A Drug Therapy Smorgasbord Practical Issues for Dietitians

1. A Drug Therapy Smorgasbord Practical Issues for Dietitians Presented by David B. Goldwater R.Ph Clinical Consultant Pharmacist

2. Objectives • Review Practical Pharmacokinetic principals to create a deeper understanding of absorption, distribution and excretion of drugs. • Review several commonly used drugs often reviewed for consideration by Dietitians which involve considerations of pharmacokinetics and specific drug/ food interactions.

3. Objectives continued…. • Discuss important considerations for Warfarin interactions with enteral feedings • Review the Pharmacodynamic effects of antipsychotics with specific focus on weight gain and blood sugar control

4. Closer Collaboration between Pharmacists and Dietitians • Changes to revised Dietary F Tag: F325. June 2008 AND • Definition of MRR in revised Pharmacy F Tag F425 (Dec 2006) • BOTH REVISIONS have strengthened the need for communications between our two disciplines.

5. Changes to F428 –Med Regimen Review (Dec 2006) • Thorough evaluation of the medication regimen of a resident by a pharmacist with the goal of promoting positive outcomes and minimizingadverse consequences associated with medications; • The review includes: preventing, identifying, reporting, and resolving medication-related problems, medication errors, or other irregularities AND • collaborating with others members of the interdisciplinary team.”

6. Personal impact of working closer with dietitians • Appreciation of the positive influence on outcome for residents due to collaborations with Dietitians in LTC. • A strong interest in speaking to you as a group today. • The topics chosen for review today, have come directly from collaborations and discussions with individual Dietitians in my personal practice. • On a lighter note………….

7. Personal Impact of Working closer with Dietitians

8. Practical Issues For Dietitians Basic Concepts of Pharmacokinetics

9. Study of what the body does to a drug.How the body → moves drug in and out. (Absorption Distribution Excretion) Pharmacokinetics

10. Study of the influence (dynamics) of the DRUG on the BODY Pharmacodynamics

11. FIRST ORDER KINETICS • The majority of drugs are eliminated in this way. • A constant fraction of the drug in the body is eliminated per unit time. • The rate of elimination is proportional to the amount of drug in the body.

12. FIRST ORDER ELIMINATION Concentration in plasma Time

13. Volume of Distribution (Fordrugs which follow first order kinetics) • The Volume of Distribution (Vd)is the amount of drug in the body divided by the concentration in the blood. • Highly LIPID SOLUBLE DRUGS, such as digoxin, have a very High Vd.(500liters). • LIPID INSOLUBLE DRUGS, such as neuromuscular blockers, remain in the blood, and have a Low Vd.

14. Clearance (Cl) (Fordrugs which follow first order kinetics) • The Clearance (Cl) of a drug is the VOLUME of plasma from which the drug is COMPLETELYremoved per unit time. • The amount of drug eliminated is PROPORTIONAL to the concentration of thedrug in the blood.

15. Elimination (Fordrugs which follow first order kinetics) RATE of elimination EQUAL TO Clearance x Concentration in the blood. _______________________________________________________________________________________ Elimination HALF LIFE (t1/2) EQUAL TO Time taken for plasma conc. to reduce by 50%.

16. RULE OF THUMB 100% Elimination After 5 HALF-LIVES (Symbol for Half-life is t ½)

17. Half-life: Implications • We can determine how long it takes to reach steady state E.g. DIGOXIN ……t ½ = 40hrs • It takes approximately 200 hrs~8 days for DIGOXIN to reach STEADY STATE LEVELS. • It takes approximately ~8 daysfor DIGOXIN to be COMPLETELY ELIMINATEDfrom the system.

18. Simple, isn't it? • What we discussed above is a SINGLE COMPARTMENT model, • This is what would occur if the bloodstream was the only compartment in the body (or if the Vd= the blood volume). • But the human body is more complex than this! • There are many compartments: muscle, fat, brain tissue etc. • In order to describe this, we use MULTI-COMPARTMENT models.

19. MULTICOMPARTMENT MODELS Q. Why does a patient wake up after 5 minutes after an injection of Thiopentone, when we know that it takes several hours to eliminate this drug from the body? A. Initially the drug is ALL in the blood and this blood goes to "vessel rich" organs; principally the brain. • The drug then redistributes into other tissue compartments. (fat, muscle etc) • In response to the decrease in brain concentration the net effect is that the patient wakes up 5 minutes later!

20. Elimination: MULTI COMPARTMENT MODEL Rapid distribution phaseα Concentration Equilibrium phase (Plateau) Elimination phaseβ Time

21. A SIMPLE TWO COMPARTMENT MODEL • The first part is the rapid redistribution phase: (alpha phase.) • The plateau (equilibrium phase)(where blood concentration = tissue concentration) • The slower phase, the beta phase, is the elimination phase where blood and tissue concentrations fall in tandem

22. BIOAVAILABIILITY • This is the fraction of the administered dose that reaches the systemic circulation. • Bioavailability is 100% for intravenous injection. • It varies for other routes depending on • incomplete absorption, • first pass hepatic metabolism etc. • When we plots plasma concentration Vs. time, the bioavailability is the area under the curve.

23. BIOAVAILABILITY (for a drug given orally) BIOAVAILABILITY is the AREA UNDER THE CURVE Concentration in plasma Time

24. DOSAGE REGIMEN The strategy for ADMINISTRATION DOSING is to administer ONLY, sufficient amounts of drug to attain therapeutic effect, but not enough to produces toxicity! THEREFORE WE APPLY THESE PRINCIPLES…… • STEADY STATE CONCENTRATION is achieved AFTER FIVE half lives, therefore…. • At STEADY STATEMaintenance Dose = Rate of Elimination • WE THEREFORE CONCLUDE THAT……Rate of Administration = Rate of Elimination

25. DOSAGE REGIMEN • Drugs will accumulate within the body if the drug has not been fully eliminated before the next dose. • This is OK only IF, we are willing to wait 5 half lives for the drug to be fully effective ………but what if we cannot wait that long? • Then we need to "load" the volume of distribution WITH the drug to achieve target plasma concentrations RAPIDLY.

26. Hepatic Drug Clearance • Many drugs are extensively metabolized by the liver. • The rate of elimination depends on: • The liver's inherent ability to metabolize the drug • The amount of drug presented to the liver for metabolism.

27. Hepatic Drug Clearance(First Pass effect) • This is important because orally administered drugs go from Ingestion →gut → portal vein → liver. • The liver DIVERTS a varying chunk of the administered drug by (pre-systemic elimination) and therefore less is available to the body for therapeutic effect. EXAMPLE: This is why we give a higher dose of ORAL morphine, for the equipotent INTRAVENOUS dose 30 MGORAL Morphine is EQIPOTENT TO 1 MGIV Morphine. ORAL: PARENTERAL RATIO =3 : 1

28. Drug distribution FACTORS THAT EFFECT WHERE THE DRUG ENDS UP: • BLOOD FLOW • tissues with the highest blood flow receive the drug first. • PROTEIN BINDING • drugs stuck to plasma proteins are crippled, because they can only go where the proteins go • LIPID SOLUBILITY & DEGREE OF IONIZATION • this describes the ability of drugs to enter tissues • (highly lipid soluble / un-ionized drugs can basically go anywhere).

29. Protein Binding • Most drugs bind to proteins: • Albumin OR • Alpha-1 Acid Glycoprotein (AAG), • FREE drug is usually the preferred state, because FREE drug can travel throughout the body, in and out of tissues and exert a biological effect. • Free drug on the other hand is subject to metabolizing enzymes.

30. Protein Binding • HIGHLY BOUND drug has a longerduration of action and a lowervolume of distribution. Why is this important? • For HIGHLY protein bound drugs, we need to give more of it to get a therapeutic effect; as so much is stuck to protein. • If another drug comes along and starts to compete with the drug for the binding site on the protein→the amount of FREE drug is ↑ ↑ INCREASED

31. Clinical Implications for HIGHLY Protein Bound Drugs • DRUG-A ------ 97% BOUND TO ALBUMIN……3% free drug. • Addition of DRUG-B displaces DRUG-A from its binding sites • Causing 3% reduction in Protein binding for DRUG-A RESULTS in a 50% increase in FREE DRUG-A concentration from 3% to 6% • DRUG-X ------ 70% BOUND TO ALBUMIN……30% free drug. • Addition of DRUG-Y displaces DRUG-X from its binding sites • Causing 3% reduction in Protein binding for DRUG-X RESULTS in a NEGLIGIBLE increase of FREE DRUG-X concentration from 30% to 33%

32. Clinical Implications for HIGHLY Protein Bound Drugs The HIGHLY BOUND drugs that we really need to focus on are: warfarin, diazepam, propranolol,phenytoin. • For example, a patient on warfarin is admitted with seizures, you treat the patient with phenytoin, next thing you know - his INR is 10. • The amount of albumin does not appear to be hugely relevant. • In disease states such as sepsis, the serum albumin drops drastically, but the free drug concentration does not appear to increase • HOWEVER: For residents with LOW serum Albumin there is a formula that we apply to DILANTIN levels results to adjust the DILANTIN level

33. Practical Issues For Dietitians Warfarin Resistance & Enteral feeding: New understanding of An Old Problem

34. History of Enteral feedings & Warfarin • Warfarin resistance first reported in the early 1980’s was POSITIVELY associated with CONTINUOUS enteral tube feedings. • Attributed to large amounts of vitamin Kcontained within the feedings. • Patients commonly received several hundred micrograms per day of vitamin K!

35. CORRECTIVE ACTIONS TAKEN • The pharmaceutical industry subsequently responded to this problem…… • Resulting in significantly reduced vitamin K contentof liquid enteral nutrition formulations. • Most current liquid enteral formulations NOW CONTAIN LESS THAN 80 MCG/LITER OF VITAMIN K.

36. Why does this issue still occur? • Still some anecdotal reports of difficulty in achieving therapeutic anticoagulation when warfarin was given concomitantly with CONTINUOUS LIQUID ENTERAL FEEDINGS • Still some anecdotal reports of significant increases in the (INR) when the enteral feeding was discontinued. • Schurgers and associates (2004)performed a study to ascertain the CLINICALIMPACT OF VITAMIN K SUPPLEMENTATION on the anticoagulation effect of the ORAL ANTICOAGULANTACENOCOUMAROL.[6]

37. Is VIT K CONTENT In Enteral FeedingSTILL THE ISSUE? NOT LIKELY ! • They concluded that other factors outside of enteral vitamin K intake were playing a greater role in these ANECDOTAL observations BECAUSE…. • ……..THE TOTAL VIT K INGESTED IN ENTERAL FEEDING WAS SIGNIFICANTLY LOWER THAN THE SUPPLEMENTAL DOSES USED IN THE STUDY

38. Guidelines for Daily Vit K Intake • Guidelines from the Food and Nutrition Board of the Institute of Medicine for adequate intake of Vit K are as follows: in healthy adult men : • Vit-K 120 mcg/day In healthy adult women: • Vit-K 90 mcg/day

39. Findings by Schurgers and colleagues [5] • A statistically significant decrease in INR by 0.4 was found when…. • The subjects’ supplemental vitamin K intake was increased to 150 mcg/day. This was in addition to their baseline55 mcg/day ______________________________________ TheGRAND TOTALofdietary vitamin K intake was 205 mcg /day

40. Findings by Schurgers and colleagues [5] • They confirmed that supplemental intake of up to 100 mcg/day of vitamin Kdid NOT significantly interfere with oral anticoagulant therapy in healthy individuals already receiving about 55 mcg of dietary vitamin K. THEY CONCLUDED: • That a total vitamin K intake of about 150 mcg daily is NOT likely to affect warfarin requirements.[5]

41. Dickerson and Colleagues Review • Dickerson and colleagues studied (INR) values in 6 patients requiring continuous enteral feeding during the first 10 days of warfarin therapy.[6] • For 3 consecutive days, feedings were interrupted for 1 hour before and after warfarin administration. • On 3 other consecutive days, feedings were NOT interrupted for warfarin administration. • The INR increased by a mean of 0.74 during the 3-day interval when the enteral feedings were interrupted for warfarin. • In contrast, the INR decreased by a mean of 0.13 during the 3-day interval when enteral feedings were NOT interrupted .

42. Dickerson and Colleagues CONCLUSION • Holding enteral feeding 1 hour BEFORE and 1 hour AFTER warfarin administration …….lessens warfarin resistance • This strategy is recommended for warfarin administration DURING CONTINUOUSENTERAL FEEDINGS.

43. KEY POINTS: Warfarin Management in Enteral Nutrition 1,6,7 • Consider an alternative method of anticoagulation. • Monitor INR frequently. • Administer warfarin BETWEEN feedings for patients receiving INTERMITTENT tube feedings. • Stop feedings ONE hour before and ONE hour after warfarin administration for patients receiving CONTINUOUS tube feedings,.

44. KEY POINTS: • Consider increasing the rate of feedings to avoid loss of calories.*** • Administer warfarin consistently (ie, hold feedings for all doses) • Do not add warfarin directly to the enteral nutrition. • Warfarin dose requirements may change if the enteral regimen is altered or if the oral diet is resumed.

45. KEY POINTS: • Warfarin dose requirements may change if the enteral regimen is altered or if the oral diet is resumed. • If Enteral feedings are Initiated in a patient stable on warfarin, the warfarin may require a dose increase • If WARFARIN is initiated in a patient currently receiving enteral nutrition, the warfarin may require a dose decrease upon resumption of oral diet.

46. Selected References • Lourenco R. Enteral feeding: drug/nutrient interaction. Clin Nutr. 2001;20:187-193. • Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil. 2001; 82:1270-1273. • Coumadin (package insert). Princeton, NJ: Bristol-Myers Squibb; 2007. • Food and Nutrition Board, Institute of Medicine. In: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001:162-196. • Schurgers LJ, Shearer MJ, Hamulyak K, Stocklin E, Vermeer C. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in health subjects. Blood. 2004;104:2682-2689. • Dickerson RN, Garmon WM, Kuhl DA, Minard G, Brown RO. Vitamin K-independent warfarin resistance after concurrent administration of warfarin and continuous enteral nutrition. Pharmacotherapy. 2008; 28:308-313. • Engle KK, Hannawa TE. Techniques for administering oral medications to critical care patients receiving continuous enteral nutrition. Am J Health Syst Pharm. 1999; 56:1441-1444.

47. Practical Issues For Dietitians Other Drug-Enteral feeding interactions

48. Study by Dickerson et. Al. Roland N. Dickerson, George O. Maish III, Gayle Minard and Rex O. Brown. Clinical Relevancy of the Levothyroxine − Continuous Enteral Nutrition Interaction Nutr Clin Pract 2010 25: 646

49. STUDY CONCLUSION: • More than half of our patients receiving concurrent Levothyroxine–continuous EN developed subclinical or overt hypothyroidism within the first 2-3 weeks of therapy. • Holding EN for ONE hour PRE- and POST Levothyroxine administration, may be ineffective for some patients. • If a Levothyroxine dosage escalation is attempted following development of hypothyroidism, only a 25-mcg dosage increment is suggested.

50. STUDY CONCLUSION: • Serial (e.g. weekly) monitoring of TFT’s for all patients receiving concurrent levothyroxine and EN therapy is recommended. • TFT monitoring should be continued until a pharmacokinetic-pharmacodynamic steady state is achieved. • If an incremental dosage increase is chosen for therapeutic management of hypothyrotic patients, the dosage should be reduced when the EN is discontinued. • Further study to ascertain the best method for managing patients with concurrent levothyroxine-EN is warranted.