1. Drug nutrient depletion: The obvious but sometimes not so obvious root cause Dr Ivy Branin, ND Simplicity Health Associates

2. Learning Objectives  Which commonly prescribed medications deplete nutrients?  What are the nutrient depletions associated with these medications?  Signs and symptoms that patients might present due to these deficiencies  The mechanism by which certain nutrients are depleted  How to supplement nutrients appropriately while patients are on the medication

3. Drug-Nutrient Depletion

6. Antacids and Proton Pump Inhibitors (PPIs)

7. Antacids and PPIs Common Nutrient Depletions  Magnesium  Calcium  Iron  Zinc  Vitamin B12  Vitamin C

8. Antacids and PPIs Deficiency Signs and Symptoms  Calcium: increase risk of hip fracture, muscle cramps, insomnia, tetany  Iron: fatigue, dysphagia, cough, brittle nails, poor immunity  Magnesium: muscle weakness and cramping, tremors, apathy, confusion, nausea  Zinc: dermatitis, diarrhea, apathy, depression, male fertility problems, poor immunity, hair loss  Vitamin B12: asthenia, peripheral neuropathy, edema, spinal chord degeneration, gait disorders, falls, depression, dementia  Vitamin C: bleeding gums, hair loss, easy bruising, poor wound healing, joint pain

9. Antacids and PPIs MOA Calcium  Gastric acid secretion can facilitate Ca absorption  An acidic environment in the stomach facilitates the release of ionzed Ca from insoluble Ca salts  Ca is thought to be absorbed in ionized form primarily in the upper small intestine  PPI use >6 years was associated with a 92% increase in all fractures and PPI use >5years with a 62% increase in hip fractures  Note: Limited experimental evidence indicate that PPIs may also potentially affect bone resorption by inhibiting the osteoclastic proton transport system, and this affect may ameliorate the negative affect of PPIs increasing osteoporosis by decreasing Ca absorption

10. Antacids and PPIs MOA Iron  Non-heme Fe’ s absorption is markedly improved by gastric acid.  Gatric acid helps the non-heme Fe containing food sources to dissociate Fe salts  Helps to solubilize the iron salts which allows them to be reduced to the ferrous state, which allows the formation of complexes with ascorbate, sugars and amines which in term, facilitates absorption  PPI administration for 7 days decreased non-heme Fe absorption from a meal, and long-term PPI use resulted in a significant reduction (P<0.01) in the yearly volume of blood that needed to be removed to keep body Fe stores at the appropriate level

11. Antacids and PPIs MOA Magnesium  MOA of the PPI induced hypomagnesemia is not clear  Most likely due to gastrointestinal magnesium loss  Decreased luminal pH in the intestine may alter the affinity of the transient receptor potential melastatin-6 and transient receptor potential melastatin- 7 (TRPM6/7) channel for Mg2+, reducing active transport of Mg2+  Severe hypomagnesemia is seen in use longer than 8 years

12. Antacids and PPIs MOA Zinc  PPIs might reduce absorption of zinc from supplements, but PPIs don't seem to affect zinc absorption from food  Studies support reduced zinc absorption only when there a reduction in acid secretion  In some studies looking at zinc levels without supplementation, PPI users have had lower plasma zinc levels in comparison to controls  Zinc needs gastric acid and proteases (also nucleases) to hydrolyze Zinc from attachment to protein and nucleic acid

13. Antacids and PPIs MOA Vitamin C  PPIs reduce bioavailability of vitamin C from food  Patients with elevated intragastric pH because of spontaneous hypochlorhydria or PPI therapy have been shown to have markedly lowered concentrations of AA and total vitamin C in their gastric juice  Low concentrations of vitamin C in gastric juice of high pH is not fully understood  Vitamin C is unstable at neutral or high pH  The reduced form of Vitamin C (DHAA) can be readily hydrolysed to 2,3-diketogulonic acid at pH > 4  The body cannot regenerate vitamin C from 2,3-diketogulonic acid and thus this reaction results in loss of the bioactive form of Vitamin C  Some of the ingested vitamin C will be irreversibly denatured in the stomach before reaching the small intestine for absorption.

14. Antacids and PPIs MOA Vitamin B12  Gastric acid secretion is needed for B12 absorption from foods  Gastric acid is needed for the pancreatic proteases to cleave the B12 from the protein, allowing its reassociation with intrinsic factor and eventual absorption in the terminal ileum  In short-term studies various acid suppressants (histamine H2-receptor antagonists, PPIs) have been reported to decrease the absorption of B12 from foods, but not to decrease absorption of crystalline B12 which is not protein bound

15. Antacids and PPIs Supplement requirements  Ca: 1000 mg (citrate form)  11 achlorhydric subjects who in the fasting state demonstrated impaired absorption of a calcium carbonate gelatin capsule but normal absorption of a calcium citrate solution  Fe: 15 mg  A case report of two anemic patients who failed to respond to oral iron treatment while taking a PPI, but whose iron status improved when the PPI was withdrawn  Mg: The hypomagnesemia resolved when the PPI therapy was stopped and recurred if the PPI therapy was re-introduced  Zn: 25-50mg (picolinate form)  Vitamin B12: 200 mcg  8 weeks of VB12 nasal spray (500mcg/once per week), there was a significant increase in serum VB12 levels compared to pretreatment in the chronic PPI users, and a significant decrease in the frequency of VB12 deficiency in the chronic PPI uses  Vitamin C: 1000mg tid or to bowel tolerance

16. Diabetic Medications

17. Diabetic Medications Common Nutrient Depletions  Vitamin B12  Folate  CoQ10 ?

18. Diabetic Medications Deficiency Signs and Symptoms  Vitamin B12 see previous slides  Folate: megablastic anemia, glossitis, graying hair, ulcers, poor memory, birth problems  CoQ10: rhabdomyolysis, fatigue, angina, cardiomyopathy, hypertension, stroke, cardiac dysrrhythmias, loss of cognitive function

19. Metformin MOA Vitamin B12  Patients treated with Metformin for 16 weeks were shown to have a 14% decrease in Vitamin B12  Several mechanisms have been proposed by which metformin causes vitamin B12 deficiency.  Alterations in the motility of the small intestines,  Bacterial overgrowth  Alteration in the calcium-dependent uptake of B12–intrinsic factor complex at the ileum  Rosiglitazone has not shown to decrease B12

20. Metformin MOA Folate  Patients treated with Metformin for 16 weeks were shown to have a 7% decrease in Folate  Mechanism is unkown  Decrease in intestinal absorption  Possibly due to lower B12 levels  Vitamin B12 removes a methyl group (CH3) from tetrahyrofolate (THF)  If this doesn’t occur folate is trapped in cells and is unable to support DNA synthesis and cell growth

21. Metformin MOA CoQ10  No definitive studies supporting deficiency or mechanism of depletion by metformin  Studies have shown metformin’s suppression of hepatic glucose output is accompanied by the inhibition of complex 1 of the mitochondrial electron transport chain  Demonstrated by inhibition of mitochondrial oxidation of malate and glutamate, but not succinate  CoQ10 is the product of complex 1 Figure 21.1 P 380 Marks_ Basic Medical Biochemistry A Clinical Approach, 2nd Edition - Colleen Smith

22. Metformin Supplement requirements  Vitamin B12: 800-1000 mcg  Calcium 1200 mg/day may decrease the severity of B12 deficiency  Treatment with oral vitamin B12 appears to reverse the deficiency within 2–3 months  Folate: 400 mcg  CoQ10: 100mg 

23. Antidepressants & Anxiolytics

24. Anti- depressants & Anxiolytics Common Nutrient Depletions  Vitamin B2  Vitamin B6  Inositol  Vitamin D  CoQ10

25. Anti- depressants & Anxiolytics Deficiency Signs and Symptoms  Riboflavin: Pellagra (4Ds= dermatitis, diarrhea, dementia, death)  Vitamin B6: irritability, depression, mouth ulcers, peripheral neuritis, dermatitis, seizures  Inositol: hair loss, memory loss, eczema, psoriasis, constipation, atherosclerosis

26. Tricyclic Anti- depressants MOA Riboflavin  Tricyclic antidepressants have shown to alter various aspects of flavin metabolism  The phenothiazine ring of chlorpromazine and the isoalloxazine ring of riboflavin have a number of structural features in common and have been shown to form a molecular complex in vitro  Inhibited riboflavin transport in small intestine and colon  Enhanced urinary riboflavin excretion  Accelerated depletion of tissue stores of flavin adenine dinucleotide  Reduced hepatic flavin stores

27. Tricyclic Anti- depressants MOA CoQ10  Tricyclic antidepressants can interfere with NADH- oxidase and succinoxidase, coQ10 enzymes, and may induce coQ10 deficiency  These actions may contribute to well-known association with cardiac adverse side effects

28. MAO Inhibitors MOA B6  Phenelzine (Nardil) may act as a pyridoxine antagonist by reacting with PLP to form metabolically inactive hydrozone compound and could reduce blood levels of vitamin B6.  Administration of B6 reported to reverse drug-induced effects such as neuropathy.

29. Benzo- diazepines MOA Vitamin D  Some studies show that benzodiazepines may increase Vitamin D catabolism  May inhibit cellular response to parathyroid hormone

30. Lithium MOA Inositol  Depletion of inositol brain stores through inhibition of inositol monophosphatase, the enzyme that returns inositol monophosphate back to myo-inositol  Inositol can reverse adverse effects such as psoriasis and polyuria-polydipsia syndrome

31. Anti- depressant & Anxiolytics Supplement requirements  Riboflavin: 10mg for patients on TCAs  Should be co-adminstered with B1, B6 and B12  Vitamin B6:  Folate: 400 mcg  CoQ10: 100mg  Inositol: 3 g for lithium  Vitamin D: 1000-4000 IU for benzodiazepines 

32. Corticosteroids

33. Cortico- steroids Common Nutrient Depletions  Calcium  Magnesium  Chromium  Zinc  Selenium  Vitamin D

34. Corticosteroid Deficiency Signs and Symptoms  Selenium: muscle weakness, cardiomyopathy, hypothyroidism  Chromium: impaired glucose tolerance

35. Cortico- steroids MOA  Calcium: malabsorption of calcium, depletes calcium stores, increased renal loss  Magnesium: depletion and impaired absorption  Selenium: Oral corticosteroids have been found to increase urinary loss of selenium  Chromium: increased renal excretion  Zinc: Shift of zinc from the blood into the tissues and possibly increased loss in the urine.  Vitamin D: reduce body’s ability to activate vitamin D

36. Cortico- steroids Supplement requirements  Calcium: 1000-1,200 mg  Vitamin D: the active form of vitamin D as the prescription alfacalcidol has been shown to be superior as kidney activation is impaired  Magnesium: 250-400 mg  Selenium: 50-200 mcg  Chromium: 60 mcg has been shown to prevent corticosteroid induced diabetes  Zinc: 25-50 mg

37. Cardiovascular Medications

38. Cardio- vascular Medications Common Nutrient Depletions  B6: Hydralazine, loop diuretics  Folate: bile acid sequestrants, K sparing diuretics  Thiamine: loop diuretics  B12: bile acid sequestrants, fibrates  Fat soluble vitamins: bile acid sequestrants

39. Cardio- vascular Medications Common Nutrient Depletions  Calcium: loop diuretics  Magnesium: loop diuretics, thiazide diuretics  Zinc: ACE inhibitors, angiotensin-converting enzyme inhibitors, thiazide diuretics  CoQ10: Hydralazine, thiazide diuretics, HMG-CoA reductase inhibitors, β-blockers

40. Cardio- vascular Medications Deficiency Signs and Symptoms  Thiamin:  Beri-Beri (anorexia, weight loss, heart enlargement, paresthesias, muscle weakness, lassitude, foot drop, edema )  Wernicke-Korsakoff (paralysis of eye motor nerve, nystagmus, psychosis, impaired cognitive function)

41. Cardio-vascular Medications Loop diuretics MOA Thiamine  Furosamide doubles the rate of thiamine urinary excretion  Observational studies of patients receiving furosamide were severely deficient in thiamine.  Furosemide and digoxin were shown to inhibit thiamine uptake by cardiac cells in culture

42. Cardio- vascular Medications MOA B6  Hydralazine (vasodilator) complexes with pyridoxine to form a hydrazone and depletes the circulating pyridoxine.  Loop diuretics (furosemide) increases urinary excretion of B6 in chronic renal failure

43. Cardio- vascular Medications MOA B12  Bile acid sequestrants (BAS) impair absorption and reduce bioavailability.  BAS strongly absorb intrinsic factor-cyanocobalamin complex  Fenofibrates/fibrates impair absorption  Bind and activate peroxisome-proliferator activated receptors alpha causing hyperhomocysteinemia

44. Cardio- vascular Medications MOA Folate  Bile acid sequestrants impair absorption and reduce bioavailability.  K-Sparing Diuretics impair absorption and bioavailability  May act as a competitive inhibitor of folate intestinal absorption  May also decrease biologically active folates by acting as relatively weak folate antagonist through dose-related inhibitory effect on dihydrofolic reductase

45. Cardio-vascular Medications Loop diuretics MOA Calcium  Loop diuretics can cause excessive urinary Ca excretion and Ca depletion  Act by competing for the chloride site on the Na-K- 2Cl cotransporter  Inhibiting NaCl reabsorption also inhibits the backleak of K+ and the generation of the lumen- positive potential.  As a result, Ca excretion increases  Calcium excretion is diminished by thiazide diuretics and amiloride  Increases renal Ca reabsorption

46. Cardio-vascular Medications MOA Fat soluble vitamins  Bile acid sequestrants reduce fat absorption thus reducing absorption of fat soluble vitamins and nutrients  Vitamin A  Vitamin E  Vitamin D  Vitamin K

47. Cardio- vascular Medications MOA Zinc  Thiazide diuretics and angiotensin-converting enzyme inhibitors (ACE-I) cause excessive urinary Zn excretion and Zn depletion  ACE-Is contain a thiol radical (-SH) within the compound that can chelate serum Zn

48. Cardio- vascular Medications MOA Magnesium  Thiazide diuretics and loop diuretics cause excessive urinary Mg excretion and Mg depletion  Even short term thiazide use (1-3 weeks) has been shown to induce mild hypomagnesemia in some patients

49. Cardio- vascular Medications Supplement requirements  Folate: 400 mcg (K-sparing diuretics, bile sequestrants, fibrates)  5-MTHFR is recommended for K-sparing diuretics  Folate should be given 1 hour before or 4-6 after bile sequestrants  B6: 10-25 mg ( vasodilators, loop diuretics, fibrates)  B1: 320 mg (loop diuretics)  IV treatment of 200 mg daily may be required for 1 week prior to oral supplementation  B12: 200 mcg (fibrates, bile acid sequestrants)  Vitamin A: 20,000 IU (bile acid sequestrants)

50. Cardio- vascular Medications Supplement requirements (continued)  Magnesium: 1000 mg (bile acid sequestrants, K- sparing diuretics, loop diuretics, thiazide diuretics)  Calcium: 1,000 mg (bile acid sequestrants,K- sparing diuretics, loop diuretics) Avoid with thiazide diuretics  Iron: 15 mg (bile acid sequestrants)  CoQ10: 100-300 mg (fibrates, HMG-CoA reductase inhibitors, vasodilators, beta-blockers, K-sparing diuretics, thiazide diuretics)  Zinc: 25mg (ACE inhibitors, thiazide diuretics) 

51. Drug-Nutrient Depletion Resources  Handbook of Drug-Nutrient Interactions, Boullata, Joseph, Armenti, Vincent, Hardy, Gil  Drug-induced Nutrient Depletion Handbook, Pelton, Ross, LaValle, James B.  Nutritional Medicine, Gaby, Alan  Natural Medicines Comprehensive Database

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54. References 16Rubio-Luengo MA, Maldonado-Martín A, Gil-Extremera B, González-Gómez L, Luna del Castillo JD. “Variations in magnesium and zinc in hypertensive patients receiving different treatments.” Am J Hypertens. 1995 Jul;8(7):689-95. 17Zumkley H, Bertram HP, Vetter H, Zidek W “Zinc metabolism during captopril treatment.” Horm Metab Res. 1985 May;17(5):256-8 18Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. “Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.” J Clin Invest. 2005 Jun;115(6):1651-8. 19Morrow LE, Grimsely EW. Long-term diuretic therapy in hypertensive patients: effects on serum homocysteine, vitamin B6, vitamin B12, and red blood cell folate concentrations. Southern Medical J1999;92:866–870 20Kishi H, Kishi T, Folkers K “Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10-enzymes by clinically used anti-hypertensive drugs.” Res Commun Chem Pathol Pharmacol. 1975 Nov;12(3):533-40. 21Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. “Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine.” Dig Dis Sci. 1985 May;30(5):477- 82. 22Koren-Michowitz M, Dishy V, Zaidenstein R, Yona O, Berman S, Weissgarten J, Golik A. “The effect of losartan and losartan/hydrochlorothiazide fixed-combination on magnesium, zinc, and nitric oxide metabolism in hypertensive patients: a prospective open-label study.” Am J Hypertens. 2005 Mar;18(3):358-63.

55. Question?