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Counseling onDrug-Induced Nutrient Depletions

By Ross Pelton, R.Ph, Ph.D., CCNScientific Director: Essential Formulas

author ofa) Drug-Induced Nutrient Depletion Handbookb) The Nutritional Cost of Drugs

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Counseling onDrug-Induced Nutrient Depletions

This presentation has been accredited by ACPE for pharmacists & technicians:ACPE 0154-0000-17-018-L01-PACPE 0154-0000-17-018-L01-T

Ross Pelton has not disclosed any financial or conflicts of interest in relation to this program

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Goals & Objectives

• Be a better health educator and a more effective healthcare professional

• Win/Win: Improve patient’s health outcomes

• Be more financially successful

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Increased Sales(200 Rxs/day)

• Oral Contraceptives: 5 Rxs/day• Statins: 6 Rxs/day• Antibiotics: 15 Rxs/day• Metformin: 5 Rxs/day• GERD/acid suppressing drugs: 6 Rxs/day• Acetaminophen pain meds 15 Rxs/day • TOTAL: 52 Rxs/day

52 Rxs/day x 24 days/month x $20/sale$24,960 per month or $299,520/year

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Drug-Induced Nutrient DepletionsFemale Hormones: FA, B6, B1, B2, B3, B12, C, E, Mg, Se

Zn, tyrosine, CoQ10, DHEA, GSHAnticonvulsants: D, K, FA, CaAnti-diabetic Drugs: CoQ10, B12Anti-hypertensives: B6, CoQ10, Ca, Mg, K, Zn, Anti-inflammatory: Ca, K, Zn, Fe, B6, C, D, FA, KCholesterol-lowering: CoQ10Beta-blockers: CoQ10, melatoninPhenothiazines/Tricyclics: B2, CoQ10SSRIs/SNRIs/NDRIs,TCAs Tryptophan/5-HTP, tyrosine, p-alanine Benzodiazepines: MelatoninAcid-blocking medications: B12, FA, C, D, Ca, Mg, Fe, Zn, proteinAntibiotics: B-vitamins, vitamin K, Amino acidsPain meds/acetaminophen Glutathione

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Drug Side Effects• New Rx: nausea, vomiting, rash, etc.• Drug-induced nutrient depletions: gradual

onset; often overlooked • Oral contraceptives (B12, FA, Mg, CoQ10)

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Oral ContraceptivesOral contraceptives deplete more nutrients than any other

class of commonly prescribed drugs

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Female Hormone Medications

Oral contraceptives: deplete B1, B1, B2, B3, B6, B12,C, CoQ10, Mg, Se, Zn, tyrosine, DHEA, GSH

Estrogen replacement therapy (ERT & HRT): deplete B6, Mg, CoQ10

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Nutritional Effects of Oral Contraceptive Use: A Review

• Enovid introduced in May 1960• “After 2 decades of use, concern about the

nutritional status of women consuming OC prompted this review: OC shown to depress levels of vitamins B2, B6, B12, C, folic acid, Zn."

J. L. Webb, Nutritional Effects of Oral Contraceptive Use: A Review J Reprod Med 25(4) (Oct 1980) : 150-56.

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Folate Depletion withOral Contraceptive Use

Folate deficiency problems:• Birth defects• Cervical dysplasia• ↑ Homocysteine = ↑ cardiovascular disease risk• Anemia: weakness, low energy• Depression• ↑ breast and colorectal cancer

Drugs That Deplete Folic Acid

• Oral Contraceptives

• Anti-convulsants for epilepsy

• Antibiotics

• Metformin/Glucophage for diabetes

• Potassium-sparing diuretics: Dyazide, triamterene

• Anti-inflammatory drugs; steroids, NSAIDS (Motrin/ibuprofen, etc)

• All acid-suppressing/GERD drugs: Tagamet, Zantac, Pepcid, Prilosec, Prevacid

• Chemotherapy

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Vitamin B-6 Depletion with Oral Contraceptive Use

• Reduced synthesis of serotonin and melatonin; elevated homocysteine/plaque

• Symptoms: depression, anxiety, decreased libido, impaired glucose tolerance

• Therapy: 40 mg B6/day restores biochemical values and relieves clinical symptoms

Bermond P. Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol 1982;4(1-2):45-54

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Oral ContraceptivesB6 & Depression

• 30 women using OCs for 2-5 years (none with depression) 10 of 30 (1/3) developed depression.

M. Shaarawy, et al., Serotonin metabilism and depression in oral contraceptive users. Contraception 26(2) (Aug1982) : 193-204.

• In 9 of 12 clinical trials: depression occurs in 16-56% of women using oral contraceptives.

GB Slap. Oral contraceptives and depression: impact, prevalence and cause.J Adolescent Health Care 1981 Sept;2(1):53-64

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Women & Depression

Many more women are depressed than men • A literature review spanning 33 years from 1966-1999 reported

that depression occurs twice as often in women than in menOkiishi CG, et al. Gender differences in depression associated with neurologic illness: J Gender Specific Medicine 2001;4(2):65-72.

• A study sponsored by the World Health Organization (WHO) reported that depressive disorders occur from 1.5 to 3 times more frequently in women than men

Ustun TB. Cross-national epidemiology of depression and gender. J Gender Specific Medicine 2000 Mar-Apr;3(2):54-8.

Vitamin B-6 / pyridoxine• Vitamin B-6 is required for the conversion of 5-HTP to serotonin

•Drugs that deplete B-6; birth control pills, hormone replacement therapy, loop diuretics (Lasix/furoseminde), corticosteroids (prednisone)

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Oral Contraceptives Deplete Tyrosine

• Precursor for synthesis of dopamine & norepinephrine

• Dopamine/norepinephrine neurotransmitter pathways are critical for overall mental & emotional health

Moller SE, et al. Tyrosine metabolism in users of oral contraceptives. Life Sci. 1995;56(9):687-95.

Nutrient Precursors / CofactorsRequired for Neurotransmitter Synthesis

Serotonin Pathway DopamineNorepinephrine

Iron Folic AcidCalcium IronFolic Acid Vitamin B-6 MagnesiumVitamin B-6 Vitamin B-6

MagnesiumVitamin B-6Vitamin C Vitamin CMagnesium CopperZinc

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Drug-Induced Nutrient Depletions & DepressionNeurotransmitter Precursors / Cofactors

Female Hormones: FA, B6, B1, B2, B3, B12, C, E, Mg, (birth control pills & HRT) Se, Zn, Co Q10, DHEA, tyrosineAnticonvulsants: D, K, FA, CaAnti-diabetic Drugs: CoQ10, B12Anti-hypertensives: B6, CoQ10, Ca, Mg, K, Zn, Anti-inflammatory: Ca, K, Zn, Fe, B6, C, D, FA, KCholesterol-lowering: CoQ10Beta-blockers: CoQ10, melatoninPhenothiazines/Tricyclics: B2, CoQ10Benzodiazepines: MelatoninAnti-acid/GERD meds: B12, FA, D, Ca, Fe, Zn, proteinAntibiotics: B-vitamins, vitamin KChemotherapy: Destroys GI/most nutrients depleted

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OCs: Weakened Immune SystemKey antioxidants depleted by oral contraceptives• Vitamin C• Vitamin E• Selenium• Zinc• Coenzyme Q10• Glutathione

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Estrogen Replacement TherapyERT or HRT

• Vitamin B6

• Magnesium

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Increased Need for Magnesium with the Use of Combined Oestrogen and Calcium

for Osteoporosis Treatment• “Prophylactic treatment of postmenopausal osteoporosis

with oestrogen and calcium, often in combination, disregards the likelihood that an excess of each agent may increase magnesium requirements and decrease magnesium levels.”

• Low Mg = increase in thromboembolic cardio & cerebrovascular events.

Seelig, MS. Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment. Magnesium Research 3(3) (Sept 1990) : 197-215.

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• If magnesium is depleted, bone stores contribute magnesium to the extra cellular fluid

• “The serum magnesium can be normal in the presence of intracellular magnesium depletion; the occurrence of a low serum level usually indicates significant magnesium deficiency.”

S. M. al-Ghamdi, Magnesium Deficiency: Pathophysiologic and Clinical Review Am J Kidney Disease 24(5) (Nov 1994) : 737-52.

Magnesium Deficiency: Pathophysiologic and Clinical Review

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Blood Pressure Meds

Hydralazine: B6, CoQ10Loop: Ca, Mg, K, Zn, B1, B6, CThiazides: Mg, K, Zn, CoQ10Potassium-sparing: Ca, Zn, FABeta-blockers: CoQ10, melatoninClonidine/Methyldopa: CoQ10ACE: ZnChlorthalidone: Zn

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Loop Diuretics & Thiazide Diuretics: Magnesium depletion & Heart Attacks

• Low magnesium ↑ risk of sudden cardiac death• Only 1% of magnesium is in bloodEisenberg M., Magnesium deficiency and sudden death. Am Heart Journal. 1992; 124(2):544-549.

Al-Ghandi SM. Magnesium deficiency: pathophysiologic and clinical overview.Am J Kidney Dis. 1994 Nov;24(5):737-52.

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CoQ10

• Propranolol: Decrease CoQ10-succinoxidase and CoQ10-NADH-oxidase

• Metoprolol, HCTZ, hydralazine and clonidine inhibit CoQ10-NADH-oxidase

• Methyldopa: weak succinoxidase inhibitor

H. Kishi, T. Kishi, K. Folkers, Bioenergetics in Clinical Medicine. III. Inhibition of Coenzyme Q10-enzymes by Clinically used Anti-hypertensive Drugs. Research Communication Chemical Pathology Pharmacol 12(3) (Nov 1975) : 533-40.

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Cholesterol LoweringDrugs

HMG-CoA ReductaseInhibitors “Statins”: deplete Coenzyme Q10

The “fibrates”: depletes B12, E, Cu, Zn

Gemfibrozil: depletes CoQ10, E

Bile Acid sequest: depletes A, D, E, K, B12, Ca, Mg, P, Zn, Fe, Folic Acid, beta-carotene, fat

Statins: How They Work• Statins inhibit an enzyme named HMG-CoA reductase

(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase)

• This prevents/reduces synthesis of cholesterol in the liver

• Blocking HMG-CoA reductase also blocks synthesis of CoQ10

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Co Q10: 2 main functionsa) lipid soluble antioxidant

b) required for mitochondrial energy production

New Theory of Aging: Professor Anthony LinanneMitochondrial DNA (mDNA) damage

Linnane A. Human aging & global function of coenzyme Q10. Ann NY Acad Sci 2002 April; 959: 396-411.

Coenzyme Q10

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1) K. Folkers, et al., Lovastatin Decreases Coenzyme Q Levels in Humans. Proc Natl Acad Sci USA 87(22) (Nov 1990) : 8931-34.

2) S. A. Mortensen, et al. Coenzyme Q10: Clinical Benefits with Biochemical Correlates Suggesting a Scientific Breakthrough in the Management of Chronic Heart Failure. Mortensen, et al., Int J Tissue Reactions12(3) (1990) : 155-62.

3) G. Ghirlanda, et al., Evidence of Plasma CoQ10-lowering Effect by HMG-CoA Reductase Inhibitors: A DB PC Study. J Clin Pharmacol 33(3) (March 1993) : 226-29.

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Mortensen: Dose-related CoQ10 Decline• CoQ10, an essential mitochondrial redox-

component; endogenous antioxidant packaged into LDL and VLDL fractions of cholesterol; and it is an important protector against atherosclerosis

• 45 hypercholesterolemic patients DB, 18 weeks; lovastatin (20-80 mg/d); pravastatin (10-40 mg/d)

• Significant dose-related decline in serum CoQ10• Pravastatin:1.27 to 1.02 mmol/l = - 19.7%• Lovastatin: 1.18 to 0.84 mmol/l = - 28.8%

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Ghirlanda: HMG-CoA RI Lower CoQ10 • DB PC trial: 2 groups of 5 healthy subjects

and 30 hypercholesterolemic patients

• Pravastatin or simvastatin 20mg/day x 1 mo.

• Results: in both healthy and hypercholesterolemic patients there was a 40% reduction in total cholesterol and a corresponding 40% reduction in CoQ10

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Coenzyme Q10: Clinical Benefits with Biochemical Correlates Suggesting a Scientific Breakthrough in the

Management of Chronic Heart Failure

• Patients with myocardial failure have lower CoQ10 and CoQ10 deficiency increases with increasing symptoms

• CoQ10 100mg/day: 69% cardiomyopathy and 43% ischaemic heart disease good clinical response

• “Results suggest that CoQ10 is a novel and effective breakthrough in heart failure therapy & no side effects”

S. A. Mortensen, et al., Int J Tissue Reactions 12(3) (1990) : 155-62.

Statins:Cardiovascular Side Effects

Low levels of CoQ10:

• Weakens the heart musclePiquereau J, et al. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? Front Physiol. 2013; 4: 102.

• Increase in congestive heart failureMortensen SA, Coenzyme Q10: clinical benefits with biochemical correlates suggest a scientific breakthrough in the management of chronic heart failure.Int. J. Tissue Reactions 1990;12(3):155-62.

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Treatment of Essential Hypertension with Co Q10• 109 patients: 80 % of patients average time

of diagnosis over 9.2 years

• Average dose = 225 mg/day added to their existing antihypertensive medications

• 51% of patients were able to completely discontinue from 1 to 3 medications within the first 6 months (average time 4.4 months)

Langsjoen P, et al. Treatment of Essential Hypertension with Co Q10. Molecular Aspects of Medicine 1994; 15 Suppl: S265-72

Cardiovascular Drugs ThatDeplete Coenzyme Q10

1. Statins2. Thiazide diuretics (HCTZ)3. Hydralazine vasodilators 4. Adrenergic agonists (clonidine, methyldopa)5. Beta-blockers (propranolol, atenolol, etc… over 20)

Other drugs depleting CoQ10: OCs, HRT, Sulfonylureas & Biguanides, Tricyclic antidepressants (Elavil + others), Major tranquilizers (Thorazine, Haldol, + others)

Dose: 200-400 mg/day/largest meal/fat for enhanced absorption

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Anticonvulsants

Barbiturates: Vitamins D, K, FA, Biotin, CaDilantin: Vit.D, K, FA, B12, B1, Biotin, CaTegretol: Vitamin D, FA, BiotinMysoline: Vitamins D, K, FA, Biotin, CaDepakane: FA, Carnitine, Cu, Se, Zn

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AnticonvulsantsFolate & Pregnancy• Serum &red cell folate:50 non-pregnant and 46 pregnant epileptic women (49 pregnancies)

• All women: serum and red cell folate inversely related to plasma levels of Phenobarb and Dilantin

• 10 abnormal (20.4%): 4 spontaneous abortions (8.2%) and 6 congenital malformations (12.2%)

• Folate significantly lower in abnormal outcomes

Dansky LV, et al Anticonvulsants, Folate Levels, and Pregnancy Outcome: A Prospective Study. Annals of Neurology 21(2) (Feb 1987) : 176-82.

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Anti-diabetic Drugs

Sulfonylureas: CoQ10

Biguanides:CoQ10, B1, B12, FA

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Malabsorption of Vitamin B12 and Intrinsic Factor Secretion during Biguanide Therapy

• 46 diabetic patients: 30% had malabsorption of vitamin B12• Withdrawal normalized absorption in only half of those with

malabsorption• Biguanides can induce malabsorption by 2 different

mechanism:a) one is temporary and unrelated to intrinsic factorb) the other causes permanent ↓ in intrinsic factor secretion

Recommend sublingual methylcobalamin or IM injections

J. F. Adams, et al., Diabetologia 24(1) (Jan 1983) : 16-18.

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Psychotherapeutic DrugsPhenothiazines: deplete B2, CoQ10, melatonin

Tricyclics: deplete B2 & CoQ10Phelelzine (MAOI): deplete vitamin B6Haloperidol: deplete CoQ10, vit. E, melatonin Lithium: deplete inositol

SSRIs: deplete sodium, melatonin, tryptophan

SNRIs, NDRIs, NRIs RIs deplete amino acid precursors

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Antidepressants Deplete Amino Acids

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GERD &Acid-Suppressing Drugs

H-2 Receptor Antagonists: B12, folic acid, vit. DCa, Fe, Zn (protein)

Proton Pump Inhibitors: B12, C, Ca, Mg, Fe, Zn,(protein)

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Acid Suppressing/GERD Drug Depletions

• Bradford GS, Taylor CT. Omeprazole and vitamin B12 deficiency. Ann Pharmacother. 1999 May;33(5):641-3.

• Saltzman JR, et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am College Nutr. 1994; 13(6):584-91.

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Anti-inflammatory Drugs

Corticosteroids: Vit A, C, D, B6, B12, FA, Ca, Cr Mg, K, Se, ZnSulfasalazine: Folic acid

Indomethacin: Folic acid, iron

Colchicine: Vit B12, Ca, Na, K, P, B-carotene

NSAIDS: Folic acid, melatonin, microbiome

Salicylates: Vit C, FA, B5, Ca, Fe, Na, K

The Microbiome:New Frontier In Medicine & Healthcare

• Common rice plant Oryza sativa has 45,000 genes• Over 99% of your DNA is bacterial

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Microbiome-Disrupting Drugs

• Antibiotics• Proton Pump Inhibitors• H2 Blockers• NSAIDs• Corticosteroids• Chemotherapy Drugs• Estrogen-containing meds (OCs & HRT)

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• Probiotics produce B-vitamins, vitamin K, & aromatic amino acids (tryptophan, tyrosine & phenylalanine)

• Beneficial bacteria produce proteases, lipases, lactase that aid in digestion of food & absorption of nutrients

• Dysbiosis causes inflammation which further disrupts digestion and absorption of nutrients

Microbiome-Disrupting DrugsDysbiosis

Nutrient Depletions

DNA Gene Sequencing Technologies

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Human Microbiome ProjectThe New Frontier in Medicine

• 2007-2012 ($115M; 200 scientists/80 institutions)

• Our 100 trillion bacteria: not passive passengers; they are active participants directing & controlling much of our life

May 2016Funded with $521 million

$121million from US gov. $400 million from private institutions

The Discordant Identical Twin Study

Gordon JI, et al. Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice. Science Sept. 6, 2013:Vol. 341, No. 6150.

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Can Yogurt Cure depression?Psychology Today/April 2014

The Psychobiotic RevolutionThe Gut-Brain Connection

How gut bacteria control& influence moods,

emotions & state of mind

Revolution In Psychiatry

Postbiotics: Microbiome Revolution Diversity & Balance

• Probiotics: multi-strain

• Prebiotics: Feeding yourprobiotics

• Postbiotic Metabolites:Short-chain fatty acids (SCFAs)B-Vits, vit. K & amino acidsAnti-microbial peptides (AMPs)H2O2, antioxidants, fulvic acid,immune system, cell signaling

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Chemotherapy Drugs

• Most nutrients are depleted• Beneficial bacteria are killed• Cytotoxic drugs can cause:

– damage to gastric & GI mucosa/malabsorption– inflamed GI tract/painful, decreased appetite– nausea and vomiting– dysbiosis

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Glutathione Depletion (IDEAL) I = Immune system regulationDE = DetoxificationA = AntioxidantL = Lactobacillus fermentum ME-3

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Acetaminophen & Glutathione Delpetion

1) Depletes glutathione and cysteine in kidneys- 34%/young, - 58%/mature, - 64% old

24-hr recovery 95%/young, 98% mature, 56% old Richie JP, et al. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Biochem Pharmacol 1992 Jul 7;44(1):129-135

2) Depletes glutathione & catalase in liver; GSH 83% lower in 60 min.; increase in H2O2 & hydroperoxides, which causes cell/tissue injury

Amaiz SL, et al. Oxidative stress by acute acetaminophen administration in mouse liver. Free Radical Biology & Medicine 1995 Sept;19(3):303-310

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Acetaminophen & Liver Failure

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Keystone Strains

Sub-dominant StrainsOf Probiotic Bacteria

With Large Biological Effects

Lactobacillus fermentum ME-3A Glutathione-Producing Probiotic

• Isolated 1995 from GI track/healthy 1-year old child

• Boosts glutathione via 3 mechanisms

• Glutathione/Master Antioxidant & Master Detox Agent

• Produces MnSOD & increases paraoxonase activity

• Human clinical trials: 49% increase in GSH/GSSG and 26% increase in total antioxidant activity

Boosting Glutathione LevelsGlutathione: BioMarker of Aging

Glutathione is not effective orally

Glutathione nutritional precursorsNAC, lipoic acid, selenium, milk thistle

Liposomal delivery system (better)

Lactobacillus fermentum ME-3 (exceptional)

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Questions & Discussion