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Specific Drug–nutrient Interactions

Several medications interact with EN, and patients should be monitored for altered clinical response or subtherapeutic drug levels.^[13] The more common drug–nutrient interactions are described below.

Phenytoin

For patients receiving EN who cannot safely swallow phenytoin capsules, the liquid preparation is the preferred formulation for delivery through a tube. However, there is a well-documented interaction between phenytoin suspension and enteral feeds. When administered concurrently, phenytoin absorption may be reduced by up to 70%, thus decreasing serum drug levels.^[28] This interaction was first reported by Bauer^[29] in 1982 among neurosurgical patients receiving both continuous NG feedings and phenytoin suspension; subtherapeutic serum phenytoin concentrations were noted. The author suggested stopping the enteral feeds for two hours before and after phenytoin administration, as well as flushing the tube with 60 mL of water after drug delivery. Possible reasons for the impaired absorption include phenytoin adhering to the enteral tube itself and phenytoin binding to certain components of the enteral formulations, particularly proteins and calcium salts.^[30,31] Another approach for minimizing this interaction involves withholding the enteral feedings for a slightly shorter time period, one hour before and after phenytoin administration, with appropriate irrigation in between to ensure drug delivery and to maintain tube patency. To minimize the amount of time that the feedings are held, phenytoin suspension should be given twice daily rather than more often if possible.^[28] Alternatively, if the enteral feedings cannot be held, then the dose of the phenytoin suspension should be increased to account for the interaction. Larger doses are usually needed to reach therapeutic levels with this strategy, and closely monitoring phenytoin levels will help determine the required dosage. However, when EN is stopped and an oral diet resumed, a phenytoin dose reduction may be necessary.^[14,28] In general, when phenytoin suspension is given through a feeding tube, it should be diluted with 20–60 mL of water to enhance absorption and increase the dissolution rate.^[19,32]

Other formulations of phenytoin may be administered with EN. Gilbert^[28] described a strategy of using the contents of extended-release phenytoin capsules mixed with water to form a slurry for delivery with continuous tube feeding. This method involves administering the total 24-hour phenytoin dose as a single daily dose made into a slurry, with the tube feeds held for 2 hours before and after drug administration. Controversy exists regarding opening phenytoin extended-release capsules. As Hatton and Magnuson^[28] indicated, this should not be done since the drug's extended-release properties may be affected. Crushing phenytoin chewable tablets may be a possible option, too.^[33] Another strategy involves administering the parenteral formulation of phenytoin through the enteral tube, although it should be diluted before administration because of extreme hypertonicity.^[28,34] Whichever method is employed to minimize this drug–nutrient interaction, it should be used consistently throughout therapy. Close monitoring of serum phenytoin concentrations and patient clinical response is required.

Consideration should be given to the type of EN formulation administered concurrently with phenytoin. Hennessy^[33] confirmed that higher protein feeding formulas resulted in a greater level of binding and less phenytoin recovery.

Carbamazepine

A few studies suggested that enteral feedings decrease absorption of carbamazepine suspension.^[35,36] Although the exact mechanism of the drug–nutrient interaction is not clear, carbamazepine may adhere to the actual feeding tube. Because of this, carbamazepine suspension should be diluted with an equal volume of sterile water or normal saline solution before administration via the enteral tube. Similar to phenytoin, close monitoring of serum concentrations is warranted when carbamazepine is given via the enteral route.^[13,36]

Riss et al.^[37] described the administration of extended-release carbamazepine capsules through the feeding tube in children. Capsule contents were mixed with 15 mL of water, and tube flushes also occurred before and after drug administration. However, it was noted that tube occlusions developed in some children.

Warfarin

Several case reports have documented warfarin resistance in patients receiving EN.^[38-40] Initially, this altered response was attributed to the high amounts of vitamin K in the enteral feeding formulations. Subsequently, the enteral products were reformulated to reduce the vitamin K content.^[39] However, challenges with anticoagulation were still reported between warfarin and these reformulated enteral feeding products, which suggested another reason for this interaction.^[38,41] Since warfarin is highly protein bound, it may bind to the proteins in the enteral formulas, reducing the bioavailability and interfering with its anticoagulant effect.^[39,41] The prothrombin time, or International Normalized Ratio, should be closely monitored when warfarin is used concurrently with EN. The warfarin dose may need to be increased, or a switch to another anticoagulant, such as a low-molecular-weight heparin, may be necessary. Alternatively, continuous enteral feedings may be held for at least one hour before and after warfarin administration to help lessen the interaction. As the patient transitions from enteral feeding to an oral diet, a reduction in the warfarin dosage may be required.^[5,14,18,40]

Fluoroquinolones

Controversy exists regarding concurrent fluoro-quinolone administration with enteral feedings. The bioavailability of this antibiotic class may be reduced when given with multivalent cations such as calcium, magnesium, aluminum, and iron. Commonly used enteral products contain varying amounts of these cations, although their concentrations are much lower compared with antacids or mineral supplements. Concomitant administration may impair quinolone absorption.^[18,42]

Various studies have evaluated the interaction between enteral feeding and quinolones. However, limitations to the studies exist and include small sample size, different study populations, and different EN delivery methods.^[43-47] These limitations make it difficult to reach any consistent conclusions. Although this drug–nutrient interaction is considered a class effect, the extent of the interaction appears to vary among the quinolones. Wright et al.^[48] showed that when quinolones were directly mixed with an enteral feeding formulation, ciprofloxacin loss was the greatest, followed by levofloxacin and ofloxacin. Mueller et al.^[44] also showed that enteral feedings decreased absorption of ciprofloxacin significantly more than ofloxacin. In contrast, Burkhardt et al.^[47] demonstrated that moxifloxacin absorption was not affected by concurrent EN.

There are several proposed mechanisms to reduce this interaction. Ideally, quinolones should not be given simultaneously with enteral formulas. A common practice is to hold EN for at least one hour before and two hours after quinolone dosing,^[49] although this may not apply to moxifloxacin. Another option is to increase the dose of ciprofloxacin when given concurrently with EN.^[13,49] When quinolones are administered through the feeding tube, the tablets should be thoroughly crushed and diluted in 20–60 mL of sterile water.^[45-47] It is important to note that ciprofloxacin suspension should not be given through the feeding tube because it may adhere to the tube and cause occlusion.^[5]

Healy et al.^[45] noted a greater reduction in both ciprofloxacin peak concentration and bioavailability when administered via jejunostomy tubes versus gastrostomy tubes. A possible explanation may be that ciprofloxacin is primarily absorbed in the duodenum; therefore, jejunal administration should probably be avoided with this medication.^[42]

Proton Pump Inhibitors

The administration of proton pump inhibitors via feeding tubes presents a unique challenge. These medications are acid labile and inactivated by gastric acid, so they are specially formulated to maintain their integrity until delivery to the alkaline pH of the duodenum, where absorption occurs.^[5,10] Omeprazole, esomeprazole, and lansoprazole are available as delayed-release capsules containing enteric-coated granules,^[50-52] but pantoprazole and rabeprazole are formulated as delayed-release, enteric-coated tablets.^[53,54]

Various studies have discussed alternative methods for delivering omeprazole and lansoprazole via enteral feeding tubes.^[55-58] When administered through large-bore NG or gastrostomy tubes, the capsule contents (omeprazole and lansoprazole) may be mixed with apple juice or orange juice, poured down the tube, and flushed with more juice. Using acidic juices as the diluent allows the enteric-coated granules to remain intact until delivery to the small intestine, where the coating dissolves. Because of the potential for occlusion, this method of administration should not be used with small-bore feeding tubes. Mixing the granules with water rather than acidic juices causes clumping and may lead to tube occlusion.^[5,19,55] However, esomeprazole granules, which are found in the delayed-release capsules and delayed-release oral suspension, should be mixed with water before delivery through the NG tube.^[51]

When administering omeprazole or lansoprazole capsules through small-bore jejunostomy or gastrostomy tubes, oral alkaline suspensions may be prepared. This involves dissolving the intact enteric-coated granules in sodium bicarbonate 8.4% solution, which makes a simplified suspension. This formulation prevents drug degradation from stomach acid by raising the gastric pH. It is also less likely to cause tube occlusions.^[5,58]

In addition to delayed-release capsules, other formulations of omeprazole and lansoprazole are available for administration via the enteral tube. A commercial preparation of immediate-release omeprazole with sodium bicarbonate (Zegerid, Santarus Inc., San Diego, CA) is available as a powder for oral suspension; however, it is important to note that the suspension should be mixed only with water and not other liquids or foods that affect gastric pH, and continuous NG and OG tube feedings should be held for three hours before and one hour after medication administration.^[59] A delayed-release, orally disintegrating tablet form of lansoprazole is also available. It dissolves on the tongue or may be mixed with a small amount of water in an oral syringe and injected through the NG tube.^[52] It is important to note that the lansoprazole oral suspension, unlike the esomeprazole oral suspension, should not be administered through feeding tubes because of its increased viscosity and potential for tube occlusion.^[5,52]

Pantoprazole is available as an enteric-coated tablet and a new delayed-release oral suspension. This new suspension contains enteric-coated granules that are emptied into an oral syringe and mixed with apple juice for delivery via the NG tube.^[53] Before the oral suspension was commercially available, a pantoprazole extemporaneous suspension was compounded using sodium bicarbonate solution.^[60,61]