1. Effect of nutrient-devices on drugs
Title
Skouroliakou M.

2. Effect of nutrient-devices on drugs
One of the most frequent drug-related problems in patients receiving clinical nutrition is drug interactions with enteral or parenteral nutrition, and inappropriate drug administration techniques

3. The problem (1) Effect of nutrient-devices on drugs
Not much is known about drug and enteral or parenteral feed incompatibilities. This is due partly to the huge variability in composition of EN and, especially, TPN solutions, and the range and concentration of drugs which may be administered simultaneously
less is known about drug-parenteral feed incompatibilities. This is due partly to the huge variability in composition of TPN solutions, and the range and concentration of drugs which may be administered simultaneously

4. The problem (2) Effect of nutrient-devices on drugs
One can find few things in current literature or in the manufacturer’s product summary, therefore most recommendations are theoretical
Usually, drugs are not licensed for administration in EN or PN, so pharmacists need to combine theory with empiricism, knowing that in most cases they cannot rely on published data to confirm the safety of their actions.

5. General mechanisms of interactions between nutrients and drugs (1)
Effect of nutrient-devices on drugs
European Association of Hospital Pharmacists
Amsterdam 2001
General mechanisms of interactions between nutrients and drugs (1)
stimulation of splachnic capillary blood flow (increase in first-pass effect)
chelation of drug molecules by minerals such as calcium and iron (eg. quinolones)
competing with the action of the drug (eg. warfarin-vita K)

6. General mechanisms of interactions between nutrients and drugs (2)
Effect of nutrient-devices on drugs
General mechanisms of interactions between nutrients and drugs (2)
changing the pH of the GI tract to increase or decrease absorption
inhibiting or enhancing drug metabolism
changing GI motility to increase or decrease absorption
enhancing drug solubility

7. Role of therapeutic drug monitoring
Effect of nutrient-devices on drugs
Role of therapeutic drug monitoring
Appropriate monitoring for altered response or altered plasma levels of drugs (especially those with a narrow TI) is of vital importance. If drug interactions are not identified but doses are adjusted due to lack of therapeutic response, toxicity may ensue when feeds are discontinued.

8. Drug administration in enteral nutrition
Effect of nutrient-devices on drugs
Drug administration in enteral nutrition
General considerations:
Formulation to be used
Interaction with the feed or other drugs
Timing of drug administration
Moreover, type of tube, placement site, and the site of drug absorption
The preferred and easiest way to administer drugs through a tube is as a liquid preparation.

9. Formulations commonly used in EN
Effect of nutrient-devices on drugs
Formulations commonly used in EN
Liquid preparations are easy to administer through a tube and are usually preferred to other forms.
soluble tablets
dispersible tablets
capsule contents
When changing formulations, drugs may require dosage or frequency adjustments

10. Interactions in enteral nutrition
Effect of nutrient-devices on drugs
Interactions in enteral nutrition
Interactions most usually encountered are related to drug precipitation, and chelation with mineral cations, which may result in inadequate absorption of the drug and impaired therapeutic effect
Furthermore, these may lead to tube blockage (~15 % of patients) which occupies nursing time, limits feed and drug intake, and increases trauma to the patient
Examples: quinolones-Ca, Mg…
Tube blockage may also require additional surgical intervention to replace tubes
Tube blockage can guarantee increased health care costs

11. Increased probability of clinically significant interactions with:
Effect of nutrient-devices on drugs
Increased probability of clinically significant interactions with:
Drugs interacting with food, vitamins or electrolytes
Drugs that need to be given on an empty stomach
Drugs which are given in liquid form particularly when multiple drugs or high volumes are given this way
Drugs with a narrow therapeutic index
Problems with liquid drugs:problems regarding the acidity, osmolality, sorbitol content of the formulation
Narrow TI:Lithium, Digoxine, Phenytoin, Theophylline etc

12. Examples of interactions (1):
Effect of nutrient-devices on drugs
Examples of interactions (1):
Theophylline
The bioavailability of theophylline may be altered by food. The mechanism may be related to changes in metabolism as a result of nutrient effects on stimulating and inhibiting cytochrome P450. Varying effects have been reported in patients on enteral feeds
Feeding should be stopped for one hour before and two hours after dose and drug levels should be monitored
Differences in pharmacokinetics may be related to the protein and carbohydrate contents of diet.

13. Examples of interactions (2):
Effect of nutrient-devices on drugs
Examples of interactions (2):
Aluminium-containing antacids
While receiving high protein enteral feeds an obstructing protein-aluminium complex oesophageal plug in patients may be formed
Antacids should not be given to patients receiving high molecular weight protein feeds or, if necessary, the feed should be stopped and the tube thoroughly flushed.
Antacids may also bind phosphate from enteral feeds, thereby causing hypophosphataemia

14. Examples of interactions (3):
Effect of nutrient-devices on drugs
Examples of interactions (3):
Quinolone antibiotics
Ciprofloxacin and ofloxacin possess good absorption characteristics, so they are usually given enterally rather than intravenously. However, in patients receiving enteral feeding, studies suggest that significantly lower plasma concentrations than expected are attained. This is due to the formation of insoluble chelates with divalent ions (calcium, magnesium, etc) in the feeds, thus reducing absorption from the GI tract

15. Examples of interactions (4):
Effect of nutrient-devices on drugs
Examples of interactions (4):
Quinolone antibiotics
When a severe infection is being treated it has been suggested that NG tube administration to these patients should not be used unless facilities for plasma concentration monitoring are available. In other patients, consideration may be given to prescribing larger doses to be given through the enteral feeding tube.

16. Examples of interactions (5):
Effect of nutrient-devices on drugs
Examples of interactions (5):
Quinolone antibiotics
Although ofloxacin is considered to exhibit this phenomenon to a lesser extent, the interaction is thought to be a class effect and should be managed accordingly

17. Examples of interactions (6):
Effect of nutrient-devices on drugs
Examples of interactions (6):
Phenytoin
Phenytoin may perhaps be the most researched drug in respect of its interactions with enteral feeding. Significant problems in attaining and maintaining therapeutic levels of phenytoin may arise in clinical practice, and various courses of action have been suggested in order to minimize this effect
In some cases parenteral therapy may be required, for example with intramuscular fosphenytoin
A recent study of the use of phenytoin sodium powder from capsules, instead of the acid salt in the liquid, found no evidence of improved absorption

18. Examples of interactions (7):
Effect of nutrient-devices on drugs
Examples of interactions (7):
Phenytoin
Administration of the undiluted suspension without flushing the tube first, may result in a 75% loss of the initial dose
Administration of the liquid without shaking it first, may result in variable absorption due to its viscosity

19. Examples of interactions (8):
Effect of nutrient-devices on drugs
Examples of interactions (8):
Phenytoin
Factors that may inhibit proper absorption of the drug include:
binding to the feeding tube
binding to proteins or electrolytes in the formula
inadequate dissolution
decreased transit time
inadequate dissolution due to the high pKa of phenytoin and the acidic nature of enteral formulae
decreased transit time due to hyperosmolar feeds or enteral feed-associated diarrhoea

20. Examples of interactions (9):
Effect of nutrient-devices on drugs
Examples of interactions (9):
Phenytoin
Further problems occur when the patient also receives other drugs which interact with phenytoin, or when he/she is hypoalbuminaemic. The result of such multiple interactions may sometimes be unpredictable

21. Examples of interactions (10):
Effect of nutrient-devices on drugs
Examples of interactions (10):
Phenytoin
Recommendations include (A):
Phenytoin to be administered as a single daily dose
Enteral feeding to be stopped two hours before administration of the drug and continue two hours after
Tube to be flushed with adequate amounts of water before and after administration
Alternatively to stopping enteral feeding 2h before and after, suspend feed between 10pm and 6am (that is, during sleeping hours) and give phenytoin as a single daily dose at midnight (this allows for six hours drug absorption)

22. Examples of interactions (11):
Effect of nutrient-devices on drugs
Examples of interactions (11):
Phenytoin
Recommendations include (B):
The liquid should be shaken before use
Dilution of the suspension with at least equal parts or 20ml of water
Serum level concentrations should be closely monitored especially when changing from one dosage form to another
(dilution up to 1:3 has also been recommended)
The dosage form and volume of liquid should always be documented on the patient's prescription chart to avoid confusion

23. Drug administration in TPN
Effect of nutrient-devices on drugs
Drug administration in TPN
When possible, drugs should not be given simultaneously with the TPN solution
Y-site connection should only become a necessity when there is no other route or parenteral access available and when a multi-lumen catheter is being used to full capacity
Where possible, drugs should be given separately from the TPN solution but this is not always possible, particularly in areas where the number of IV drugs required exceeds the access sites available such as in cancer and intensive care unit (ICU) patients.

24. Interactions in total parenteral nutrition
Effect of nutrient-devices on drugs
Interactions in total parenteral nutrition
The most frequently encountered drug-TPN solution interactions result in:
loss of stability
precipitation of the admixture
which may minimize absorption of the drug by the patient

25. Effect of nutrient-devices on drugs
Factors which may largely affect interactions between drug-TPN solution (1)
composition of TPN regimen
contact time between drug and TPN solution:
brand and concentration of drug added
exposure of admixture to light and temperature

26. Effect of nutrient-devices on drugs
Factors which may largely affect interactions between drug-TPN solution (2)
For 3-in-1 TPN admixtures containing fat emulsion:
stability of the emulsion
bioavailability of drug from emulsion
formation of precipitates
A significant risk is that of a precipitate forming but being obscured by the fat emulsion

27. Mixing drugs with TPN solutions (1)
Effect of nutrient-devices on drugs
Mixing drugs with TPN solutions (1)
A large number of the various substances found in a TPN solution may interact with drug additives. In the case of 3-in-1 admixtures, the potential risk of incompatibility and stability problems is even greater due to the addition of a fat emulsion. It has been recommended that no other drugs or solutions should be added to fat solutions due to the risk of disturbing the stability of the emulsion or affecting the bioavailability of the drug

28. Mixing drugs with TPN solutions (2)
Effect of nutrient-devices on drugs
Mixing drugs with TPN solutions (2)
Mixing drugs with TPN solutions cannot be recommended without stability or compatibility data on specific TPN regimens and drug concentrations
Exposure to temperature and light, as well as prolonged contact time of a drug-TPN admixture may increase the risk of stability and compatibility problems
Ranitidine is considered to be compatible (?)

29. Poor education Effect of nutrient-devices on drugs
Nursing staff who routinely administer drugs via feeding tubes usually possess inadequate level of knowledge
Clinical practice is based on "trial and error“, little use or development of guidelines
Few stop feeds before and after giving NG phenytoin

30. Sources of info Effect of nutrient-devices on drugs
Ask the manufacturer!
ESPEN, ASPEN, or other local organizations’ publications
Drug databases over the internet or in CD-ROMs