1. Most Common Drugs that
Cause Nutrient Depletions
Presented at: Dilworth Drug & Wellness Center
Joseph Helms
Wingate University School of Pharmacy
2. Objectives
• List drugs that cause, discuss the pathophysiology, and signs and
symptoms of Drug Nutrient Depletions
• Discuss Treatment and Treatment Benefits of Drug Nutrient
depletions including counseling points, commonly discussed drug-
drug interactions, cost, storage, and kinetics
• Describe the Natural Role of Drug Nutrient Depletion Treatments in
the Body
• Discuss Relevance of this Information to Dilworth Drug and to
Patients
• Summarize Conclusions & Important Takeaways
3. Epidemiology
• 4.27 billion prescriptions are estimated to be filled in 2016
• 262.5 million courses of antibiotics written in the U.S. (50% may have
not been appropriate)
• 119 million prescriptions for Proton Pump Inhibitors (now available
Over-The-Counter) in 2009
• 16% of women aged 15-44 are using “the pill;” 7.2% are using long-
acting contraception (IUD or contraceptive implant)
• From 2003-2012 the use of statins increased from 18% to 26%; 42%
of the patients used simvastatin; 17% of adults aged 40-59 used a
statin whereas 48% of adults age > 75 used a statin
• 259 million prescriptions written for painkillers in 2012
All sources of statistics listed in beginning of other References
4. General Risk Factors for Drug-
Nutrient Depletions
•Elderly
•A higher dose of the medication; sometimes
physicians will increase the dose of a medication
thinking it has benefit, but the additional dose
provides no benefit to the patient, and will ultimately
deplete the patient of nutrients
•Longer duration of use of the medication
•Taking multiple medications that have high risk for
causing drug-nutrient deficiencies
5. Common Reasons Patients Do Not Take
Supplements or Take Low Quality Supplements for
Nutrient Depletions
• “I already have a probiotic.”
• “I believe I will hold off on that today.”~cost of the supplements
• “I already have some CoQ10. I haven’t taken it in a while.”
• “I don’t have a B12 deficiency, so why do I need to supplement with it?”
• “I don’t like that it’s a liquid. Do you have it in a tablet?”
• Patients may not think it will work
• Patients may fear that because they are already taking a supplement that by taking
another supplement they may experience toxicity, as well as fear they are taking the
wrong dose
• Patients may think that “feeling bad” as you age is normal (healthy aging is
preferred)
• Patients may not feel they are educated on supplements, and are afraid to ask
• Patients may not understand the cost-savings benefit that living a healthier lifestyle
may have
6. Common Concerns/Questions from
Providers
• “There have been minimal to no studies to show that supplements
are effective. So why would the patient waste their money on this?”
• “The supplement may interact with the patient’s medications.”
• “Do these supplements correlate with improvement of quality of life
for the patient?”
• Providers may not know where patients are purchasing supplements
from, and may be afraid to recommend supplements (even if know
pharmacy where patient is getting prescriptions)
7. Our Job as a Team & Opportunities
• Recognize the common drug-nutrient depletions
• Communication: Remind other team members of drug nutrient depletions
when possible
• Discuss the drug-nutrient depletion with the patient
• Readily be able to find product on the shelf, and know what’s in stock
• Be able to provide patient basic information about drug-nutrient depletion,
while being able to provide some information that will “Wow” the patient
• Be able to discuss with patient why products we sell are of the highest
quality
• If concerned about drug interactions or other concerns about supplement
can set up consultation with Josh
8. Knowledge & Customer Service
• If do not have basic knowledge of supplement, then it is much harder to
communicate to the patient why the supplement may help them
• Must be expressed on patient level, and in way that catches patient’s attention
• Opportunity: Can refer patients to Josh for a consultation
• “CoQ10 may improve muscle pain caused by statins.”
• It is necessary to know when a patient should be on a supplement due to a
drug nutrient depletion, and there are also other opportunities that may
be used to improve a patient’s overall health that may need to be taken
into consideration
• Opportunity: Must remember that most physicians/providers have very
little time to spend with patients, and have to treat the patients’ most
acute problems
• Can make patients feel that at pharmacy everyone is interested in their overall health
and well-being, because have time to spend with patients discussing all health
problems
9. Drugs That Cause Nutrient Depletions
Drugs that Cause Nutrient
Depletions
Antibiotics
Statins
Metformin
PPIs
Birth Control
10. Match the Drug with the Depletion
Depletion
“Good Bacteria”
CoQ10
Vitamin B12
Magnesium, Calcium, and others
Probiotics, Magnesium, Zinc, any B Vitamin,
Vitamin C
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways to Restore Them [Internet]. Rodale; 2011. Common Drug Muggers [cited 2015 October
12]; [p.91-92]. Available from: Amazon
Drugs that Cause Nutrient
Depletions
Antibiotics
Statins
Metformin
PPIs
Birth Control
11. Vitamins
Water-Soluble- Vitamins that are dissolved in
water, not stored in the tissues of the body
though they pass through the tissues of the
body, and must be taken every day; not as easy
to build up toxic levels as fat soluble vitamins
Fat-Soluble- Vitamins that are stored in fat in
the tissues of the body; easier to build up toxic
levels of these
-Known As ADEK
Vitamin B Vitamin A
Vitamin C Vitamin D
Vitamin E
Vitamin K
13. “The Solar System”
Metformin:
Vitamin B12
Birth Control:
Probiotics,
Mg, Zn, any B
Vitamin,
Vitamin C
Proton
Pump
Inhibitors &
Antacids:
Mg, Ca
Statins:
CoQ10
Antibiotics:
“Good
Bacteria”
Drug Nutrient Depleted State
Earth- “Where
no drug nutrient
depletion exists.”
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways to Restore Them
[Internet]. Rodale; 2011. Common Drug Muggers [cited 2015 October 12]; [p.91-92]. Available from: Amazon
14. “A Negative Plus A Negative Still Equals A…”
ACE
Inhibitors
Oral
Contraceptives
All May
Deplete
Good
Bacteria
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural
Ways to Restore Them [Internet]. Rodale; 2011. Common Drug Muggers [cited 2015 October 12]; [p.91-92].
Available from: Amazon
15. When Planets Collide in the “Black Hole?”
Metformin
Antibiotics:
(Especially
Chloramphenicol)
Oral
Contraceptives
All May
Deplete B
Vitamins
Metformin Statins
All May
Deplete
CoQ 10
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways
to Restore Them [Internet]. Rodale; 2011. Common Drug Muggers [cited 2015 October 12]; [p.91-92]. Available
from: Amazon
16. When Planets Collide in the Black Hole
(continued)
Proton
Pump
Inhibitors
/Antacids
Antibiotics Birth
Control
All May
Deplete
Magnesium
and
Calcium
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways to Restore Them [Internet].
Rodale; 2011. Common Drug Muggers [cited 2015 October 12]; [p.91-92]. Available from: Amazon
17. Possible Common Combinations of Drugs Patients
May Be Prescribed That Cause Depletions
Medications Depletions
Antibiotics, Metformin, & Glyburide All May Deplete B Vitamins (especially B12 for diabetic
medications)
Statins, Antidepressants (i.e., amitriptyline), Beta
Blocker, (i.e., atenolol, metoprolol) Calcium Channel
Blockers (i.e., nifedipine, verapamil, amlodipine),
Clonidine, Methyldopa, & Metformin
All May Deplete CoQ10
Proton Pump Inhibitor (i.e., omeprazole), Antibiotics,
ACE Inhibitors (i.e., lisinopril), Diuretics (i.e.,
furosemide), Colchicine, Oral Contraceptives,
Salicyclates (i.e., Aspirin), Medications for Thyroid (i.e.,
Synthroid, Armor), and Laxatives (i.e., Mineral Oil)
All May Deplete Magnesium and Calcium
Colchicine: Only Calcium
Oral Contraceptives: Especially Magnesium (when
taken with ACEI or Diuretic any may deplete Zinc)
Salicylates: Only Calcium
Thyroid Medications: Only Calcium
Mineral Oil: Particularly Calcium
Antibiotics & Oral Contraceptives “Good” Bacteria
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways to Restore Them [Internet]. Rodale; 2011.
Common Drug Muggers [cited 2015 October 12]; [p.91-92]. Available from: Amazon
18. Antibiotics Most Likely to Cause Diarrhea
Most Likely to Cause
Diarrhea
Diarrhea Type
Amoxicillin, Augmentin
(Amoxicillin/Clavulanate)
Ampicillin
Cefpodoxime (3rd generation
cephalosporin)
Cefixime (3rd generation
cephalosporin)
Clindamycin Clostridium difficile (bacteria) or
C. difficile
19. How Antibiotics Cause Diarrhea
• Antibiotics may cause a depletion of the “good bacteria” in
the small and large intestines which allows more room for
bad bacteria to grow
• There are approximately 40-100 trillion bacterial cells in the
body (though this number varies), and are found particularly
in the large intestine
• Commonly said bacterial cells would weigh 2-3 lbs.
• There are about 10-30 trillion human cells
• Up to 1000 different species of bacteria live in the large intestine
• However, 30-40 species of bacteria make up 99% of these species
20. How Antibiotics Cause Diarrhea
• Antibiotic-associated diarrhea often begins a week after start
taking the antibiotic, but the diarrhea may appear even up to
several weeks later
• Risk Factors: Past Medical History of Antibiotic Associated
Diarrhea, Long Duration of Therapy, and Polypharmacy
• Large part of immune system tissues are in same area the
Gastrointestinal tract
21. Antibiotic Associated Diarrhea
• Symptoms/Diagnosis:
• Watery Stools
• Loss of Potassium
• Increased Bowel Movements
• No pathogen identified (though cultures may not be reliable)
• Risk Factors: Use of Antibiotics, Immunocompromised, Elderly, Children,
Abdominal Surgery, Other Comorbidities, Decreased Gastric Acid (PPI), and
Length of Hospital Stay
• Prevalence: 3.2-29.0%, 14% in those who do not undergo treatment
• 10-20 % of these are from Clostridium difficile
• Clostridium Difficile:
• Anaerobic, Gram Positive Rod
27. Definitions & Facts
• “Gut”- refers to intestines when referring to body in biomedical language,
although sometimes may be referring to whole digestive tract
• GALT (Gut-Associated Lymphoid Tissue)- the largest part of the immune
system in the body; the large intestine is a part of this system
• Stomach (Sterile)--- small intestine (bacteria present)--- large intestine
(more bacteria present, and are usually anaerobic bacteria)
• pH of stomach= 1.5-3.5, pH of small intestine= 6-7.4, pH of large intestine=
5.5-7
• In general, “bad bacteria” (pathogenic bacteria) prefer a pH closer to 7
(though may range from 4.6-7.0)
• There is no particular recommended percentage of how much intestinal
bacteria should be “good” vs. “bad”
• Some of the “good” bacteria are lactic acid producing (i.e., lactobacillus)
28. Picture of Immune System & GALT
https://www.aids.gov/images/aids-infographics/immune-system101-2-1.jpg http://www.integrativepsychiatry.net/_uploaded_files/galt.png
29. Definitions & Facts
• The stomach could kill off bacteria, but bacteria may not sit in the stomach
for a long period of time and if keep filling diet with “bad bacteria” then
may be pushing those “bad bacteria” to colonize in large intestine
• Bacteria particularly inhabit the large intestine
• Definition for Customer and Employee Purposes
• Probiotic- means “good” or supportive bacteria
• Prebiotic- a source of nourishment (usually fiber) for bacteria that
already exist
• Are probiotics dead bacteria? No probiotics are living bacteria.
• Aggregation is a desired property of probiotics, because it allows the
probiotics to interact with the “bad” bacteria
30. Sources of Probiotics/Prebiotics for Human
Consumption
• Food Sources of Probiotics
• Yogurt, Sauerkraut (unpasteurized), Miso soup, Soft Cheeses, Kefir, Sourdough
Bread, Milk Containing Probiotics, Sour pickles (no vinegar in process),
Tempeh
• Food Sources of Prebiotics
• Asparagus, Jerusalem artichokes, bananas, oatmeal, redwine, honey, maple
syrup, and legumes
• Probiotics that are produced by manufacturers
• Prebiotics that are produced by manufacturers
31. Frequently Asked Questions (FAQs)
• Where do probiotics work?
• Particularly in the small and large intestines
• How many probiotics are needed to make a significant difference in the
number of good bacteria? There is no definitive answer to this, though
usually seems to be 10^6-10^9 cfu/mg/day (lower dose for small intestine
and higher dose in the large intestine)
• When do you need a higher dose of probiotic? For more acute infections
such as diarrhea
• Will the probiotics reach the site of action?
• Do probiotics create an environment easier for “good bacteria” to grow or
do they just “add” good bacteria to the gut?
32. Frequently Asked Questions (FAQs)
• Enteric coating of Probiotics?
• Why is it good to take probiotics even if not currently on antibiotics?
• More “good” bacteria already in intestines and digestive system before taking
antibiotic
• What if the patient is immuno-deficient? Controversial, but “good
bacteria” are needed to balance out the “good” vs. “bad” bacteria,
and play a role in activating the immune system; however, if severely
immunocompromised, American Family Physicians do not
recommend it, although they also say it is effective
• Adverse effects: Flatulence, and rarely sepsis
33. Benefits of Probiotics at the Cellular Level
• There needs to an appropriate balance of “good” vs. “bad” bacteria; exact
balance not calculated
• “Good bacteria” help make Vitamin K
• Help digest food
• Can stimulate the production of Peripheral Blood Mononuclear cells
• Regulatory T cells
• Specific uses for specific strains
• Gut bacteria produce some neurotransmitters: Serotonin, dopamine, and GABA
• Help strengthen linings of the digestive system
• It is speculated that the bad bacteria learn to feed off “fast foods,” while good
bacteria “like” to feed off of sources already mentioned, and this is part of
cravings
34. Importance of Fiber
• Fiber is what prebiotics are made of
• If do not have enough fiber, then the “bad bacteria” can sit in the
intestine which allows them to multiply in your intestine over time
• Fiber feeds the probiotics (good bacteria)
• Suggest that patient eat diet high in fiber or take pre-biotic
• Generally recommended to take in at least 25 grams of fiber per day
with water
• Soluble
• Insoluble
• In general, many bad bacteria feed off of sugar
35. General Characteristics of Effective Bacterial
Strains
• Has demonstrated safety & efficacy; none of the usual renal or
hepatic adjustments
• Resistance to acid, bile, pepsin, and pancreatin
• Adherence to the GI epithelial tissue
• Ability to store bacteria
• May enhance immune response by stimulating cytokines to come to
infected site
• If lactic acid bacteria this is generally good characteristic
• If has strains of pathogenic bacteria it targets, this is good
characteristic
36. Mechanisms of Action of Saccharomyces
boulardi
• Saccharomyces works by binding to glycoprotein receptor site (and
ingesting it) for Toxin A at intestinal brush border
http://8b7a91801591cac4b290-abbac3ca2ecec271a197a4cd05b43329.r61.cf3.rackcdn.com/saccharomyces-boulardii-purple.jpg
37. Importance of Different Bacterial Strains
Contained in Probiotics
• NCFM (North Carolina Food Microbiology; isolated at NC
State in the 1970s); strain of Lactobacillus acidophilus:
• Gram (+); found in intestine, mouth, and vagina; also found in kefir; has
excellent tolerance to acid, bile salt, and pancreatin, and very good
resistance to pepsin; has very good adherence to epithelial cell lines
38. Importance of Different Bacterial Strains
Contained in Probiotics
• HEAL-9 (Lactobacillus plantarum):
• Effective in reducing the risk of the common cold
• Lpc-37 (Lactobacillus paracasei):
• Gram (+); has excellent acid tolerance and excellent pancreatin
resistance; has fair bile salt tolerance and fair pepsin tolerance;
has excellent adhesion to epithelial cell lines; has excellent
inhibition of salmonella typhimurium, staphylococcus aureus,
Escherichia coli, and good inhibition of Listeria monocytogenes;
produces only L(+) Lactic acid; improves immune response as
related to cytokine IL-12 (improves more than L. plantarum); in a
5-strain formula restored the good bacteria in the GI
39. Importance of Different Bacterial Strains
Contained in Probiotics
• 8700-2 (Lactobacillus paracasei):
• Effective in reducing the risk of the common cold
• GR-1 (Lactobacillus rhamnosus):
• Prevents adhesion from “bad” bacteria and adhere to cells of vagina,
bladder, and intestine; due to acid production has antiviral properties
(i.e., can destroy HIV); has anti-inflammatory effect
• RC-14 (Lactobacillus reuteri):
• Prevents adhesion from “bad” bacteria and adhere to cells of vagina,
bladder, and intestine; due to acid production has antiviral properties
(i.e., can destroy HIV); may prevent surgical infections, particularly
caused by Staph Aureus
40. Importance of Different Bacterial Strains
Contained in Probiotics
• Ls-33 (Lactobacillus salivarius):
• Gram (+); has excellent acid tolerance, excellent bile salt tolerance, excellent
pancreatin tolerance, and very good pepsin tolerance; has overall excellent
adherence to epithelial cells; manufactures only L(+)-Lactic acid; improves
immune response as related to IL-10 (when compared to Lc lactis), and
stimulates IL-12 more than E. coli; has excellent activity against
Staphylococcus aureus, very good activity against Escherichia coli, and good
activity against Listeria monocytogenes and Salmonella typhimurium; anti-
inflammatory properties (animal studies)
• Bi-07 (Bifidobacterium lactis):
• Helps reduce bloating in patients with bowel disorders
• HN-019 (Bifidobacterium lactis):
• May decrease infant diarrhea caused by E. Coli or rotavirus
41. Importance of Different Bacterial Strains
Contained in Probiotics
• Lp-115 (Lactobacillus plantarum):
• may increase the lactic acid in the gut to kill the “bad” bacteria; great at degrading oxalate
(better than other strains of lactobacillus); Lactobacillus 115 has good activity compared to
other strains in inducing the secretion of IL-10 & IL-12; may help increase immune function
so patient can more easily receive vaccine; easily survives in the GI, because has high
tolerance to acid, bile, pepsin, and pancreatin; easily adheres to the intestinal mucosa which
means it is close to the intestinal immune system, which may affect the immune response
more and also keeps the “bad” bacteria from colonizing in the intestine
• St-21 (Streptococcus thermophiles):
• Does not “like” being outside of the refrigerator
42. Importance of Different Bacterial Strains
Contained in Probiotics
• Bi-04 (Bifidobacterium lactis):
• Gram (+); survives in the GI, because has tolerance to acidic
conditions and bile; has very good adherence to human epithelial
tissue; produces L(+)- lactic acid; rapidly restores bacteria after
antibiotic treatment; stimulates the immune system (IgG
induction)
43. What to Say to Customer Regarding Probiotics
• Cost: Saccharomyces boulardi: $8 for 14 count bottle; other prices
listed previously
• “The saccharomyces probiotic can be used in any age of children
though sprinkling it on food is probably best for infants. It is a
probiotic that is designed to be taken with the antibiotic. Most of the
bacteria in the body are located near the intestines, and most of the
immune system is located near the intestines. So it is important to
keep the bacteria in the intestines healthy. A healthy diet is also
important, because feeding the good bacteria is crucial to keep a
healthy balance in the digestive system. “Bad” bacteria feed off of
glucose. Good bacteria also help assemble neurotransmitters such as
serotonin, dopamine, and GABA. This can affect your mood.”
44. Studies: Results Summarized
• One review article indicated that the studies for the use of probiotics to
prevent Antibiotic Associated Diarrhea showed good data, but were not
powered (did not have enough people to show that the probiotics had a
favorable outcome on a rare condition). Because there are so many
different probiotics, because the probiotics used in the studies differ, and
because Antibiotic Associated Diarrhea is not a very common condition, it
makes it harder to conduct clinical trials. However, there also seems to be
little evidence that probiotics have any significant adverse effects. Also, it is
very difficult to quantify the favorable long-term effects of probiotics,
because they have been a product for only a short time. As the review
article mentioned, it is not known which populations except those taking
antibiotics have the most need for probiotics.”
45. What to Say to Provider Regarding Probiotics
• “It is good to recommend probiotics to your patient, because your GI
tract is next to 70% of the body’s immune tissue and the GI tract also
produces neurotransmitters as well which can affect cognitive
functioning. Studies have shown that probiotics have benefit in
patients, but it is difficult to find patients for these studies, because
Antibiotic Associated Diarrhea is reported as a rare condition
(probably because it is difficult to measure this in the outpatient
setting). Even if patients are not likely to develop antibiotic associated
diarrhea (which is what the saccharomyces would be used for), it is
better that patients take probiotics for their long-term health since
the GI system seems to be connected to so many different organ
systems in the body.”
46. Risk of Each Statin Causing Myopathy
High Risk of
Myopathy Statins
(Most Concern)
Intermediate to
Low Risk of
Myopathy
Low Risk of
Myopathy
Lovastatin
(Mevacor,
Altoprev)
Rosuvastatin
(Crestor)
Pravastatin
(Pravachol)
Simvastatin
(Zocor)
Fluvastatin
(Lescol)
Atorvastatin
(Lipitor)
Pitavastatin
(Livalo) (Newer, so
more data
possibly needed)
47. Reason Some Statins At Higher Risk of
Causing Myopathy
• Thought that hydrophilic (“water-loving”) statins such as
pravastatin, rosuvastatin, and fluvastatin are less likely to
cause myopathy, because theoretically they would not cross
the muscle tissue as easily as hydrophilic (“fat-loving”)
statins
• Lipophilic statins (“fat-loving”) include lovastatin,
simvastatin, and atorvastatin
• However, this isn’t well-documented in the literature and
more of a theoretical mechanism
48. Mechanism of How Statins Work
• Statins work by lowering HMG-CoA reductase (an
enzyme) which reduces the production of the
mevalonic acid; lower mevalonic acid causes an
increased expression of LDL receptors on the liver,
which then removes LDL from the circulation
• The enzyme HMG-CoA reductase is also used for the
synthesis of Co-enzyme Q10
49. Mechanism of How Statins Deplete CoQ10 &
Importance of CoQ10
• CoQ10 is part of the electron transport chain which produces 34/36
body’s ATP (rest of ATP produced from Krebs Cycle)
• CoQ10 is also known as Ubiquinone
• ATP are needed for synthesis and transport of macromolecules (i.e.,
proteins)
• Found in highest quantity in mitochondria of high-energy organs
(i.e., heart)
• The recommended amount of CoQ10 per day at Dilworth Drug &
Wellness Center is 100 mg of CoQ10 for every pill the patient is
taking
50. Mechanism of How Statins Deplete CoQ10 &
Importance of CoQ10
• CoQ10 is a large molecule that reportedly resembles a vitamin, is fat
soluble (easily crosses cell membranes), is an antioxidant (helping
produce Vitamins C & E)
• Possible Adverse of effects of CoQ10 include: Diarrhea, increased liver
function tests, and loss of appetite
• Never want to give too high a dose of antioxidants, because more
likely to cause cancer; also oncologists often will not give
antioxidants, because they believe can contribute to tumor growth
• Note: If taking Red Yeast Rice would still want to take CoQ10; also
may find CoQ10 in Cold water fish, beef, and chicken
52. Structure of Vitamin K
http://www.omjournal.org/images/images%20052014/R_vitk-f1.jpg
53. Importance of the Mitochondria
• What is a mitochondria? An organelle within a cell that breaks down
nutrients into ATP
• ATP (Adenosine Triphosphate) is needed for muscles to contract,
endocytosis and exocytosis, and other cellular functions such as the
synthesis of RNA and DNA
• Mitochondria per human cell: 1,000-2,000
• Mitochondria are especially prevalent in high energy areas such as
the heart and brain
• Heart cells have a very low capability for regeneration; controversial
as to whether brain cells have capability for regeneration, but would
not want to damage
55. Picture of Electron Transport Chain
http://www.ims2000.org/images/coenzyme-q10-natural-wealth-3092.jpg
56. Myopathy
• Proposed Mechanism of Myopathy
• If not enough CoQ10 may limit the ability of the mitochondria to
produce energy, and disturb cellular respiration
• If cellular respiration is disturbed this may lead to a “back-up” of
substances in the cell
• Some of the harmful products may include lactic acid and oxygen
(the lack of oxygen leading to formation of free radicals)
• If not enough CoQ10 which is an antioxidant may also lead to build
up of free radicals in the muscle cells
• More likely happens in muscle than in fat cells, because muscle
cells require a lot of mitochondria and ATP, and if those products
are not being produced it leads to a “back-up” of the substances in
the cell that may cause myopathy
57. Statin Nutrient Depletion Treatment
• Co-enzyme Q10 (commonly referred to as CoQ10)
• Naturally made in the human body
• Antioxidant
• Very lengthy process to synthesize
• Found in highest quantity in high-energy organs (i.e., heart, brain)
• Important to have Quality Product
• Lipophilic
• Crystal Forms (not preferred)
• Large Molecule
• Is it ok to take Co-enzyme Q10 with warfarin? Studies
• What other Uses Does CoQ10 have? May help treat diastolic heart failure,
high blood pressure, Parkinson’s Disease, Huntington’s Disease, gum
disease, diabetes, and anthracycline cardio-induced toxicity (systolic)
58. What to Say to Customer Regarding CoQ10
• Cost:
• Dilworth Drug & Wellness Center 100 mg $19.90
• Dilworth Drug & Wellness Center 400 mg $39.90
• “CoQ10 is found in almost every organ in your body, though it is especially found
in your heart and brain, so it may help raise energy levels in the human body. It’s
main indication is if you are taking a statin to prevent muscle pain, but it may also
be used to help to lower blood pressure and for treating heart failure. It may also
provide some benefit to immune function (make specific to patient’s most
needed indication). If taking warfarin would recommend letting physician know
before taking CoQ10. It has been said there are some case reports out there that
CoQ10 could make INR (how fast your blood clots) increase (meaning it doesn’t
clot as fast, which is what warfarin is supposed to do. However, it would seem
more believable that if it did anything it would make the INR decrease (not clot as
fast), because CoQ10 is similar in structure to Vitamin K, which is actually used as
an agent to stop warfarin from thinning the blood. To help CoQ10 absorb better it
should be taken with food.”
59. Other Points About CoQ10 & Statins
• Take CoQ10 with meal (especially fatty meal, because CoQ10 is fat soluble,
meaning it will be absorbed more easily if ingested with fat); makes sense
because has a very similar structure to the fat soluble vitamin, Vitamin K
• Absorption increased when taking with food: Lovastatin
• Absorption decreased when taken with food: Pravastatin, Fluvastatin,
Atorvastatin
• Doesn’t matter if taken with food or not: Simvastatin, Rosuvastatin
• Statins that should be taken at bedtime: Fluvastatin, Lovastatin, Simvastatin
• Cholesterol produced most during fasting states (often nighttime is longest
fasting state for many people)
60. Studies: Results Summarized
• One Meta-Analysis with data conducted (up to the year 2015) found that statins
do significantly decrease the amount of CoQ10
• Lipophilic and hydrophilic statins reduced the amount of CoQ10 in the body the
same amount
• In a case report, one 72-year-old female was treated with both warfarin and
CoQ10; the results showed that she experienced a reduced amount of effect from
warfarin (lower INR: International Normalized Ratio- to the patient would say
lower INR means blood clots faster than higher INR which means blood clots
slower); did not report what dose of CoQ10 or the Therapeutic Range of Warfarin
in the study
• In a randomized double blind placebo controlled cross-over trial, the study results
found that the CoQ10 nor the Ginkgo biloba moved the INR of the patients out of
the therapeutic range (INR: 2-4); included patients with mean age of 64; only
included 24 patients and confidence intervals were very large; opinion: not a very
good study
61. What to Say to Provider Regarding CoQ10
• “Studies show that statins significantly deplete CoQ10. I would
caution giving it to a patient who is taking warfarin, though it is
unlikely to increase INR, although it may decrease it. It is similar to
Vitamin K in structure. It may have a lot of other benefits such as
lowering blood pressure as well. Do not recommend crystallized
CoQ10, because it is not absorbed well in the intestines.”
62. Metformin
• Note: Diabetics may already be pre-disposed to have a low level of Vitamin B12
• Very effective at reducing Hemoglobin A1C (a measure of glycated hemoglobin;
usually measured every 3 months)
• A1C goals: For most adults <7.0%, though elderly may have a higher A1C
goal(varies depending on which guidelines are used)
• The recommended daily intake of Vitamin B12 is ranges from 0.4-2.8 mcg/day
• Some diabetics may not be aware their product has metformin in it if they are on
a brand-name or combination product
• Other Causes of Vitamin B12 Deficiency: Dietary, Inhibition of Absorption (i.e.
Crohn’s Disease, Celiac Disease), PPIs/H2RAs > 2 years, and Alcoholism
• Note: Brain’s only fuel is glucose; nothing but glucose (no other types of sugar,
protein, or fats) are used for energy supplies in the brain
64. Importance of Vitamin B12 (Cyanocobalamin,
Cobalamin)
• Vitamin B12 is a water soluble vitamin, meaning that if patients take in an
excess of this vitamin there is little risk of toxicity, because it is excreted
through the kidneys
• Consequence: Because water soluble vitamins are not stored easily,
humans need to continuously take in water soluble vitamins such as
Vitamin B12
• How is Vitamin B12 different from the other B Vitamin? Liver stores ~90%
of Vitamin B12 content (stores will last up to 5 years); cobalt is contained in
B12
• Deficiency possibly caused by decreased calcium absorption due to
metformin which is needed to absorb Vitamin B12 at the terminal ileum
• Calcium supplementation may help if patient suffering from B12
absorption
65. Vitamin B12 Levels
High (>900) pg/mL
Normal 300-900 pg/mL
Lower Normal/Low 150-300 pg/mL
Low <150 pg/mL
66. Importance of Vitamin B12
• Vitamin B12 Deficiency Can Lead To the Following: Neuropathy,
Reduced Cognitive Functioning, lesions of the GI, and Anemia
(Megaloblastic if due to Vitamin B12 deficiency; size too large to
move from bone marrow, because RBCs did not divide normally and
are too large); need Red Blood Cells to carry oxygen to organs
• Vitamin B12 Functions: Helps Red Blood Cells B/C Need Vitamin B12
as a nutrient to mature, Helps Protect Nerves (Myelin)
• Dietary sources of Vitamin B12: Meat, Eggs, Cheese; Beef Liver, Clams
• Vegans at increased risk of deficiency
67. More on Vitamin B12
• Vitamin B12 Deficiency may also mimic Neuropathy which is common in
diabetics
• Proton Pump Inhibitor (and use of H2RAs) use > 2 years may also cause
Vitamin B12 Deficiency
• Adequate serum blood level of Vitamin B12 does not mean have adequate
tissue levels of Vitamin B12
• Possible Mechanism of Depletion: Metformin causes malabsorption of
cobalamin from food at the distal ileum (30%); for PPIs & H2RAs may be
because they reduce stomach acid (hydrochloric acid) which removes the
Vitamin B12 from food
• Adverse of Effects High Vitamin B12: Levels > 900 pg/mL cause bone cell
proliferating disorders (rarely), liver injury (rarely), and kidney injury (rarely);
people with higher than normal B12 levels are asymptomatic; would be
difficult to build up toxic levels of B12 because Vitamin B is water soluble,
though it is possible if taking in really high amounts of B12
68. More on Vitamin B12
• Thought that absorbed better sublingually, because absorbs more directly into blood
and bypasses digestion; large doses of B12 may bypass the usual digestive
mechanisms (meaning it can be more easily absorbed if taken in large doses than in
small doses)
• Factors affecting B12 Absorption: stomach needs to produce low pH, intrinsic factor,
pancreatic function (Exocrine: digestion of food), and absorption of food in the
stomach
• Liposomal form more easily absorbed, because Vitamin B12 is water soluble; the
fat-soluble “carries” the water-soluble part to the ileum (small intestine) where it
is absorbed
• Vitamin B12 is not synthesized by humans except in the large intestine where it is
not absorbed
• Elderly patients stop making stomach acid which leads to decreased absorption of
Vitamin B12
• 1.5-15% of the population is estimated to have a Vitamin B12 deficiency
• Interesting Fact: Can be used to treat cyanide poisoning (dose unclear)
69. Examples of Customers Who May Need
Vitamin B12 Even Though Not on Metformin
• Elderly Patients
• Anemic Patients
• Patients with liver dysfunction (i.e., alcoholism)
• People with bowel dysfunction and disease (i.e., Crohn’s Disease and Celiac
Disease)
• Other Medications (i.e., PPIs, H2RAs)
• Patients with diabetes; patients experiencing neuropathy
• Patients who are elderly, because Vitamin B12 deficiency could be
contributing to or causing Alzheimer’s type symptoms
• Pregnant patients
• Patients who do not eat meat
70. What to Say to Customer Regarding Vitamin
B12
• Cost:
• Dilworth Drug & Wellness Center Vitamin B12 (Methylcobalamin & Hydrocobalamin
Liposomal) 2 fl. oz. (60 mL): $24.90
• “Vitamin B12 is needed to protect nerves, and blood cells. Vitamin B12 is
definitely needed for people who have Vitamin B12 Deficiency, and all
diabetics, even those not on metformin. A vitamin B12 Deficiency itself
can lead to neuropathy, and to symptoms that may look like dementia. Just
because blood levels are normal does not mean that tissue levels are
normal. It is also critical to take Vitamin B12 if you are a heavy drinker or
have anemia. Because of the neuropathy, Vitamin B12 deficiency can lead
to cognitive disorders. Vitamin B12 is a water soluble vitamin excreted by
the kidneys and it’s rare that toxic levels of it build up in the body. Vitamin
B12 may also reduce homocysteine which is linked to increased risk of MI
and stroke. The Dilworth Liposomal form of Vitamin B12 is great to take,
because it is hard to absorb Vitamin B12 anyway, but the liposomal form
helps the Vitamin B12 reach the small intestine for optimal absorption.”
71. Studies: Results Summarized
• In Type II Diabetics, Metformin showed to reduce Vitamin B12 levels compared to those who were not
taking Metformin
• There is a decrease in Vitamin B12 levels and folic acid in those who have been using Metformin short-
term
• One cross-sectional study with 203 type 2 diabetic patients showed that the longer the patients had
diabetes the more chance patients had of having a Vitamin B12 deficiency; the study also showed that
patients who took a multivitamin were statistically significantly less likely to have a Vitamin B12
deficiency; also, there was no statistically significant difference in incidence of B12 deficiency in
diabetics who were taking metformin and those were not currently using metformin (meaning
diabetics taking or not taking metformin may have a Vitamin B12 deficiency), although patients taking
metformin had lower B12 levels and were at higher risk of B12 deficiency; researchers said that when
serum blood levels fell below <350 pg/mL that patients were more likely to have a tissue deficiency of
Vitamin B12 even though they had no serum deficiency; patients who had B12 levels of 100-350 and
had methylmalonic acid levels >243 nmol/L or homocysteine >11.9 nmol/L were considered to have
Vitamin B12 deficiency
• One retrospective study of 259 elderly patients, found that patients who had Vitamin B12 deficiency
were also more likely to have cognitive decline; there was a higher rate of cognitive decline in patients
who had dyslipidemia in addition to the Vitamin B12 deficiency
72. What to Say to Provider Regarding Vitamin
B12
• “I would suggest probably screening patients for B12 deficiency if
they are diabetic, because the prevalence of B12 deficiency is
significantly higher in those who are diabetic vs. those who are not. In
has been proven statistically that diabetics taking metformin are at
higher risk of developing B12 deficiency and have lower B12 levels,
but they still do not have a higher prevalence of B12 deficiency than
those diabetics not taking metformin. B12 deficiency may also
contribute to what may seem to be psychological disorders.”
74. Histamine-2 Receptor Antagonists (H2RAs)
Ranitidine (Zantac, Select)
Cimetidine (Tagamet); avoid in the elderly
because of possible confusion, and metabolized
by the liver
Nizatidine (Axid)
Famotidine (Pepcid, Fluxid, Select)
75. Other Drugs that May Lead to Magnesium
Depletion
Diuretics (Loop and Thiazide)
Aminoglycosides (Amikacin, Gentamicin, Tobramycin)
Amphotercin
Cisplatin
Cyclosporine
Pentamide
Foscarnet
76. Common Drugs that Deplete Potassium
• If potassium in deficient state, then magnesium will not allow the
potassium to be corrected
• Hypokalemia (too little potassium) or Hyperkalemia (too much potassium
can cause arrhythmias
• Diuretics, Methylxanthines (i.e., caffeine), Penicillins, Quetiapine,
Amphotercin B, Gentamicin, Cisplatin, Epinephrine and Other Beta Agonists
• Recommended Daily Intake of Potassium ranges from 3,000 mg/day to
5,100 mg/day depending on age
• What other foods besides bananas have potassium?: Spinach (cooked),
sweet potato, cooked broccoli
77. GERD (Gastroesophageal Reflux Disease)
• PPIs in the outpatient setting are most commonly used to treat
Gastroesophageal Reflux Disease (GERD)
• Mechanism of GERD:
https://static1.squarespace.com/static/517d1f3ee4b02921d70b3783/t/528d58bbe4b04fc308321b94/1384995006130/Reflux+mechanism.png
78. Mechanism of Action of PPIs & H2RAs
https://cme.dannemiller.com/media/articles/429/Figure-5.pnghttp://www.nps.org.au/__data/assets/image/0004/299182/PPI-pharmacology.png
79. Theoretical Mechanisms of PPIs Depletion of
Magnesium
• Theoretical Mechanism PPIs: PPIs possibly could be causing the
intestines to not absorb magnesium well; PPIs could be causing
magnesium depletion, because it is commonly thought when patients
stop PPIs it may help replete magnesium.
80. Proton Pump Inhibitors Nutrient Depletions
• If on an OTC proton pump inhibitor then do still need repletion?
• What if they are on an H2RA or antacids?
• Proton Pump Inhibitors may deplete Magnesium and Calcium
• Unfavorable Effects of PPIs on Micronutrients:
• Lowers Calcium-----Fractures (Elderly already at risk)
• Vitamin B12 Deficiency (being treated > 3 years)-- Neuropathy
• Other Consequences of Taking PPIs:
• C. difficile Associated Diarrhea
• Aspiration Pneumonia
• For Gastroesophageal Reflux Disease, patient should be on PPI for 4-8
weeks and H2RA for 6-12 weeks with lifestyle modifications in addition
81. Importance of Magnesium
• Why is Magnesium Oxide not ideal for a patient?
• 50-60% of Magnesium is stored in the bone, with ~40% being
stored in soft tissues (i.e., muscles and organs), and <1% being in
the blood
• The amount of Magnesium in the body is regulated by the
kidneys
• Magnesium is used as a cofactor for many reactions in the body
• Normal Intake of Magnesium is 300-360 mg/day; generally
calcium is 1,000 mg/day to 1,250 mg/day for premenopausal
women and 1,500 mg/day for postmenopausal women
82. Importance of Magnesium
• Passive Paracellular Non-Saturable Pathway (80-90%) responsible
for intestinal uptake
• Active Transcellular Pathway (10-20%) responsible for intestinal
uptake
• Magnesium and Calcium are cations
• Depletion: Seizures, tremors, involuntary muscle contractions, QT
prolongation, and arrhythmias
• Functions: Protein synthesis, muscle function, nerve function,
regulation of blood glucose, and regulation of blood pressure;
helps prevent osteoporosis and migraine headaches
83. Importance of Calcium
• 99% of calcium in the body is stored in the bones
• Also used for muscle contraction, neurotransmitter release, blood
clotting and cell signaling
• Adverse Effects of High Calcium (Hypercalcemia): Digestive issues (i.e.,
constipation), increased urination, weak muscle and bones, and
increased thirst (higher percentage of calcium and less water in the
blood)
• Food with calcium: Milk, Cheese, Yogurt, Orange Juice, Dark Greens
like Spinach and Collard Greens
84. Why Magnesium Bisglycinate and Magnesium
Malate?
• Bisglycinate has two bisglycinate molecules, which makes it very
absorbable as the glycine inhibits the magnesium from binding to
phytates, and is said to cross the blood brain barrier which is good for
emotional and psychological disorders; chelate means the magnesium
has an amino acid (in this case glycine) attached to it; magnesium is
oxide is beneficial because it can help improve absorption of other
drugs, and may have stool softening properties
• Malate is part of the Krebs Cycle, so when given with malic acid with
magnesium this helps the Krebs Cycle continue to cycle, which may
reduce backload of substances like lactic acid and produces ATP
86. GI Tract Absorption of Magnesium
http://www.albionminerals.com/human-nutrition/magnesium-white-paper
87. Comparison of Different Magnesium Products
Characteristics Magnesium Bisglycinate
(Magnesium Glycinate)
Magnesium Malate
Magnesium Deficiency (Best
Choice)
X
Muscle Pain, Fatigue (Best
Choice)
X
Better at Getting Rid of
Lactic Acid (Best Choice)
X
Less Diarrhea (Theoretically)
(Best Choice)
X
Best Bioavailablility (Best
Choice)
X
88. More Thoughts
• Need healthy GI tract to absorb Magnesium, especially healthy
bacteria in the ileum (small intestine)
• Calcium citrate may be the best calcium to take, because even if acid
production is suppressed (i.e. if taking PPI), it still doesn’t need acid to
be absorbed, because citrate is a derivative of citric acid
• Calcium carbonate contains the most elemental calcium (~40%), but
calcium citrate has better absorption
• Separate Magnesium and/or Calcium by 2 hours from
Fluoroquinolones & Tetracyclines due to chelation; reduces the levels
of the antibiotics; so if taking antacid would separate by 2 hours
89. More Thoughts
• Magnesium Malate binds Aluminum in the body
• Necessary to have Magnesium oxide to help absorb other
medications and also increases absorption of Magnesium
Bisglycinate
• Advise patient to eliminate caffeine in diet (perhaps could
keep a list of foods and beverages with caffeine in them)
90. What to Say to Customer Regarding
Magnesium
• Cost:
• Dilworth Drug & Wellness Mg Malate 90 ct: $19.90
• Dilworth Drug & Wellness Mg Bisglycinate 90 ct: $25.90
• “Magnesium is often depleted when taking acid reducing medications
and this can have serious side effects. If you don’t get enough
magnesium, your muscles can hurt and you can feel a lack of energy.
Also, a lack of magnesium can keep low potassium from correcting.
Magnesium Bisglycinate is better for correcting a magnesium
deficiency and causes less diarrhea, while Magnesium Malate is
better for relieving muscle soreness, fatigue, and getting rid of lactic
acid.”
91. Studies: Results Summarized
• PPIs are associated with causing hypomagnesemia when used for >3
months, although many of the authors studies show there is no
causation associated with hypomagnesemia. However, a recent meta-
analysis showed that there is an increased risk of hypomagnesemia
when taking PPIs, though more homogeneous studies are needed.
92. What to Say to Provider Regarding
Magnesium & Calcium
• “Both Calcium and Magnesium are very important to the body.
Depleting Calcium can cause fractures and depleting magnesium can
lead to arrhythmias. Some data have shown that patients who take
PPIs and/or H2RAs are at risk of depleting Magnesium and/or
Calcium. I would suggest checking the Calcium and Magnesium levels
in patients taking these drugs, and it would be a good idea to
supplement especially with magnesium in these patients, because of
the extreme side effects of magnesium depletion. Magnesium
Bisglycinate is better for absorption and not causing diarrhea, but
Magnesium Malate is better for those patients feeling fatigued,
because malate is part of the Krebs Cycle and the extra malate helps
generate the Krebs Cycle.”
98. Oral Contraceptives Drug Nutrient Depletions
• Probiotics, Magnesium, Zinc, any B Vitamin (including B2, B6, B12, and folic acid),
Vitamin C, Vitamin E, and Selenium
• Zinc is an important cofactor for many reactions in the body and may be taken
prophylactically to prevent colds
• Important that mother treat these depletions for herself and in case she were to
become pregnant, because babies need all of these substances
• Infant receives its first probiotics from its mother after birth
• Theoretical Mechanism: Could be that the liver needs too many of these vitamins
to metabolize the active ingredients in most birth control pills; also may be
because causes bleeding, and that both Vitamins B and C are both water-soluble
vitamins (meaning if there is bleeding, and because blood has a high percentage
of water in it that because these vitamins dissolve in water there could be a low
level of these vitamins in the blood, because these vitamins are leaving the blood
through bleeding)
99. What to Say to Customer Regarding Depleted
Nutrients When Given Oral Contraceptives
• Cost: DD&WC Women’s Multivitamin $25.99
• “Oral Contraceptives can deplete nutrients, and especially if taken
over a long period of time. It is best to take a multivitamin to help
supplement the vitamins and minerals that these deplete.”
100. Studies: Results Summarized
• Oral contraceptives may decrease the amount of nutrients that are
absorbed. One review stated that because certain nutrients are
depleted that women should supplement with those nutrients,
because not only may the contraceptives be depleting the nutrients,
but the woman additionally may have poor diet and/or absorption.
101. What to Say to Provider Regarding Depleted
Nutrients When Given Oral Contraceptives
• “Studies show that patients lose a lot of nutrients when taking
contraceptives, so it is probably best for the woman’s health if she
replaces the nutrients lost as a result of the OCs. Some patients
already may not have good diets and/or absorption, so it is better to
recommend that the patient replace the lost nutrients vs. not
replacing them.”
102. Other Lifestyle Choices & Key Information
• Diet:
• ~80% of having a better quality of diet is due to lifestyle change, while
supplements provide the extra 20% (common knowledge)
• Suggest Mediterranean Diet
• Why Isn’t Diet Enough? Blood is cycled because of the heart, but the
lymphatic system does not get filtered unless exercise
• Sleep: The body has to sleep to repair itself
• Blood Vessels: The blood vessels are the route that nutrients get to the cells;
exercise, quality sleep, and a quality diet are key to maintaining the health of
blood vessels
• Mitochondria: Humans receive all of their mitochondrial DNA from their mother,
and once mitochondrial DNA is damaged it cannot be repaired
• Micronutrients: Micronutrients are needed to help the cells break down the
macronutrients so that food (carbohydrates, protein, and fats) can be used in the
correct way
103. “What Supplements Do You Recommend For
My Children/Infant?”
• Find out patient’s concerns about their children and why they are
considering the supplement for their child
• Check label; ask Josh & other pharmacists if appropriate
• Depending on the supplement, it may be better for the child to start
the supplement earlier in life than later in life
Probiotics CoQ10 Magnesium & Calcium Vitamin B12
Depends on the Age,
but some probiotics
can be given from
birth
Has Not Been
Significantly Studied in
Children, but Dosings
Available for <18
Mg: 0-6 months: 30
mg/day, 7-12 months: 75
mg/day, 1-3 years: 80
mg/day ;Ca: 0-6 months:
200 mg/day; 7-12
months: 260 mg/day; 1-3
years: 700 mg/day
0-6 months: 0.4
mcg/day, 7-12
months: 0.5
mcg/day, 1-3 years:
0.9 mcg/day
S
104. Future Directions
• Create Repletion Protocol for Lacto-Ovo Vegetarians, Vegans,
Fruitarians, & Patients Who Eat Raw/Living Food
• Create Repletion Protocol for Elderly on Certain Medications
• Create Repletion Protocol for Pregnant Women on Certain
Medications
• Monitor Results of the Different Treatments for the Drug Nutrient
Depletions & Later Advertise Those Results if Wanted
105. Conclusions Regarding Customer Service
• Want to improve the patient’s quality of life while also making $ (ultimate
goal is for the patient to make a lifestyle change, not just to have improved
quality of life)
• Ideally, want good relationship with patient/customer and providers that
commonly prescribe medicines to Dilworth Drug, so that providers will
recommend supplements to certain patients, improving health outcomes
for the patients, which may improve health outcomes for pharmacies and
providers
• Can suggest in some cases for patients to start with cheaper (but quality)
supplements, and then increase to take more expensive supplements (let
patient see the difference that taking one inexpensive supplement makes)
• Can also suggest starting with one expensive supplement that may help
improve the patient’s overall health more significantly
106. Basic Takeaways
• There are minimal studies on supplements, because drug companies
will not spend money to conduct clinical trials, because supplements
cannot usually be patented
• Discussed pathophysiology of drug nutrient depletions and
mechanisms of drug nutrient repletion
• There are a lot of drugs that are taken together that may deplete the
same nutrients
• Many of the nutrients have functions that overlap
• Discussed cost of the medicines
• Discussed what to say to customers & providers
107. Studies Used For Each Nutrient Depletion
Regiment References
• Probiotics:
• Issa I, Moucari R. Probiotics for Antibiotic Associated Diarrhea: Do We Have a Verdict?. World J Gastroenterol [Internet].
2014 Dec 21 [cited 2016 October 16]; 20(47): 17788-17795. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273129
• CoQ10:
• Banach M, Serban C, Ursoniu S, Rysz J, Muntner P, Toth PP, Jones SR, Rizzo M, Glasser SP, Watts GF, Blumenthal RS, Lip GY,
Mikhalilidis DP, Sahebkar A. Statins therapy and plasma coenzyme Q10 concentrations- A systematic review and meta-
analysis of placebo-controlled trials. Mayo Clinic Proc. [Internet]. 2015 January [cited 2016 OCTOBER 16]; 90(1): 24-34.
Available from: www.mayoclinicproceedings.org/article/S0025-6196(14)00799-X/abstract
• Landbo C, Almdal TP. [Interaction Between Warfarin and Conenzyme Q10]. Ugeskr Laegar [Internet]. 1998 May 25 [cited
2016 October 16]; 160(22): 3226-7. Available from: https://www.ncbi.nlm.nih/gov/pubmed/9621803
• Engelsen J, Nielsen JD, Hansen KF. [Effect of Conenzyme Q10 and Ginkgo biloba on warfarin dosage in patients on long-term
warfarin treatment. A randomized, double-blind, placebo-controlled cross-over trial]. Ugeskr Laegar [Internet]. 2003 Apr 28;
165 (18):1868-71. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12772396
• Vitamin B12:
• Pfilpsen MC, Oh RC, Saquil A, Seehusen DA, Seaquist D, Topolski R. The prevalence of Vitamin B(12) Deficiency in Patients
With Type 2 Diabetes: A Cross Sectional Study. J Am Board Fam Med [Internet]. 2009 Sep; 22(5): 528-34. Available from:
www.jabfm.org/content/22/5/528.long
• Isaac TG, Soundarya S, Christopher S, Chandra SR. Vitamin B12 Deficiency: An Important Reversible Co-Morbidity in
Neuropsychiatric Manifestatios, Indian J Pshcol Med [Internet]. 2015 [cited 2016 October 16]; 37(1). Available from:
httpsL://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341306
108. Studies Used For Each Nutrient Depletion
Regiment References
• Magnesium:
• Park CH, Kim EH, Roh YH, Kim HY, Lee SK. The Association Between the Use of Proton
Pump Inhibitors and the Risk of Hypomagnesemia: A systematic Review and Meta-
Analysis. PLoS One [Internet]. 2014 November 13 [cited 2016 October 16]; 9(11):
e1122558. Available from: http://www/ncbi.nlm.nih.gov/pubmed/25394217
• Oral Contraceptives:
• Palmery M, Saraceno A, Vaiarelli A, Carlomagno G. Oral Contraceptives and changes
in nutritional requirements. Eur Rev Pharmacol Sci [Internet]. 2013 July [cited 2016
October 16]; 17(13): 1804-13. Available from: www.europeanreview.org/article/4579
• Widely used Reference:
• Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs; [cited 2016
October 4]. Available from: https://online.lexi.com/lco/action/home
109. ReferencesStatistica.com [Internet]. Statistica.com. c2016. Total number of retail prescriptions filled annually in the United States from 2013 to 2021 (in billions)*; 2016 [cited 2016 October 10]; available from: https//:www.statistica.com/statistics/2613303/total-number-of-retail-prescriptions-
filled-annually-in-the-us/
CDC.gov [Internet]. CDC. C2016. Measuring Outpatient Antibiotic Prescribing; 2016 [cited 2016 October 10]; available from: www.cdc.gov/getsmart/community/programs-measurement/measuring-antibiotic-prescribing.html
Bezak K, Eliss B, Ryskina K, Zemedkun M, Daniyan T, Ferng T, Rotman S, West M, Chung A, Loden A, Waldman L, Wong C, Ayres E, Lin FS, Mark S, Bishop T, Lee JI. ACP Online [Intetnet]. Weill Cornell Medical College. Generic Over Brand-Name Proton Pump Inhibitors; 2011-2012 [cited
2016 October 10]; available from: https://www.acponline.org/system/files/documents/clinical_information/high_value_care/medical_educator_resouces/curriculum_educators_residents/pdtoolbox_hvc_presentation_6_sample_hvc_qi_poster.pdf
CDC.gov [Internet]. CDC. C2016. Contraceptive Use; 2016 [cited 2016 October 10]; available from: www.cdc.gov/nchs/fastats/conctraceptive.htm
CDC.gov [Internet]. CDC. C2016. Prescription Cholesterol-Lowering Medication Use in Adults Aged 40 and Over: United States 2003-2012; 2014 [cited 2016 October 10]; available from: www.cdc.gov/nchs/data/databriefs/db177.pdf
CDC.gov [Internet]. CDC. C2016. Opioid Painkiller Prescribing; 2014 July [cited 2016 October 10]; available from: www.cdc.gov/vitalsigns/opioid-prescribing/
Elseviers MM, Camp YV, Nayaert S, Dure K, Annemans L, Tanghe A, Vermeersch S. Prevalence and Management of Antibiotic Associated Diarrhea in General Hospitals. BMC Infect Disease [Internet]. 2015 March 17 [cited 2016 October 10]; 15(129). Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404881
WebMD [Internet]. WebMD LLC. c2005-2016. The Truth About Probiotics and Your Gut; 2015 [cited 2016 October 10]; available from: www.webmd.com/digestive-disorders/probiotics-15/slideshow-probiotics
Prebiotin.com [Internet]. c.2016. Foods Containing Prebiotics; 2010 [cited 2016 October 10]. Available from: https://www.prebiotin.com/foods-containing-prebiotics/
Kligler B, Cohrssen A. Probiotics. American Family Physician [Internet]. 2008 Nov 1 [cited 2016 Octoberr 10]; 78(9): 1073-1078. Available from: www.aafp.org/afp/2008/1101/p1073.htm
Castagliulo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Infect Immun; 1999 [cited 2016 October 10]; 67(1): 302-307. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9864230
Probion.edu [Internet]. Danisco. c2016. Lactobacillus plantarum Lp-115; 2010 [cited 2016 October 12]. Available from: www.probion.edu/files/2012/01/TM_Lp-115_June20101.pdf
Probion.edu [Internet]. Danisco. c2016. Lactobacillus acidophilus NCFM- a probiotic with proven efficacy; 2010 [cited 2016 October 12]. Available from: www.probion.edu/files/2012/01/TM_NCFM_June20101.pdf
Berggren A, Lazou Ahren I, Larsson N, Onning G. Randomised, Double-Blind and Placebo-Controlled Study Using New Probiotic Lactobacilli for Strengthening the Body Immune Defence Against Viral Infections. Eur J Nut [Internet]. 2011 Apr [cited 2016 October 18]; 50(3). Available from:
https://www.ncbi.nlm.nih.gov/pubmed/20803023
Probion.edu [Internet]. Danisco. c2016. Lactobacillus paracasei Lpc-37; 2010 [cited 2016 October 12]. Available from: www.probion.edu/files/2012/01/TM_Lpc-37_June20101.pdf
Reid, G. Jarrow.com [Internet]. Jarrow Formulas (Canadian Research and Development Centre for Probiotics). C2016. Probiotics for Women’s Health: The Story of Lactobacillus Rhamnosus GR-1 and Lactobacillus Reuteric RC-14. 2016 [cited 2016 October 10]. Available from:
www.jarrow.com/articles/release/id/403/Probiotics_for_Women’s_Health:_The_Story_of_Lactobacillus_Rhamnosus_GR-1_and_Lactobacillus_Reuteri_RC-14
Netsolstores.com [Internet]. Danisco. c2016. Lactobacillus salivarius Ls-33; 2010 [cited 2016 October 15]. Available from: 03a5bcb.netsolstores.com/images/research/Lsalivarius.pdf
Ringel Y, Ringel-Kulka T, Maier D, Carroll I, Galanko JA, Leyer G, Palsson OS. Clinical Trial: Probiotic Bacteria Lactobacillus Bifidobacterium lactis Bi-07 Versus Placebo for the Symptoms of Bloating in Patients with Functional Bowel Disorders- A Double Blind Study. J Clinical Gastroenterol
[Internet]. 2011 Jul [cited 2016 October 12]; 45(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372813/
ShuQ, Qu F, Gill HS. Probiotic Treatment using Bifidobacterium lactis HN019 reduces weanling diarrhea associated with rotavirus and Escherichia coli infection in a piglet model. J Pediatr Gastroenterol Nutr [Internet]. 2001 Aug [cited 2016 October 12]; 33(2). Available from:
https://www.ncbi.nlm.nih.gov/pubmed/11565619
Probion.edu [Internet]. Danisco. c2016. Bifidobacterium lactis BI-04; 2010 [cited 2016 October 12]. Available from: www.probion.edu/files/2012/01/TM_BI-04_June20102.pdf
110. References
Cohen, Suzy. Drug Muggers: Which Medications Are Robbing Your Body of Essential Nutrients—and Natural Ways to Restore Them [Internet]. Rodale; 2011 [cited 2015 October 12]. 371 p. . Available from:
Greshko, Michael. How Many Cells Are in the Human Body-And How Many Microbes? [Internet]. Washington, D.C.: National Geographic Society; 2016 Jan 13 [cited 2016 October 12]. Available from: news.nationalgeographic.com/2016/01/160111-microbiome-estimate-count-ratio-
human-health-science/
Mayo Clinic Staff. Mayoclinic.org. Rochester, Minnesota. Mayo Clinic; c1998-2016. Antibiotic Associated Diarrhea. 2016, July 29 [cited 2016 October 12]; [Symptoms and Causes; Symptoms and Causes: Risk Factors]. Available from: www.mayoclinic.org/diseases-conditions/antibiotic-
associated-diarrhea/symptoms-causes/dxc-20229977
Lanas A, Scarpignato C. Bacteria Flora in Digestive Disease: Focus on Rifaximin. Digestion [Internet]. New York: Karger; 2006 [cited 2015 October 12]; 73 (Suppl. 1): Title Page-151. Available from: https://books.google.com/books?id=tqVQLbrYApYC&pg=PA6&lpg=PA6&dq=30-
40+species+bacteria&source=bl&ots=d4FV2CYJ5Z&sig=5gJsu5QqmlV3xty9BtFVLHtuOfE&hl=en&sa=X&ved=0ahUKEwiHxYLOyNbPAhWDPCYKHRC6D0QQ6AEINzAE#v=onepage&q&f=false
Purdom, Georgia. Bacteria: More Good than Bad and Ugly. [Internet]. Petersburg (KY): Answers in Genesis; 2007, June 16 [cited 2016 October 12]. Available from: https://answersingenesis.org/natural-selection/antibiotic-resistance/bacteria-more-good-than-bad-and-ugly/
Mustafa M, Iftikhar M, Shafi S, Shah MJ. Clostridium Difficile infection and Antibiotic –Associated Colitis. IOSR Journal of Pharmacy [Internet]. 2014 May [cited 2016 October 12]; 4(5): 29-34. Available from: http://www.iosrphr.org/papers/v4i05/E045029034.pdf
BCSB.org [Internet]. BSCB (British Society For Cell Biology). c.2016. Mitochondria- much more than an energy converter; 2016 [cited 2016 October 12]. Available from: bscb.org/learning-resources/softcell-e-learning/mitochondrion-much-more-than-an-energy-converter/
NINDS.NIH.GOV [Intetnet]. National Institute of Neurological Disorders and Stroke. C.2016. Mitochondrial Myopathy Fact Sheet; 2015 [cited 2016 October 15]. Available from: www.ninds.nih.gov/disorders/mitochondrial_myopathy/detail_mitochondrial_myopathy.htm
WebMD [Internet]. WebMD LLC. c2005-2016. Get Smart: Brain Cells Do Regrow, Study Confirms; 2015 [cited 2016 October 10]; available from: www.webmd.com/brain/news/20000306/get-smart-brain-cells-do-regrow-study-confirms#1
MedlinePlus [Internet]. Medlineplus.gov. c.2016. Vitamin B12; 2015 [cited 2016 October 14]; available from: https://medlineplus.gov/ency/article/002403.htm
Group E. GlobalHealingCenter [Internet]. GlobalHealingCenter.com. c.1998-2016. What is Sublingual Vitamin B12?; 2016 [cited 2016 October 14]; available from: www.globalhealingcenter.com/natural-health/what-is-sublingual-b12?
Lets Talk Health [Internet]. LetTalkHealth.com c.2016. Liposomal B Complex (16 oz); 2016 [cited 2016 October 14]; available from: www.letstalkhealth.com/Liposomal-B-Complex-16oz-p/626.htm
HealthyImmunity.com [Internet]. Healthyimmunity.com. c.2016 Magnesium Bisglycinate; 2016 [cited 2016 October 14]. Available from: www.healthyimmunity.com/products/Magnesium-Bisglyinate.asp
Albion Minerals [Internet].Albionminerals.com c.2016. Advantages of Magnesium Bisglycinate Chelate Buffered; 2016 [cited 2016 October 16]. Available from: www.albionminerals.com/human-nutrition/magnesium-white-paper
NIH.Gov [Internet]. ODS.OD.NIH.GOV. c.2016. Magnesium: Fact Sheet for Healthcare professionals; 2016 [cited 2016 October 16]. Available from: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional
NIH.Gov [Internet]. ODS.OD.NIH.GOV. C2016. Vitamin B12 Dietary Supplement Facts Sheet; 2016 [cited 2016 October 16]. Available from: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional
NIH.Gov [Internet]. ODS.OD.NIH.GOV. C2016. Calcium Dietary Supplement Facts Sheet; 2016 [cited 2016 October 16]. Available from: https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional
NIH.Gov [Internet]. ODS.OD.NIH.GOV. C2016. Fact Sheet For Health Professionals; 2016 [cited 2016 October 16]. Available from: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional
