Loperamide: A Review of its Pharmacological Properties and Therapeutic Efficacy in Diarrhoea

Summary

Synopsis: Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses.

In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery, It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.

Pharmacodynamic studies: Loperamide is an orally-active drug which reduces gastrointestinal motility in animals and man. In isolated-organ studies loperamide caused a dose-related reduction of pressure-induced activity of longitudinal and circular muscles in the ileum and inhibited the spasmogenic effects of electrical stimulation, nicotine and prostaglandins. Loperamide is more potent than diphenoxylate, morphine or codeine in slowing gastrointestinal progression of a charcoal bolus in mice and in reducing castor oil-induced diarrhoea in rats and mice. Oral doses (2.5 to 40mg/kg) several times the antidiarrhoeal dose, unlike diphenoxylate, do not produce narcotic-like actions. Intravenous (0.1mg/kg) or high subcutaneous doses (40 to 240mg/kg) of loperamide may however, result in opiate agonist activity. Loperamide, unlike diphenoxylate, does not possess analgesic activity after non-toxic oral doses.

In man, loperamide has a significant constipating effect in healthy volunteers, with a similar onset but longer duration of activity than diphenoxylate. Central opiate activity, as demonstrated by pupillary diameter measurements with or without challenge by the narcotic antagonist naloxone, does not occur at normal therapeutic oral doses.

Pharmacokinetic studies: Peak plasma levels occur within 4 hours after administration and the plasma half-life in man is 7 to 15 hours. 25 % of an oral dose is excreted in the faeces unchanged in 3 days, and 1 to 2 % in the urine as free drug or glucuronic acid conjugate. Biliary elimination is an important route of excretion in rats but this has not been studied in man.

Therapeutic trials: Loperamide has been effective and safe in the symptomatic treatment of both acute and chronic diarrhoea and in reducing ileostomy output in patients with ileostomies. Most controlled studies in acute diarrhoea have shown loperamide to provide more rapid control of symptoms than a placebo, kaolin-morphine mixture or diphenoxylate plus atropine. In 2 studies involving large numbers of patients, about one-half of patients receiving loperamide required further treatment after the first 12 to 24 hours compared with about two-thirds of those on diphenoxylate. In patients with severe chronic diarrhoea associated with chronic inflammatory bowel disease or following gastrointestinal surgery, loperamide is superior to a placebo and probably superior to diphenoxylate. Patient preferences and reduction in stool frequency have favoured loperamide over diphenoxylate, and in 1 study it had a more rapid onset of action. Further studies involving larger numbers of patients are needed to clarify the relative efficacy of the 2 agents in chronic diarrhoea, but the possibility of once daily dosage with loperamide is an advantage. Loperamide has not been compared with codeine in therapeutic trials but has the advantage of a longer duration of effect and apparent freedom from opiate side-effects.

In a single dose study in acute diarrhoea, 4mg loperamide had a much longer duration of effect than 5mg diphenoxylate or 400mg clioquinol plus 40mg phanquone.

In studies in acute and chronic diarrhoea involving a flexible dosage according to unformed bowel movements, loperamide 2mg per dose has controlled diarrhoea at a lower dose level (i.e. total number of doses or average daily doses) than diphenoxylate 2.5mg per dose. It seems that a larger initial and subsequent dosage of diphenoxylate is needed to provide equivalent control of diarrhoea. Thus, in 1 study which compared loperamide 2mg per dose with diphenoxylate 5mg per dose in chronic diarrhoea, the number of doses required for control did not differ, although diarrhoea was better controlled by loperamide in terms of reduced stool frequency and improved stool consistency. In acute diarrhoea, a larger initial dose ( 10mg instead of 5mg) and subsequent larger fixed dosage (5mg every 6 hours instead of 2.5mg as needed) of diphenoxylate achieved similar control as the standard flexible dose schedule of loperamide (4mg initially then 2mg after each loose bowel movement).

Side-effects: Loperamide appears to be well tolerated. Side-effects are usually gastrointestinal in nature and may be related to the diarrhoeal condition rather than to the drug itself. Nausea, abdominal cramping, dizziness, rash, and dry mouth have occasionally been reported.

Dosage: In adults the initial dose for acute diarrhoea is 4mg followed by 2mg after each loose bowel movement. For chronic diarrhoea, an initial dose of 4mg should be subsequently adjusted to obtain 1 or 2 normal stools daily. When the optimum individual dosage has been established, it may be given on a once daily basis or in divided doses. Adult dosage in acute diarrhoea should not exceed 16mg per day. Children* over 8 years of age should receive 2mg initially with subsequent adjustments not to exceed 8 to 12mg daily. In children younger than 8 years, the therapeutic dosage is of the order of 0.08mg/kg body weight per day.