Mechanisms of Action of Lomotil and Loperamide
Both Lomotil (diphenoxylate-atropine) and loperamide work by slowing intestinal motility, but loperamide has additional antisecretory effects and is generally more effective with fewer central nervous system effects. 1, 2
Loperamide Mechanism of Action
- Loperamide binds to opiate receptors in the gut wall, inhibiting the release of acetylcholine and prostaglandins, which reduces propulsive peristalsis and increases intestinal transit time 2
- It has multiple antisecretory actions, some of which are not mediated by opiate receptors 1
- Loperamide increases anal sphincter tone, thereby reducing incontinence and urgency 3
- Unlike other opiates, loperamide has low oral absorption and does not cross the blood-brain barrier, minimizing central nervous system effects 4
- Loperamide is metabolized by the cytochrome P450 system, primarily by CYP3A4 and CYP2C8 enzymes 2
- Excretion of unchanged loperamide and its metabolites occurs mainly through the feces 2
Clinical Effects of Loperamide
- At therapeutic doses (4 mg), loperamide does not significantly slow orocaecal transit in healthy adults 1
- Higher or repeated doses can retard jejunal or orocaecal transit, but in diarrheal states, the therapeutic dosage normalizes transit 1
- Loperamide prolongs the transit time of intestinal contents, reduces daily fecal volume, increases stool viscosity and bulk density, and diminishes the loss of fluid and electrolytes 2
Lomotil (Diphenoxylate-Atropine) Mechanism of Action
- Diphenoxylate is a peripherally acting opiate derivative that slows intestinal motility 5
- Atropine, the second component in Lomotil, is an antimuscarinic agent that antagonizes the muscarine-like actions of acetylcholine 6
- Atropine inhibits the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles 6
- The combination of diphenoxylate and atropine produces a more pronounced effect on intestinal transit than loperamide 1, 5
Clinical Effects of Lomotil
- Diphenoxylate with atropine is generally less effective than loperamide for acute diarrhea 1, 7
- Intestinal transit is more prolonged by both diphenoxylate and atropine than by loperamide 5
- Atropine can cause additional anticholinergic effects including tachycardia, urinary retention, and dry mouth 6
Comparative Efficacy and Safety
- Loperamide is more effective than diphenoxylate for providing rapid control of diarrhea symptoms 8
- In studies comparing the two medications, loperamide provides better symptomatic control of chronic diarrhea than diphenoxylate 9
- Side effects, particularly central nervous system effects, are greater with diphenoxylate and least with loperamide 9
- Loperamide has a longer duration of effect than diphenoxylate at comparable therapeutic doses 8
Important Clinical Considerations
- Neither agent should be used in patients with severe dysentery with high fever or blood in stool 1, 7
- Both medications are contraindicated in children under 2 years of age due to the risk of rare adverse central and peripheral side effects 1, 7
- Loperamide is available over-the-counter, while Lomotil requires a prescription due to its greater potential for central effects 5
- Tolerance to the antidiarrheal effect of loperamide has not been observed, even with long-term use 2