UG Food-Drug interaction.presentation...

Food drug interaction slide;

1. FOOD-DRUG INTERACTIONS BY PROF. MBAH A.U.

2. Classes of Interactions Pharmacodynamic : food and a drug can reinforce or interfere with each other’s pharmacological actions. Pharmacokinetic: this is the interference of food and drugs during absorption, distribution, excretion or enzymatic transformation of one substance is altered by another. Most adverse interactions are of this type.

3. Types of interaction Type I are ex vivo bioinactivations , which refer to interactions between the drug and the nutritional element or formulation through biochemical or physical reactions, such as hydrolysis, oxidation , neutralization, precipitation or complexation. These interactions usually occur in the delivery device. • Type II interactions affect absorption. They cause either an increase or decrease in the oral bioavailability of a drug. The precipitant agent may modify the function of enzymes or transport mechanisms that are responsible for biotransformation. • Type III interactions affect the systemic or physiologic disposition and occur after the drug or the nutritional element has been absorbed from the gastrointestinal tract and entered the systemic circulation. Changes in the cellular or tissue distribution, systemic transport, or penetration to specific organs or tissues can occur. • Type IV interactions refer to the elimination or clearance of drugs or nutrients, which may involve the antagonism, impairment or modulation of renal and/or enterohepatic elimination

4. Pharmacokinetic Mechanisms Alteration of drug solubility . Alteration of gastrointestinal pH. Stimulation, induction or inhibition of enzymes involved in biotransformation or transport of drugs or nutrients . Displacement of a drug from binding to plasma proteins. Alteration of urinary pH.

5. Overview Drug issues ADME Administration issues Drugs through feeding tubes Compatibility of injectable drugs Stability of ingredients Vitamin stability Contaminants

6. Drug Issues ADME Absorption Involves how the drug dissolves and is released in GI Distribution – Involves drug moving in blood stream Metabolism – clearance of the drug by enzymes Excretion – liver or kidney removal

7. Absorbtion Swallowing Disintegration tablet swells breaks up Dissolution reactions with acid faster when ionized Absorption most post pyloric in basic environment require non-ionized state

8. Tablet breakup

9. Kinetic changes Liquid vs Tablet Liquids absorbed faster Onset faster Extent of absorption may be greater In stomach liquids expose drug to greater acidic degradation

10. Food Interactions with Drug Absorption Milk products alter pH Metals chelate some medications Some foods compete for same absorption sites Food speeds GI transit – reduced absorption Degree of significance is important

11. Food-Drug Interactions Characteristics of the drug Physical, chemical... Characteristics of the meal Size, composition… Fasting (definition) No food intake for at least 1 hour before and at least 2 hours after drug intake

12. Possible Interactions Outcomes Nutrient depletion : Individual nutrients may have their dietary requirement increased by specific drugs (or supplements ). Adverse drug reaction : A specific supplement may undesirably decrease or increase the effect of a drug or supplement being taken . Beneficial drug action : Drugs (or supplements) may have their actions enhanced or side effects diminished by specific supplements.

13. Drug-Induced Nutrient Depletion About half the drugs used in clinical practice have documented nutrient depleting effects. Co-enzyme Q10, folic acid, B2, B6, Mg, Zn are nutrients most likely to be depleted. Mechanisms include impaired absorption or bioactivation ; increased excretion.

14. Co-enzyme Q10 Depletion Statin-induced Co-Q depletion impairs mitochondrial function, raising the serum lactate/pyruvate ratio . Simvastatin but not atorvastatin depletes myofibrillar Co-Q. Supplemental Co-Q , 100 mg/day, prevents the decline in serum Co-Q levels without impairment of the lipid-lowering effect of statins and may reverse symptoms of statin myopathy.

15. Co-enzyme Q10 Depletion (cont’d) Statin-induced Co-Q depletion is increased by vitamin E (700 IU/day). Co-Q is consumed in recycling tocopheryl quinones back to tocopherols . Thiazides, some beta-blockers and many older psychotropic drugs have been shown to interfere with Co-Q dependent enzymes, creating a possible need for Co-Q supplementation in patients receiving them.

16. Food-Drug Interactions Bisfosfonates have an exceptionally high affinity for chelation with dietary bivalent cations (Ca 2+ , Fe 2+ ) When taken ½ hr before a meal Clodronic acid BIO  31 % When taken with meal Clodronic acid BIO  90 % When taken 2 hrs after a meal Clodronic acid BIO  66 %

17. Vitamin E and Statins α -Tocopherol prevents statin benefits in people with low HDL-C and normal TC. Related to tocopherol inhibition of statin-induced elevation of HDL2-C. Selenium (100 mcg/day) and fish oil have the opposite effect. α -Tocopherol depletes gamma-tocopherol by competitive binding to transport protein.

18. Clinically Significant Depletions-1 Adriamycin depletes co-enzyme Q10. Adriamycine -induced cardiotoxicity is reduced by Co-Q and propionyl -L-carnitine. Cisplatin depletes Mg. Cisplatin-induced nephtrotoxicity is reduced by i.v. and oral Mg (160 mg tid ). Thiazides deplete folate, raising homocysteine concentration.

19. Clinically Significant Depletions-2 Loop diuretics increase excretion of K, Ca, Mg, Zn, B1, B6, C. Correcting B1 deficit improves cardiac function of CHF patients. Cephalosporins (parenteral) can deplete vitamin K2, causing hemorrhage. Steroids deplete Ca and Mg, causing bone loss. Reversible with calcium and vit D3 administration.

20. Antiretroviral Nutrient Depletion Azidothymidine (AZT) depletes muscle carnitine and increases lymphocyte apoptosis. Reversed with carnitine supplementation. AZT is associated with decreased serum zinc and copper; zinc 200 mg/day reduced Candida and Pneumocystis infections in patients taking AZT.

21. Phenytoin-induced Depletions Phenytoin may deplete biotin, folate, thiamine, vitamin D (causing hypocalcemia and osteomalacia and vitamin K. Memory impairment is associated with reduced RBC folate. Folic acid, 1 mg/day, prevents deficiency without adversely affecting phenytoin metabolism.

22. Valproic Acid Depletions Valproate depletes carnitine, raising ammonia; reversed with carnitine 2 g/day. Valproate lowers serum folate and P5P, raising homocysteine; reversed with 400 mcg folate, 120 mg B6 and 75 mg B2. Valproate inhibits biotinidase . Biotin 10 mg/day reverses valproate-associated hair loss and dermatitis in children.

23. Chelation and Drug Absorption Chelation by minerals impairs absorption of quinolone or tetracycline antibiotics, thyroid, bisphosphonates, L-DOPA, some ACE inhibitors. Even some herbs like dandelion and fennel, can be so rich in minerals that they inhibit absorption of these same drugs. .

24. The Cytochrome P450 System and Drug-Supplement Interactions Expressed chiefly in liver, intestines, lungs and kidneys (“Phase 1 detoxication ”). 20 different human CYPs, grouped by amino acid homology, not by function. CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 most important for oxidation of drugs, xenobiotics.

25. CYP1A2 Found in the liver only. Inactivates caffeine and bioactivates aromatic and heterocyclic amines; large inter-individual differences (up to 100-fold).  Induced by char-broiled meat, cigarettes, pollutants, vegetables.

26. CYP2: Drug-Drug Interactions CYP2C9 accounts for 30% of CYP activity in human liver. May be modified by Ginkgo biloba . CYP2C19 is primarily hepatic. Phenotype reflects the interaction of 8 gene alleles. CYP2D6 is extra-hepatic. Bioactivates codeine/ codones . 55 alleles . CYP2E1 in liver, lung, brain. Metabolizes organic solvents like ethanol. Induced with chronic ethanol use, fasting, obesity. Inhibited by acute alcohol intake, tea, broccoli, garlic, onion, watercress.

27. CYP3A4 Liver and small intestine. Transforms about 50% of common drugs. Induced by St. John’s wort (liver, intestine) and Echinacea (liver only). Inhibited by peppermint oil and piperine. Intestinal but not liver CYP3A4 is inhibited by grapefruit juice, Seville orange juice and Echinacea.

28. CYP3A4 and St. John’s Wort CYP3A4 stimulation by St. John’s wort reduces blood levels of benzodiazepines, calcium channel blockers, anti-retrovirals, estrogens (including OCPs), amitriptyline, cyclosporine, methadone, tacrolimus and possibly warfarin.

29. Intestinal CYP3A4 Inhibition Increases blood levels of amiodarone, artemisinin, atorvastatin, buspirone, carbemazepine, cyclosporine, diazepam, diltiazem, erythromycin, estradiol, felodipine, fentanyl, fluoxetine, lovastatin, methyl-prednisolone, nifedipine, nimodipine, praziquantel, saquinavir, sertraline, sildenafil, simvastatin, verapamil

30. Fruit/Vegetable-Drug Interactions: Effects on Drug Transporters Efflux transporters expressed in the intestine and liver include: P-glycoprotein ( Pgp , ABCB1) Bile salt efflux pump (BSEP, ABCB11) Multidrug resistance proteins (MRP1- 6, ABCC1-6) Breast cancer resistance proteins (BCRP, ABCG2) All the members of the ATP-Binding Cassette superfamily (ABC transporters)

31. P-glycoprotein Efflux Transporter (P- gp ) Ejects xenobiotics from cells and causes backflow of some drugs from intestinal mucosa into the lumen. Produces multi-drug resistance to cancer chemotherapy. Inhibited by piperine , milk thistle and acutely by St. John’s wort. Stimulated by continued St. John’s wort.

32. Alteration of Intestinal CYP3A4 and/or P-glycoprotein Often involves the same substrates. Primarily effects drugs that pass slowly through intestinal mucosa. Interactions in vivo may not be predicted by interactions in vitro .

33. Adverse Pharmacodynamic Interactions 5-HTP and SSRI’s Licorice and horsetail, diuretics or laxatives Phenylalanine or kava and neuroleptics Bee venom and ACE inhibitors Brewer’s yeast and MAO inhibitors Interferon-alpha and bupleurum

34. Antithrombotic Interactions 35 natural products inhibit platelet function in vivo following oral use. They may reinforce each other or interact with antithrombotic medication. Aspirin-vitamin E interaction: aspirin inhibits platelet aggregation; vitamin E inhibits platelet adhesion to endothelium.

35. Aspirin-Vitamin E Interactions a-Tocopherol (50 IU/day) raised risk of gingival bleeding 25% among ASA users. 400 IU/day a-tocopherol added to 325 mg ASA/day reduced incidence of TIAs compared to aspirin alone. Vit E 50 IU/day, decreased ischemic stroke by 30% but increased hemorrhagic stroke by 145% in hypertensive, non-diabetic male smokers. In diabetics, there was no increase in hemorrhagic stroke and ischemic stroke decreased by 70%.

36. Warfarin Interactions 49 natural products may interfere with warfarin; 21 confirmed, 28 possible. Herbal coumarins might compete for binding to plasma protein, increasing plasma free warfarin concentration. Controlled studies found no effect on vitamin E or coenzyme Q10 on INR of patients taking warfarin.

37. Beneficial Drug-Supplement Interactions Reflect additive/complementary effects of supplements and drugs, or amelioration of toxic drug effects by supplements. Fish oils enhance anti-inflammatory, antiarrhythmic, anti-lipemic, antidepressant, and neuroleptic drugs, beta-blockers, lithium and insulin. EPA and DHA may have differential effects.

38. Metabolism – Interaction with food Cytochrome P-450 in GI and the liver. Grapefruit juice made from frozen concentrate will alter this enzyme Important for many antiretroviral and antihypertensive drugs Effect occurs 24 hours after ingestion

39. Excretion Urine acidity will change drug excretion Cranberry juice will alter pH and cause higher dissolution. This occurs with sulfonamides Lime juice is most acidic

40. Drug Administration through Feeding tubes Most drug products are not designed, tested, labeled nor approved for administration via feeding tube!

41. Clogging tubes Lumen size / circumference (French size) Length – longer  loops No residual volume in jejunum. Tubing must be flushed. Clogging is usually due to undissolved drugs

42. PEG and PEJ

43. 1 Drug Indication Possible Effects SOURCE: Compiled from references in the bibliography. Oral Anticoagulants Anticoagulant (blood thinner) Vitamin K is a nutrient in the body that helps blood to clot. Vitamin K is present in foods such as green, leafy vegetables and fish. It will interfere with a blood thinner like coumadin. Phenytoin Anticonvulsant (anti-seizure) Vitamin D and folic acid levels in the body are decreased by the taking of these types of drugs. Calcium Channel Blockers Antihypertensive (for high blood pressure) Consuming foods high in sodium (i.e., licorice, processed meats, canned foods) will decrease the effectiveness of the drug. Aspirin Anti-inflammatory/pain reliever Taking large amounts of these drugs will cause a loss of Vitamin C in the body. Birth control pills Oral contraceptives Women who take these drugs often have low levels of folic acid and Vitamin B 6 in the blood. Thiazide Diuretics Diuretics (water-eliminating) Taking diuretics often leads to a loss of potassium in the body. Tetracycline Antibiotic Calcium may interact with the effectiveness of the antibiotic. Avoid dairy products for two to three hours before and after taking the medicine. Lipitor/Zocor Statins (cholesterol-lowering drugs) Antioxidants (Vitamin A, C, E, B, folic acid) may interact with the drug by reversing its effect. Prednisone Corticosteroid The drug may increase appetite thus increasing nutrient intake. Frusemide Diuretic (water-eliminating) The drug may decrease appetite thus decreasing nutrient intake.

44. Physical Issues Drug Stability with Enteral Formula Admixture may result in reduced drug stability Examples: Ciprofloxacin, Ofloxacin and Levofloxacin was tested with electrolytes and Ensure Significant loss of drugs in Ensure

45. Osmotic Issues Common drug Side Effects associated with Enteral Nutrition: Diarrhea, nausea, vomiting, cramping, distention & bloating 40% of treatment-unresponsive diarrhea caused by excipients The Diagnostic quandary Is it caused by: The Enteral Nutrition ?? The Drug Therapy ?? Both ??

46. Parenteral Nutrition Compatibility Contain many ingredients Amino acids, dextrose, lipids, electrolytes, vitamins and trace elements Issues of compatibility can be significant. Precipitates can occur. Many patients receive medications simultaneously.

47. Lipid Compatibility Many institutions mix lipid in same container with other ingredients Lipid is an oil–in–water emulsion Electrolytes destabilize the emulsion Fat droplets aggregate Clog blood vessels – form emboli

48. Intravenous Compatibility pH - acid base interactions Concentration - Vancomycin and ceftazidime. Crystal formation – Ascorbic Acid Precipitate formation – Ca + PO4

49. Phenytoin compatibility with enteral nutrition Neurology patients get this drug through feeding tube. When given with nutrition – levels drop Recommendations to hold feeding 2 hours before and after and increase dose

50. Phenytoin Controlled studies do not find interaction Only occurs in case reports In-vitro studies document the occurrence – but fail to show mechanism

51. Phenytoin Suspension formulation is very thick Adheres to surfaces – increases dosing errors Diluting drug improves dissolution

52. Warfarin Anticoagulant used to reduce strokes Inactivated by Vitamin K - broccoli Enteral nutrition products contain Vitamin K. Warfarin activity drops when nutrition given Study shows warfarin binds to protein at pH 8

53. Warfarin Binding pH 8 is not physiological This drug binds to plastic It adheres to feeding tube It binds to protein once absorbed, but not in the stomach at pH 1.2

54. Vitamin C – Ascorbic Acid High doses advised for flu and ills Limited absorption dependent on concentration. More ingested = lower percent absorbed Higher levels produce faster excretion High excretion will continue after high doses stopped

55. Tigacycline Structurally similar to tetracycline Tetracycline is inactivated by metal Is tigalcycline affected? Being studied now

56. Aluminum Found in many drugs as a contaminant Evaluating impact on stability FDA attempting to legislate changes in amount Causes bone loss, Alzheimer's? Linked to calcium injection

57. MAOI Sensitivity to tyramine – causes hypertension Some antidepressants (new patch), antibiotics, chemotherapy Found in cheese , Chianti and beer

58. Steroids – Nutrition issues Patient education essential Increased loss of electrolytes (K) retention of Na. Increased glucose level GI irritation Slowly taper off

59. THANKS FOR LISTENING