing in a mostly older age group with underlying medical co-morbidities undergoing colonoscopy are all factors contributing to this association. In patients with other risk factors for colon ischaemia, preparations other than oral sulfate solutions should be carefully considered for bowel cleansing given the risks for colon ischaemia.
It would be incorrect to assume that all new-onset colitis following colonoscopy is ischaemia-based. For example, when the colonoscope cleansing processors malfunction, there might be inadequate removal of the disinfecting agent glutaraldehyde. When present in larger than trace amounts, contact of this solution with the colonic mucosa can lead to colitis, which is endoscopically and pathologically difficult to distinguish from ischaemic colitis. In this scenario, patients present with abdominal pain and blood per rectum hours after the procedure, and resolves with bowel rest, fluids, and parenteral antibiotic administration.
Hyperosmotic laxatives such as magnesium citrate and sodium phosphate also have been documented to cause colon ischaemia.[76,77] The mechanism leading to ischaemia with these agents involves a rapid shift of fluids from the vascular space of the colonic circulation into the luminal space resulting in local hypoperfusion. Manifestations of colonic ischaemia in patients taking magnesium citrate can develop acutely with some presenting within 3 hours of administration.
Bisacodyl is a commonly used stimulant laxative indicated for constipation and pre-operative surgery preparation which has been associated with colonic ischaemia.[79–81] The hypothesised mechanism for colon ischaemia with bisacodyl is the stimulation of colonic motility with resultant increase of intestinal luminal pressure, thereby decreasing colonic perfusion by compression of the splanchnic circulation.[13,81] In most cases of bisacodyl-induced colon ischaemia, patients develop abdominal pain and diarrhoea followed by haematochezia within 2–6 hours after drug administration.[79–81] There have been several pathologically supported case reports of bisacodyl-induced colon ischaemia with all of these patients recovering with supportive treatment without the need for surgical intervention.[79–81]
Laxatives are commonly associated with colon ischaemia through a variety of mechanisms as outlined above. The severity of colonic ischaemia resulting from these treatments varies widely with some, such as bisacodyl, resulting in mild colon ischaemia and others, for example, sodium polystyrene sulfonate- and magnesium-based laxatives resulting in severe episodes and rarely death. It remains essential for the provider to identify the precipitating agent thereby avoiding recurrent episodes.
The association of NSAIDs and upper gastrointestinal ulcers has been well documented, but their role in lower gastrointestinal enteropathy and colopathy via ischaemic mechanisms is now being increasingly appreciated. The predominant mechanism for NSAID-induced ischaemia involves the selective inhibition of cyclooxygenase-2.[5,83,84] Cyclooxygenase-2 inhibition can cause localised inflammatory alterations resulting in both isolated ulcers or continuous segmental mucosal involvement consistent with colonic ischaemia.[83,85] The most common presenting symptoms for NSAID-induced colonic ischaemia include abdominal pain, diarrhoea, and haematochezia but more subtle signs can occur including fever and weight loss. The elderly seem to be at increased risk for NSAID-induced colon ischaemia with one hypothesised mechanism being a decreased ratio of vasodilating to vasoconstricting prostaglandins, which is thought to be more pronounced in the elderly.
Low-dose aspirin is frequently used for chronic prophylaxis against cardiovascular events, but this therapy increases patients' risks for colon ischaemia. One retrospective case-control study compared patients with colonic ischaemia to randomly selected matched controls admitted during the same time period and showed that low-dose aspirin was independently associated with colon ischaemia with an odds ratio of 1.98 (CI: 1.2–3.4, P = 0.01). In a separate analysis, Hreinsson et al showed that patients presenting with lower gastrointestinal bleeding resulting from colon ischaemia were more likely to be on low-dose aspirin compared to controls (OR: 2.3, CI: 1.14–4.45, P < 0.01).  The risks for colon ischaemia in these patients are increased, but the cardiovascular benefits of low-dose aspirin outweigh these risks. Therefore, consideration of stopping low-dose aspirin in patients should only occur in individuals who have had recurrent colon ischaemia or a severe episode in whom the risk of recurrent colon ischaemia is greater than the cardiovascular benefit of the low-dose aspirin.
NSAID usage is very prevalent and the astute clinician should include colon ischaemia in his/her differential diagnosis when a patient presents with lower gastrointestinal bleeding or bloody diarrhoea. The presentation is rarely acute with severe symptoms, and most patients will present with a benign illness and improve with conservative measures. There has been some recent consideration for probiotic usage to minimise NSAID-induced mucosal damage, but further research is required in this area. Whether patients are long-term users of NSAIDs or have a history of acute abuse, attention to the possibility of colon ischaemia is warranted. Rechallenge with NSAIDs is probably unwise, although there have been no published studies that directly address this issue.
Aliment Pharmacol Ther. 2019;49(1):51-63. © 2019 Blackwell Publishing