Metoclopramide

DRUG NOTES

Metoclopramide

L Smith, M Fisher, G McKay*

Introduction Figure 1. The pharmacological action of metoclopramide Metoclopramide was first licensed for use in Europe in the 1970s for the treatment of nausea and vomit - A. Central action Vagal efferents ing. Its dual action, centrally at the chemoreceptor trigger zone and Brain D2 receptor peripherally at the gastric outlet, antagonism + CTZ + vomiting 5-HT 4 receptor provides it with efficacy as an anti- D2 receptors centres agonism emetic, in the treatment of gastro- 5-HT 3 receptors oesphageal reflux disease, to aid small bowel radiological examina - tions and for the management of Antagonism gastroparesis. The latter is a com - Synapse mon manifestation of autonomic Ø Nausea/ Smooth neuropathy in patients with long - vomiting Metoclopramide standing diabetes and metoclo - muscle pramide is part of the therapeutic Sensitises armoury to manage this difficult muscarinic receptors condition. B. Peripheral action

Pharmacology Ø Lower oesophageal

Figure 1 outlines the pharmacolog - sphincter tone ical action of metoclopramide. Ø Centrally it works by dopamine Gastric antral contraction

(D 2) receptor antagonism and Relaxation of pylorus serotonin (5-HT 3) receptor antago - Ø nism in the chemoreceptor trigger Small bowel motility zone and other emesis centres. Peripherally it stimulates smooth muscle contraction through the Improved gastric emptying release of acetylcholine from Reduced small bowel transit time enteric cholinergic neurons (sero - NOTES. Metoclopramide works (A) centrally by dopamine (D 2) receptor antagonism and tonin 5-HT 4 receptor agonism), serotonin (5-HT 3) receptor antagonism in the chemoreceptor trigger zone (CTZ) and antagonises the inhibitory neuro - other vomiting centres; and (B) peripherally by serotonin (5-HT 4) receptor agonism and transmitter dopamine and has a dopamine (D 2) receptor antagonism, and has a direct effect on smooth muscle direct effect on smooth muscle con - contraction by sensitising muscarinic receptors. This leads to increased lower traction by sensitising muscarinic oesophageal sphincter tone, increased gastric antral contraction, relaxation of the receptors. The results of these pylorus and increased small bowel motility. peripheral effects are increased lower oesophageal sphincter tone, form as well as both intravenously Side effects of metoclopramide increased gastric antral contraction, and intramuscularly. The onset of develop mostly due to its readiness relaxation of the pylorus and action is 1 –3 minutes when adminis - to cross the blood-brain barrier. increased small bowel motility tered parenterally, and maximal Symptoms of drowsiness, fatigue and resulting in improved gastric emp - plasma levels occur within 20 –30 restlessness are common as is hyper - tying and reduced transit time from minutes of oral intake. The usual prolactinaemia. Acute dystonia results duodenum to terminal ileum. dose is 10mg three times daily but in some patients, in particular young It is well absorbed orally and can it can be given up to 20mg four patients, and long-term use can result be administered in tablet or liquid times daily. in extrapyramidal side effects.

Lyn Smith, MBChB, MRCP, Specialty Consultant Physician Glasgow Royal Infirmary, 84 Castle Street, Trainee in Gastroenterology Glasgow Royal Infirmary, Glasgow, UK Glasgow, UK; Miles Fisher, MD, FRCP, Consultant email: [email protected] Physician *Correspondence to: Dr Gerry McKay, Gerry McKay, BSc(Hons), FRCP, Consultant Physician, Wards 3, 4 & 5,

Trials of safety and efficacy The efficacy of metoclopramide as Key points an anti-emetic was shown in 1969 in a double-blind trial of more than • Metoclopramide has efficacy as a centrally acting anti-emetic and a 600 patients requiring treatment of gastrointestinal tract prokinetic postoperative nausea and vomiting. • Metoclopramide has well recognised CNS side-effects and should be used Metoclopramide was shown to have with caution in younger patients greater efficacy than both placebo • Metoclopramide may be of clinical benefit in the treatment of diabetic (p<0.001) and prochlorperazine gastroparesis (p<0.05) with no significant side effects. 1 Subsequent studies have to bed for three weeks in a ran - Discussion shown efficacy when used in patients domised, double-blind, crossover Metoclopramide has a role in the with chemotherapy-induced nausea design. There was a significant management of diabetic gastropare - and vomiting. Prior to the wide - amelioration of the symptoms of sis through both its centrally medi - spread introduction of proton pump nausea, vomiting, anorexia, fullness ated anti-emetic actions and its inhibitors, metoclopramide had and bloating with metoclopramide prokinetic properties. Gastroparesis proven value in managing the symp - therapy compared with placebo remains poorly understood and toms of gastro-oesophageal reflux (p<0.05), with an overall mean symp - improvement in gastric emptying disease with several double-blind tom reduction of 52.6%. Gastric time does not always correlate with studies showing improved symptoms emptying studies after completion of improved patient symptoms. Drug compared with both placebo and the trial in seven patients, subjec - therapy is only a small part of the cimetidine. More recently, studies tively improved and receiv ing open- management of these patients. A full have also been published showing labelled metoclopramide, showed review should be made of their the benefit of metoclopramide in significantly less gastric retention. existing medications which may in postoperative ileus, hyperemesis Individual improvements in gastric themselves delay gastric emptying. gravidarum, functional dyspepsia emptying after parenteral or oral Glucose control should be opti - and gastroparesis. metoclopramide, however, could not mised as hyperglycaemia itself has be correlated with symptom change been shown to slow gastric empty - Specific evidence for use during the treatment trial. Since ing. Coexisting psychiatric disorders in diabetes then, several other studies have been such as depression and anxiety have Gastroparesis can be defined as published comparing the efficacy been shown to be associated with delayed gastric emptying in the and safety of metoclopramide an increased prevalence of gastro - absence of any mechanical obstruc - against placebo, domperidone and intestinal symptoms in diabetic tion. It can occur in patients with cisapride (subsequently withdrawn patients and these should be type 1 and type 2 diabetes, but is from the UK market). One of the addressed. 4 Nutritional support may particularly seen when there is evi - largest trials was a double-blind, be required, and patients may also dence of established microvascular multicentre comparison of the short- require referral to gastroenterology complications. It presents with term use of oral metoclopramide for consideration of Botox, naso- upper gastro intestinal symptoms of and domperidone. 3 Ninety-three jejunal feeding or even gastric pace - nausea, early satiety, post-prandial insulin-dependent diabetic patients maker insertion. fullness and vomiting. In severe with a history of symptoms of gastro - cases it can lead to weight loss and paresis for more than three months Declaration of interests malnutrition. The motor dysfunc - were randomised, with 45 receiving There are no conflicts of interest tions described in diabetic gastro - metoclopramide and 48 receiving declared. paresis are heterogeneous and the domperidone. Nausea, vomiting, pathophysiology is poorly under - bloating/distension and early satiety References stood. This makes treatment diffi - were evaluated at two and four 1. Tornetta FJ. Clinical studies with the cult and has to be tailored to each weeks. Both drugs were shown to new antiemetic, metoclopramide. individual patient. be equally effective in alleviating Anesth Analg 1969;48(2):198 –204. The efficacy of metoclopramide symptoms of gastro paresis, but cen - 2. Ricci DA, et al . Effect of metoclo - in the treatment of diabetic gastro - tral nervous system side effects were pramide in diabetic gastroparesis. J paresis was shown by a small study more severe and more common in Clin Gastroenterol 1985;7(1):25 –32. in 1985. 2 Thirteen patients with those treated with metoclopramide, 3. Patterson D, et al . A double-blind subjective evidence of gastric stasis including somnolence, akathisia, multicenter comparison of domperi - had delayed gastric emptying of an asthenia, anxiety, depression and done and metoclopramide in the isotope-labelled semi-solid meal reduced mental acuity. The current treatment of diabetic patients with symptoms of gastroparesis. Am J which was significantly accelerated NICE guidelines for type 1 diabetes Gastroenterol 1999;94(5):1230 –4. (p<0.05) after 10mg of metoclo - suggest a trial of prokinetic drugs, 4. Talley SJ, et al . Psychological distress pramide parenterally. Patients then such as metoclopramide or domperi - is linked to gastrointestinal symptoms received 10mg of metoclopramide done, in patients with suspected or in diabetes mellitus. Am J Gastroenterol and placebo before meals and prior diagnosed gastroparesis. 2001;96(4):1033 –8.