Introduction

Ischemic colitis is the most prevalent presentation of intestinal ischemia. It is classically associated with the elderly with multiple comorbidities. Several medical entities have been recognized, usually in association: arterial hypertension, diabetes mellitus, dyslipidemia, heart failure, auricular fibrillation, atherosclerotic disease and cardiovascular or abdominal surgery. ^1,2 Some drugs have also been associated like cytostatics, antibiotics, digoxin, psychotropics, nonsteroidal anti-inflammatory drugs, diuretics and laxatives.³

Ischemic colitis is a rare adverse effect of antipsychotic medication, most commonly with phenothiazine, atypical or second generation antipsychotic drugs.⁴ Its effect can be enhanced if associated to others drugs with anticholinergic activity, like tricyclic antidepressant, trihexyphenidyl or biperiden. It is hypothesized that the anticholinergic and antiserotoninergic activity induces intestinal hypomotility and constipation, reduces mucosa secretions, nociception and intestinal sensitivity, all leading to intestinal ischemia.^4,5

Clinical cases

We evaluated retrospectively (2012-2018) six schizophrenia patients of Centro Hospitalar Conde de Ferreira (CHCF), with neuroleptic-induced ischemic colitis. All the patients have schizophrenia, two of them with intellectual disability associated. Excepting P3, all are male adults. To achieve adequate disease control all had antipsychotic drug associations. The most frequent were clozapine (five patients) and haloperidol (four patients). Five were also medicated with biperiden. None of the patients had risk for thrombotic or embolic arterial occlusion, previous abdominal surgery or cardiovascular comorbidities. Clinical and therapeutic details are detailed in table 1. The spectrum of clinical presentation was wide - we point out the depressed level of consciousness and the absence of typical clinical presentation of ischemic colitis in most of them. All were referred to emergency care but the aetiological investigation was also wide – five done a CT angiography, two a colonoscopy and one an exploratory laparotomy. All the patients had endoluminal occlusion with fecal impaction and the CT angiography excluded primary vascular disease. The two patients with shock were submitted to surgery (colectomy) and vasopressor support in intensive care unit. The other patients had conservative care (fecal extraction, parenteral antibiotics and laxatives). After discharge to our hospital, it was possible to reduce the dosage of the antipsychotic drugs in two patients. All started prophylactic laxatives. None of them had recurrence of the disease, but P1 had one episode of intestinal obstruction due to surgery adhesions. He later died of an event not related to the colitis.

Discussion

These cases show how difficult it is to diagnose ischemic colitis in the schizophrenia patients. The absence of the typical clinical manifestations associated with ischemia is due to the disease itself and also the neurologic effects of the antipsychotics. All the clinicians should give special attention to common symptoms like abdominal malaise and constipation.⁵

In our study clozapine was the most prescribed neuroleptic. It is in agreement with the literature.^3,5 All of the patients had antipsychotic associations and five had also biperiden, a drug that also have antagonizing acetylcholine properties. This drug mixture potentiated anticholinergic side-effects like decreased intestinal peristalsis with functional occlusion and increased endoluminal pressure. This led to compromised intestinal mucosa perfusion and ischemia. The effect on muscarinic acetylcholine receptors is dose dependent. This is a possible explanation to the increased risk of constipation and ischemic colitis on schizophrenia patients, usually prescribed with high dosages of neuroleptics. The antiserotoninergic effects of clozapine can also per se explain these consequences. It antagonizes 5HT₂ and 5HT₃ receptors, leading to alterations of the intestinal motility, mucosa secretions, nociception and intestinal sensitivity to distension.⁶ Antipsychotics also have an effect on dopamine – its vasodilatory effects on mesenteric circulation are inhibited due to antidopaminergic effects, resulting in mucosal ischemia.⁷ All of these mechanisms can lead to severe complications (one third of our sample), like intestinal necrosis and perforation, requiring emergency surgery. It is reported higher morbidity and mortality in these cases when compared to the other causes of ischemic colitis.⁸

There is not clear evidence that drug dosage reduction diminishes the gastrointestinal side effects.⁹ There has been anecdotal reports regarding dose reduction of neuroleptics to ameliorate constipation. Some reports also describe beneficial effects on suspension after intestinal surgery, due to the apparent increased risk of anastomotic leakage associated with hypomotility and increased intraluminal pressure.⁸ Prevention seems to be the best option - all the literature emphasizes the counseling regarding the risk of complications, the role of clinical surveillance (with systematic monitoring of bowel movements) and promotion of measures that avoid constipation in these patients – nonpharmacological (high-fiber diet, adequate hydration with water, physical workout and avoidance of long periods in the same position and sedentarism) and pharmacological (laxatives with the goal of daily defecation). It should be avoided the association of antipsychotics with drugs with anticholinergic effects.^4,6,9 The standard of care of neuroleptic induced ischemic colitis is supportive care with bowel rest, intravenous fluids, endoscopic decompression and empiric broad spectrum antibiotics. In severe cases surgical intervention may be required.⁸

Quadro I

Clinical and therapeutic details of the six patients with neuroleptic-induced ischemic colitis

  BIBLIOGRAFIA  

References

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