Prokinetics

OVERVIEW

• Prokinetics are agents that increase gastrointestinal motility
• Gastroparesis common -> increased gastric residual volumes -> GORD, aspiration risk and inability to meet nutrition targets
• Theoretically, an increase in gastric motility helps in establishing target enteral feeds early in critically ill patients, which improves outcome

Definitions

• Delayed gastric emptying: Disordered gastric motility leading to slowing of the flow of gastric contents into the duodenum
• Feed intolerance: An inability to reach or maintain the targeted rate of feed delivery during enteral nutrition, commonly due to large gastric residual volumes and delayed gastric emptying

THE IDEAL PROKINETIC AGENT

Features of the ideal prokinetic agent (it does not exist!)

• increase fundal tone and pressure wave frequency
• stimulate antral wave amplitude and frequency
• reduce pyloric wave frequency and abolish pyloric tone
• the resulting gastroduodenal motor pattern would ensure antegrade movement of chyme and increase gastric emptying rate
• does not affect intestinal transit nor impair nutrient absorption
• optimises colonic function, facilitating normal bowel actions without causing diarrhoea
• lacks adverse effects
• remains effective despite continued use, as current therapies are limited by tachyphylaxis
• has a wide therapeutic index and limited interaction with other drugs
• metabolism unaffected by liver or kidney impairment

METOCLOPRAMIDE

• prokinetic and antiemetic
• prokinetic action:
  1. antagonism of D2 receptors in gut, and weak agonist at 5HT4 receptors
  2. augmentation of peripheral cholinergic responses
  3. increase smooth muscle tone
• actions: increased tone of the lower oesophageal sphincter, accelerated gastric contractions, increased small bowel transit time (increased peristalsis in duodenum and jejunum)
• administration: IV, PO, IM
• dose: 10mg Q6H
• metabolised hepatically
• adverse effects: sedation, dystonic reactions, dysrhythmias (methemoglobinemia in overdose)
• not effective in patients with brain injury and may contribute to raised ICP
• tachyphylaxis occurs

ERYTHROMYCIN

• macrolide antibiotic
• prokinetic action due to agonism at motilin receptors
  1. chronotropic effect on neuronal receptors
  2. enhances motilin release from enterochromaffin cells in duodenum
  3. enhanced contractile effects on gastric antrum and duodenum
• administration: IV or PO
• dose: 100mg Q6H or 250mg Q12H
• metabolised hepatically
• drug interactions due to CYP450 3A4 inhibition
• adverse effects: prolonged QT, hepatic dysfunction, overgrowth of non-susceptible organisms and clostridium difficile, possibly antibiotic resistance
• most effective single agent, but is limited by tachyphylaxis (over 2-7 days)
• dose dependent effects
• combination with metoclopramide is more effective than either alone

METHYLNALTREXONE

• peripheral mu-opioid-receptor antagonist with restricted ability to cross the blood-brain barrier
• RCTs support use for opioid-induced constipation in advanced illness
• only retrospective studies in critical care patients: decrease gastric residual volumes and improves feed tolerance
• only likely to be useful if opioid-induced dysmotility is the issue
• does not reverse central-mediated analgesia or precipitate withdrawal

NEOSTIGMINE

• acetylcholinesterase inhibitor
• increase intestinal contractility and transit
• trend to improved GER and feed tolerance in a pilot study

CISAPRIDE (no longer used)

• serotonin receptor agonist (5-HT4 receptor)
• selective enhancement of physiological acetylcholine release at the myenteric plexus
• prokinetic actions: oesophageal peristaltic activity, gastric emptying, intestinal propulsion and colonic transit
• oral administration only
• 10mg Q6 hourly
• metabolised hepatically
• adverse effects: prolonged QT (removed from market), arrhythmias

APPLICATIONS

• improved gastric emptying with prokinetic use documented

LIMITATIONS

• no double blind RCTs showing patient benefit
• most studies do not stratify patients by severity of illness and baseline balance uncertain
• most studies do not quantify use of other drugs that affect GI motility (e.g. narcotics and catecholamines)
• small numbers
• no studies looking at any meaningful clinical outcome (mortality or infection incidence)
• no studies assessing risk / benefit ratios (each of these agents has side effects)

FUTURE AGENTS

• Tegaserod is also a nonselective 5HT4 receptor partial agonist that has been used in the ICU setting, but was withdrawn due to concerns regarding cardiac and gut ischemia. Other (more selective) 5HT4 agonists may be used in the future.
• CCK receptor antagonists
• Ghrelin analogues
• New motilin receptor agonists

CONCLUSION

• prokinetics appear to have a beneficial effect on gastrointestinal motility in the critically ill
• should be used with caution given lack of clinical outcome data
• staged introduction of prokinetics with sequential checking of QT prolongation
• all patients on ECG monitoring
• ensure electrolytes are normalised and rule out underlying causes of feeding intolerance
• regular review about ceasing prokinetics once feed established
• my approach is to start metoclopramide 10mg q6h IV and erythromycin 250mg Q12H IV (unless contra-indicated) for feeding intolerance
• do not use cisapride

References and Links

• Deane AM, Fraser RJ, Chapman MJ. Prokinetic drugs for feed intolerance in critical illness: current and potential therapies. Crit Care Resusc. 2009 Jun;11(2):132-43. PMID: 19485878.
• Fraser RJ, Bryant L. Current and future therapeutic prokinetic therapy to improve enteral feed intolerance in the ICU patient. Nutr Clin Pract. 2010 Feb;25(1):26-31. PMID: 20130155.