Course Content

Introduction

Pharmacists are the most highly trained health care professionals on pharmacodynamics, including drug mechanism of action and adverse effects. The pharmacist holds a unique and valuable position in the multiple prescriber, multiple prescription health care environment that exists today. Daily, pharmacists accept the responsibility of detecting possible interactions and adverse effects that can occur with multiple prescribers and too many medications.

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Pharmacists have long been the most accessible health care professional in the marketplace. In the regular course of their day, pharmacists routinely see patients who fit the criteria for groups identified as being at risk for nutritional deficiencies. Each day pharmacists service athletes who are undergoing intense training and competition, bariatric surgery patients with altered nutrient absorption, obese patients, patients with diabetes, individuals on weight reduction and weight management programs, and cancer patients. But perhaps the largest group of patients subject to nutrient depletions is the most overlooked; those patients who are at risk for drug-induced nutrient depletions. A deficiency is due to inadequate dietary intake. A depletion is a loss created by an outside influence such as a prescription medication. In other words, many patients are at risk of a nutrient depletion caused by drug therapy. Pharmacists who oversee drug administration and/or dispensing are perfectly situated to identify patients at risk for drug-induced nutrient depletion. It would only follow that a pharmacist involved in the process of dispensing medications that may ultimately create drug-induced nutrient depletion should shoulder some responsibility for preventing those deficiencies.

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Looking at this situation from the business side, pharmacies manage their prescription drug inventory to satisfy the needs of the patients that they see. Pharmacies should take care however, to maintain nutritional supplement inventory variety and quantities sufficient to address the nutritional depletions created by prescribed medications.

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A well-managed nutritional supplement department is good not only for patient health, but for the health of the pharmacy business. As profit margins continue to decrease on prescription medications, the margins on nutritional supplements continue to be healthy and can be a welcome source of revenue for a pharmacy. Research has demonstrated that the nutritional supplement market is a multi-billion dollar business. Studies have estimated that 70 percent of Americans are taking some type of nutritional supplement and are constantly seeking a source for reliable education on their supplements.

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Risk Factors for Nutrient Deficiencies

• Age (older adults and infants)
• Vegetarian/vegan diet
• Eating disorder
• Swallowing disorders
• Chronic disease such as diabetes, kidney or liver disease, cancer
• Obesity
• Bariatric surgery
• Alcoholism or excessive alcohol intake
• Prescription drug use
• Smoking
• Pregnancy
• Menstruation

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Prevalence of Nutrient Deficiencies

The prevalence of nutrient deficiency varies by nutrient. The following describes the prevalence of deficiency for some nutrients.

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Magnesium deficiencies have previously been thought to be uncommon; however, some experts believe that deficiency is underdiagnosed due to the complexity of assessing magnesium status. Some research suggests that magnesium deficiency could be as high as 45% in people residing in North America. It is also estimated that as many as 60% of Americans do not achieve adequate dietary intake of magnesium. One reason for this may be the declining mineral content in commonly consumed foods (see Figure 1). Magnesium deficiency may also be more common in those with medical conditions such as liver disease, heart failure, alcoholism, and in patients taking certain drugs which will be discussed further in this course.

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Potassium deficiency is usually caused by an underlying medical condition or due to medications. Otherwise, deficiency is uncommon. Medical conditions linked to potassium deficiency including diarrhea or vomiting, eating disorders, HIV/AIDS, bariatric surgery, and alcoholism. Several drugs have been linked to potassium deficiency which will be discussed further in this course.

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Figure 1. Average mineral content (calcium, magnesium, and iron) in cabbage, lettuce, tomatoes and spinach

Nutrients. 2018 Sep; 10(9): 1202.

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Prevalence of Nutrient Deficiencies

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Iron deficiency is among the most common nutrient deficiencies. It is especially common in premenopausal women and vegetarians. In Caucasian women, the rate of deficiency is up to 12% and up to 20% in African-American and Mexican-American women. In those who don’t eat meat (e.g., vegetarians), the rate of deficiency may be over 40%.

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Folic acid deficiency has decreased significantly in North America since certain foods began to be fortified with folic acid in 1998. After fortification began folic acid deficiency declined from about 16% to 0.5%. In countries without folic acid fortification, deficiency rates are significantly higher. Several risk factors are associated with folic acid deficiency including malabsorption disorders (e.g., bariatric surgery, inflammatory bowel disease), kidney disease, pregnancy or lactation, alcoholism, smoking, and the use of certain prescription drugs.

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Vitamin B12 (cyanocobalamin) is generally uncommon in the North American population but can occur frequently in those with malabsorption (e.g., the elderly, post-bariatric surgery) and in vegetarians or vegans. Elderly patients have a decline in intrinsic factor which is needed for active transport and absorption. In the elderly, vitamin B12 deficiency occurs in about 6% and marginal deficiency occurs in about 20%.  Certain drugs are also common culprits involved in vitamin B12 deficiency, which will be discussed further in this course.

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Mechanisms of Drug-Induced Nutrient Depletion

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The use of certain medications is a risk factor for depletion of a variety of nutrients including iron, potassium, B vitamins, magnesium, and others. Drug therapy can impact nutrient levels in the body through several different mechanisms (see Figure 2).

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Disruption of nutrient intake:

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Certain drug side effects can result in patients not consuming adequate nutrition. For example, drugs that cause decreased appetite or anorexia may result in a loss of interest in food and inadequate food intake.

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Drugs that cause taste or smell disturbances may result in food not tasting as good or food not tasting the way it normally would and therefore inadequate nutrient intake.

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Drugs that cause nausea or vomiting may also decrease intake of food and could also result in throwing up following ingestion of food.

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Drugs that cause irritation of the oral mucosa or make swallowing difficult may also make it difficult to ingest, chew, and swallow food, potentially resulting in inadequate nutrient intake.

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Decreased nutrient absorption:

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Some drugs may decrease how well nutrients are absorbed. Decreased absorption may occur through a variety of mechanisms. One of the most common reasons a drug may decrease nutrient absorption is through changes in the pH of the gastrointestinal tract. For example, drugs that inhibit gastrointestinal acid production or levels (e.g., antacids, H2-receptor antagonists, proton pump inhibitors) can decrease the absorption of a variety of nutrients including calcium, vitamin B12, iron, zinc, and others (this will be described in more detail later in this course).

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Nutrient absorption can also be diminished due to physical binding or the formation of complexes in the gastrointestinal tract which prevent nutrient absorption. For example, bile acid sequestrants (e.g., cholestyramine) can bind a variety of nutrients in the gastrointestinal tract (e.g., fat soluble vitamins) and prevent their absorption.

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Drugs may also decrease nutrient absorption due to side effects such as vomiting or diarrhea, by inhibiting digestive enzymes, altering bacterial flora of the gut, and damaging the mucosa of the gastrointestinal tract.

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Increased nutrient elimination:

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Some drugs may cause nutrient depletion by increasing nutrient excretion. This may occur by stimulating normal physiological processes or by causing tissue damage. For example, loop and thiazide diuretics can increase potassium and magnesium loss through alteration of physiological processes in the kidney. Toxic effects of other drugs such as aminoglycosides may increase loss of electrolytes such as potassium and magnesium by causing damage to the kidneys.

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Altered nutrient metabolism or synthesis:

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In some cases, drugs may result in decreased nutrient levels by interfering with nutrient metabolism or synthesis. One of the best examples of this is the affect of HMG-CoA reductase inhibitors (“statins”) on coenzyme Q10. Statin drugs block the synthesis of mevalonic acid which is a precursor to coenzyme Q10 which results in significant declines in coenzyme Q10 levels. Another example is carbamazepine which stimulates the hepatic metabolism of active vitamin D to inactive compounds.

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In some cases, drug action can affect nutrient synthesis or metabolism indirectly. For example, the normal flora of the gut is involved in the production of vitamin K. Antibiotics that disrupt the normal flora may result in decreased levels of vitamin K and associated adverse effects.

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Figure 2. Disruption of Nutrient Status by Drugs

​Int J Mol Sci. 2019;20(9):2094.

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Review of Drug Class-Specific Effects on Nutrients

One of the best ways to identify potential drug-induced nutrient depletion issues is to keep in mind the effects of high-risk drug classes on nutrients. Certain drug classes are more likely to affect nutrients than others. Nutrient depletion issues are often a class effect meaning that most or all drugs in the class have the potential to decrease nutrient levels.  Many of the drug classes that affect nutrients are among the most commonly used drugs on the market. Therefore, the potential for clinically significant nutrient depletion is widespread among the population. Many of the drugs that affect nutrients are also used for chronic conditions. This means that those with chronic medical conditions may also be more likely to experience drug-related nutrient depletion. The following reviews specific drug classes and their potential impact on the levels of certain nutrients.

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Acid Blockers

Acid blockers include those medications increase gastrointestinal pH. These include medications such as antacids, H2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) (see Table 2). Many nutrients are best absorbed in an acidic environment. Medications than increase gastrointestinal pH can interfere with optimal absorption and, in some cases, lead to significant nutrient depletion over time. The biggest concern is in patients who take acid blocker medications over a long period of time. Some nutrients that may have reduced absorption after taking an acid blocker include:

• Beta-carotene
• Calcium
• Chromium
• Folic acid
• Iron
• Magnesium
• Vitamin B12
• Vitamin C
• Zinc

Although each of these nutrients may have reduced absorption in those taking acid blockers, there is not evidence indicating that this results in clinically meaningful depletion for most of these. Some of nutrients will be reviewed further in the next slides.

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Table 2. Selected Acid Blockers

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Calcium salts (e.g., calcium carbonate, calcium citrate) need to be solubilized in order to be absorbed. They are best solubilized in an acidic environment; therefore, there has been a long-running concern that those who take acid blockers long-term may absorb inadequate calcium from food or supplements.

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Several studies have evaluated the effects of acid suppression on calcium absorption with varying results. Some studies have found no effect of acid suppression using H2RAs on calcium absorption. However, in a randomized controlled trial in elderly women, taking a PPI, omeprazole 20 mg, reduced calcium absorption by about 9%. The use of PPIs have also been associated with an increased risk of fractures in some population studies, although results have been mixed.

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Researchers speculate that acid suppression with PPIs decreases nutrient absorption, including calcium, magnesium, and others, as well as results in other hormonal effects which could negatively affect bone mineral density and fracture risk (see Figure 3).

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Patients who take acid blockers can take steps to help prevent reduced calcium absorption. First, acid blockers may not significantly reduce absorption of calcium from calcium-rich foods. Therefore, getting adequate calcium intake from the diet is preferable over taking dietary supplements containing calcium.

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For those who need to take a supplement in order to achieve adequate calcium intake, calcium citrate may be preferable because this salt form has better absorption in a low acid environment compared to calcium carbonate. However, when calcium (carbonate or citrate) is taken with a meal, a low acid environment does not seem to significantly impair calcium absorption.

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In summary, patients who regularly take acid blockers can help ensure adequate calcium absorption by getting most of their calcium from their diet, taking calcium citrate, and/or taking their calcium supplement with a meal.

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Figure 3. Summary of the effects of PPIs in Elevating Fracture Risk

Int J Environ Res Public Health. 2019 May; 16(9): 1571.

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Abbreviations: IC HCY, intracellular homocysteine; EC HCY, extracellular homocysteine; ECL cells, enterochromaffin-like cells; Ca, calcium; Mg, magnesium; BMD, bone mineral density; PTHrP, parathyroid hormone-related peptide; PTHLH, parathyroid hormone-like hormone; OB, osteoblast; OC, osteoclast; ↑, increase; ↓, decrease.

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Iron absorption is improved in an acidic environment and decreases when acid levels decline. This may be especially important for dietary, plant-derived (or non-heme) iron sources. Clinical iron deficiency or anemia related to the use of acid blockers is uncommon; however, there are several reports of severe iron deficiency anemia in patients taking acid blockers such as PPIs long-term, especially in those who have other risk factors for iron deficiency.

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Nonetheless, a 2017 population study found that the odds of iron deficiency was significantly higher in those taking a PPI or H2RA for two or more years, including those without any known risk factors for iron deficiency. For those taking PPIs, the odds of deficiency was 2.49 (95% confidence interval, 2.35-2.64). For those taking H2RAs, the odds of deficiency was 1.58 (95% confidence interval, 1.46-1.71). The risk of iron deficiency is higher with the use of higher doses of PPIs or H2RAs and the risk is higher with PPIs compared to H2RAs.  Based on these data, it is advisable to monitor for iron deficiency in patients taking acid blockers long-term, especially in those with other risk factors for iron deficiency.

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Magnesium absorption is also impaired by acid blockers, specifically by the PPIs.

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Magnesium is absorbed primarily through passive mechanisms in intestines, but also through active transport mechanisms. As the pH in the intestines increases, the solubility of magnesium salts decreases, resulting in decreased absorption. Increased pH in the intestines also significantly decreases the primary passive absorption mechanism for magnesium.

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In 2011, the United States Food and Drug Administration (FDA) advised that the long-term use of PPIs could result in severe hypomagnesemia. This was based on post-marketing surveillance reports as well as published case reports and studies indicating increased risk of hypomagnesemia a relatively small percentage of those taking PPIs.

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The FDA advised clinicians to monitor patients on long-term PPI therapy for magnesium deficiency, especially those with diabetes or cardiovascular disease. Since then, several observational studies and meta-analyses of these studies have evaluated the risk of hypomagnesemia in patients taking PPIs. Overall, the evidence continues to point to a statistically significant increased risk of low magnesium levels in patients taking PPIs, however, results from studies are heterogenous.

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Symptoms of Magnesium Deficiency

• Muscle cramps or spasms
• Depressed mood
• Lethargy
• Anxiety
• Headache
• Constipation
• Agitation
• Paresthesia
• Tremor
• Loss of appetite
• Irritability
• Fatigue or weakness
• Insomnia

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Certain patients may have a greater risk of developing low magnesium levels while taking a PPI due to other risk factors. Some other risk factors for low magnesium levels include the use of diuretics, inadequate dietary magnesium intake, and other medical conditions such as kidney disease, diabetes, or cardiovascular diseases such as hypertension or cardiac arrhythmia.

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All patients taking PPIs long-term should be monitored for low magnesium levels.

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Magnesium levels should be checked at baseline (before starting a PPI) and at least annually thereafter.  This is especially important for those patients who have other risk factors for low magnesium levels. Also consider a magnesium supplement to prevent hypomagnesemia; some evidence suggests that this can help prevent excess magnesium loss. However, for up to 25% of patients, discontinuation of the PPI may be necessary to adequately address low magnesium levels. In many cases, hypomagnesemia returns when a PPI is restarted. For these patients, an alternate treatment strategy may be needed. For example, one strategy would be to alternate treatment days with a PPI and H2RA in addition to taking a magnesium supplement.

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Vitamin B12 found in foods is bound to proteins. An acidic environment is needed to release vitamin B12 from protein and allow for its absorption. As a result, acid blockers such as PPIs and H2RAs can reduce the absorption of dietary vitamin B12; however, these acid blockers do not significantly affect the absorption of vitamin B12 supplements.

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PPIs decrease vitamin B12 absorption more than H2RAs. In a population study, the odds of developing vitamin B12 deficiency was 65% higher in those taking PPIs and 25% higher in those taking H2RAs compared to those who were not taking those medications.

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Vitamin B12 deficiency is unlikely with short-term use. However, those patients who are taking H2RAs or PPIs long-term (especially 1-2 years or more) should be monitored for vitamin B12 deficiency.

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Symptoms of Vitamin B12 Deficiency

• Paresthesia
• Depression
• Weakness
• Depressed mood
• Personality changes
• Ataxia
• Memory loss

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Antibiotics

Antibiotics represent a diverse group of compounds and most have the potential to affect nutrient levels. Antibiotics can disrupt or eliminate portions of the normal gastrointestinal flora which is involved in the generation of B vitamins including vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin).  However, production of B vitamins by the gastrointestinal flora primarily occurs in the colon. Absorption of B vitamins from the colon is poor, which suggests that the affect of antibiotics on the normal flora is not likely to have a clinically significant effect on B vitamin levels.

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Additionally, most people take antibiotics for only a short-time rather than long-term. Therefore, for most patients who take antibiotics, B vitamin deficiency is not a clinically important concern, and most do not need to take a B vitamin supplement.

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Vitamin K deficiency may be an important concern for some patients who take antibiotics. The normal gastrointestinal flora is also involved in production of vitamin K.  By altering the normal flora, antibiotics may also diminish vitamin K levels which may reduce clotting and prolonging bleeding time. Certain cephalosporin antibiotics may be more likely to cause vitamin K-related issues than other antibiotics. Cefamandole is secreted into the bile in relatively large amounts and therefore may have a greater effect on vitamin K-producing bacteria.  Additionally, some cephalosporins have a methylthiotetrazole side chain which decreases vitamin K effects by directly inhibiting clotting factor production in the liver.  These cephalosporins include cefamandole, cefmetazole, cefoperazone, and cefotetan.

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In most cases, a short-course of antibiotics will not be problematic, however, longer courses of antibiotics and use in those with questionable vitamin K status due to poor dietary intake (e.g., hospitalized or critically ill patients, infants) may increase the risk of bruising and bleeding. Patients who develop easy bruising or bleeding may need a supplement dose of vitamin K.

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Aminoglycoside antibiotics may affect nutrient levels due to their harmful effects on the kidneys. Nephrotoxicity from this class of medications can result in significant losses of electrolytes including calcium, magnesium and potassium. Antibiotics in this class including amikacin, gentamicin, kanamycin, streptomycin, and tobramycin. Patients receiving these antibiotics should be monitored for renal problems as well as electrolytes disturbances.

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Anticonvulsants

Several anticonvulsant drugs have been found to increase the risk of bone disease such as reduced bone mineral density and osteomalacia. Anticonvulsant drugs have been found to cause several biochemical abnormalities linked to bone disease. These abnormalities include reduced serum calcium and phosphate, lower levels of vitamin D (measured as 25-hydroxy vitamin D) and increases of parathyroid hormone and bone turnover. These affects appear to be most common in patients who receive anticonvulsants that induce cytochrome P450 drug metabolizing enzymes. These drugs include carbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone.

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There is less evidence for other anticonvulsants drugs, however, research has identified low levels of calcium and vitamin D and increased fracture risk in patients taking other anticonvulsant drugs as well. Patients on long-term anticonvulsant treatment should be routinely monitored for vitamin D levels. These patients should also receive calcium and vitamin D supplementation.

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Some researchers recommend 1000-1200 IU daily for those taking non-enzyme inducing anticonvulsants. Those patients taking enzyme-inducing anticonvulsants should receive higher doses of 2000-4000 IU daily.

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Folic acid and vitamin B12 levels may also be reduced in patients taking some anticonvulsants. Carbamazepine, gabapentin, oxcarbazepine, phenytoin, and valproic acid are associated with lower folic acid levels and phenobarbital, pregabalin, primidone, and topiramate are associated with lower vitamin B12 levels. Decreased B vitamin levels may be caused by decreased absorption in the gastrointestinal tract and/or increase hepatic metabolism. Patients on long-term anticonvulsants should be monitored for B vitamin deficiency and anemia. Some patients may need to increase intake of folic acid and vitamin B12.

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Antipsychotics

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Many patients with schizophrenia have micronutrient abnormalities; however, it has been unclear whether these abnormalities are related to treatment with antipsychotic drugs. A population study found that schizophrenia patients have lower levels of calcium, copper, iron, and zinc. However, only copper levels appear to be associated with the use of certain antipsychotic agents, including clozapine and aripiprazole. The clinical significance of this is unclear.

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Some patients with schizophrenia also have lower plasma levels of folic acid and vitamin B12. Although some speculate that this may be due to antipsychotics, lower levels of these vitamins appear to be independent of antipsychotic treatment.

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Antihypertensive Drugs

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Drugs used for hypertension include a variety of different subclasses.  Some of these include diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta-blockers. However, only some of these antihypertensive drug classes are associated with clinically meaningful nutrient depletion issues.

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Diuretics including thiazide diuretics and loop diuretics cause the most significant nutrient depletion issues. Potassium is significantly depleted by both thiazide and loop diuretics.  Both classes of diuretics increase urinary excretion of potassium and can lead to hypokalemia.  Potassium levels should be monitored in patients taking diuretics. Low potassium levels can be prevented by increasing intake of potassium-rich foods or by taking potassium supplements.

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List of Selected Diuretics

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Symptoms of Low Potassium Levels

• Weakness
• Muscle cramps
• Fatigue
• Constipation
• Excess thirst
• Frequent urination

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Potassium-rich Foods

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Antihypertensive Drugs

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Diuretics can also increase urinary losses of magnesium. Both thiazide and loop diuretics can increase magnesium loss, however, this occurs to a greater extent with loop diuretics. Patients taking diuretics should be monitored for low magnesium levels.

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Increasing dietary intake of magnesium-rich foods or using magnesium supplements may be needed.

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Magnesium-rich foods

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Thiamine (vitamin B1) can also be depleted by diuretics. Diuretics increase urinary excretion of thiamine and can be caused by any type of diuretic but is more common when diuretics are used in high doses for many months. Most reports of diuretic-related thiamine deficiency have occurred in people over the age of 60 years who also have inadequate intake of dietary thiamine. Older patients taking long-term, high-dose diuretics should be monitored for potential thiamine deficiency.

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Zinc excretion can also be increased by 50% to 60% in patients taking diuretics. The clinical significance of this increased excretion is unclear as most patients continue to have overall normal zinc levels; however, there is some speculation that long-term diuretic treatment might deplete tissue zinc levels leading to drug-related side effects such as impotence.  Patients on long-term diuretic treatment should be monitored for potential zinc deficiency. Other antihypertensive drugs may also decrease zinc levels, including some calcium channel blockers (e.g., atenolol) and ACE inhibitors. High antihypertensive doses may increase zinc loss; however, more research is needed to determine the clinical significance of the affects of these drugs on zinc.

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Symptoms of Thiamine Deficiency

• Irritability
• Muscle cramps
• Poor sleep
• Foot drop
• Loss of appetite
• Constipation
• Stomach upset

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Symptoms of Zinc Deficiency

• Unexplained weight loss
• Loss of appetite
• Diarrhea
• Skin lesions
• Taste disturbances
• Lethargy
• Hair loss
• Poor wound healing

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Salicylates

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Salicylates, including acetylsalicylic acid (aspirin) and aminosalicylic acid, have the potential to affect levels of several nutrients including folic acid, vitamin B12, vitamin C, and iron.

Aminosalicylic acid has been shown to reduce vitamin B12 absorption by up to 55%. In addition, levels of vitamin B12 have been found to be lower in patients taking aspirin. The clinical significance of this depletion is unclear. Until more is known, consider monitoring vitamin B12 levels in patients taking these drugs long-term. Folate absorption is also reduced by aminosalicylic acid.  Preliminary research suggests that aspirin may also decrease folate levels. In rare cases, megaloblastic anemia has occurred in patient taking aminosalicylic acid, often in conjunction with reduced vitamin B12 levels. Some patients taking aminosalicylic acid may need to take folic acid supplements, especially if dietary folate intake is inadequate.

Aminosalicylic acid can decrease absorption of iron. Aspirin may also affect iron levels through gastrointestinal blood loss. Patients taking these drugs long-term should be monitored for potential iron deficiency.

Aspirin reduces vitamin C levels by reducing absorption in the gastrointestinal tract and by increasing renal elimination. Higher doses of aspirin have greater effects on vitamin C levels. For most people who take small doses of aspirin, this depletion is not likely to be clinically significant and a supplement is not usually needed.

A vitamin C supplement may be considered for patients taking larger aspirin doses long-term.

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Corticosteroids

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Corticosteroids have a variety of effects on nutrient levels. The best-known concern are the effects of corticosteroid on calcium. Corticosteroids can decrease absorption of calcium from the gastrointestinal tract and can also increase excretion of calcium. Some population data also suggest that long-term use of corticosteroids may decrease levels of vitamin D, although this evidence is preliminary and unclear. As a result, extended use of corticosteroids can lead to decreased bone mineral density resulting in osteoporosis and increased risk of fractures. Patients who take corticosteroids long-term should also take calcium and vitamin D supplements.

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In addition to calcium and vitamin D, corticosteroids may also increase excretion of magnesium, chromium, selenium, zinc, copper, and vitamin C. The clinical significance of these effects are not well documented. Patients on long-term corticosteroid treatment should be monitored for deficiencies in these nutrients.

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Estrogens

Estrogens are found in hormone replacement therapy regimens as well as most oral contraceptives. Taking estrogen in these forms have been associated with reductions in several different nutrients. Folate serum levels and levels in red blood cells have been found to be reduced in women who take conjugated estrogens or oral contraceptives. In some studies, folate levels were decreased by 40% in women taking oral contraceptives. Reduction in folate levels may occur through several different mechanisms including decreased folate absorption, increased folate excretion, increased folate protein binding, and increased metabolism of folate in the liver. Clinically meaningful deficiency appears to be uncommon in those women with sufficient dietary intake of folic acid. In rare cases, there have been reports of megaloblastic anemia in women taking oral contraceptives; however, this has occurred in women with other factors contributing to folate deficiency. Low folate levels in women taking oral contraceptives may also increase the chances of abnormal pap smear results.

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Women taking estrogen as a part of hormone replacement therapy or as an oral contraceptive should ensure adequate intake of folic acid; supplements may be needed in those who cannot achieve adequate dietary intake.

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In addition to folate, estrogens can reduce levels of other B vitamins including vitamin B6 (pyridoxine), vitamin B1 (thiamine), vitamin B2 (riboflavin), and vitamin B12 (cyanocobalamin).

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Low pyridoxine levels are speculated to be the cause of some oral contraceptive side effects such as fatigue and depression; however, taking vitamin B6 supplements does not seem to improve these symptoms.

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Additionally, some evidence suggests that, although vitamin B6 levels may initially decline, they return to normal over time, even with continued use of estrogen. For most women taking estrogens, a vitamin B6 supplement does not seem to be necessary.

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For vitamin B12, the evidence is contradictory. Some research shows decreased vitamin B12 serum levels in women taking oral contraceptives, however, other studies have found no effect on vitamin B12 levels even over several months of treatment. In studies finding lower levels of vitamin B12, levels return to normal when the oral contraceptive is discontinued. Additionally, its thought that, even though serum levels of vitamin B12 may be reduced, tissue and cells levels remain unchanged. Estrogen-related depletion of vitamin B12 appears to be clinically insignificant.

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For riboflavin, some studies have found reduced levels in women taking oral contraceptives, possibly due to decreased absorption or decreased metabolism to its active form; however, not all studies have found this effect. Many studies that have found reduced riboflavin levels included women with inadequate riboflavin intake. In women with adequate riboflavin intake, estrogens are not likely to cause meaningful nutrient depletion. Riboflavin supplements are not needed for most women taking estrogens.

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For thiamine, some studies have found modest reductions thiamine activity; however, other studies have not found this effect. Thiamine supplements are not necessary for most women taking estrogens.

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Estrogen intake is also associated with reduced serum levels of magnesium likely due to increased magnesium uptake by tissues and bone. In patients who have low dietary magnesium intake or those with other risk factors for low magnesium levels, hypomagnesemia may occur in those taking estrogens. There is some speculation that low magnesium levels in women taking estrogen may contribute to increased risk of thromboembolism. Some studies have also identified reduced levels of vitamin C and zinc in women taking estrogens from oral contraceptives or hormone replacement therapy. However, other studies are contradictory and have no effect of estrogen on these nutrients. Based on currently available data, vitamin C or zinc depletion does not seem clinically relevant and supplements are not necessary for most women.

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Lipid-Lowering Agents

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Bile acid sequestrants include cholestyramine, colestipol, and colesevelam. They work to lower cholesterol by binding bile acids containing cholesterol in the intestines which prevents their reabsorption. The complex of drug and bile acids/cholesterol is then excreted in the feces. Along with the cholesterol that is excreted are fat soluble vitamins in the gastrointestinal tract. This means that some patients taking these drugs, especially long-term, can develop deficiencies in vitamin A, vitamin D, vitamin E, and vitamin K.

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There have been some reports of osteomalacia related to vitamin D deficiency in patients taking a cholestyramine in high doses over 2 years, especially in those with other risk factors for deficiency. There have also been reports of prolonged bleeding time due to vitamin K deficiency in patients taking cholestyramine or colestipol long-term, but this appears to be uncommon.

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Routine supplementation with fat soluble vitamins likely isn’t necessary for most patients; however, patients on long-term high dose treatment with bile acid sequestrants should be monitored for potential deficiencies.

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HMG-CoA reductase inhibitors (“statins”) are the most commonly used lipid-lowering agents. Statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin. Statins are implicated in deficiencies of the vitamin-like, fat-soluble cofactor coenzyme Q10. 

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Coenzyme Q10 has numerous functions within cells including antioxidant functions, membrane stabilization, and as a cofactor in oxidative respiration to produce adenosine triphosphate. Coenzyme Q10 is produced endogenously and is only found in small amounts from some dietary sources such as meats and seafood. Statins inhibit the synthesis of mevalonic acid which is a precursor in the synthesis of coenzyme Q10. All statins have the potential to reduce coenzyme Q10 levels. High-dose statins such as atorvastatin 80 mg daily can reduce coenzyme Q10 serum levels by 52%. Simvastatin 20 mg daily can reduce coenzyme Q10 serum levels by 32%.

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There is a lot of controversy about the clinical significance of statin-related reductions of serum coenzyme Q10 levels.  There is speculation that decreased coenzyme Q10 levels causes or contributes to statin-related muscle symptoms (e.g., myalgia).

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Some clinicians recommend coenzyme Q10 supplements to prevent statin-related muscle symptoms and for its treatment. Clinical trials evaluating the effectiveness of coenzyme Q10 for this use have had variable outcomes. A 2018 meta-analysis of 12 clinical trials including 575 patients found that coenzyme Q10 significantly reduced muscle pain, muscle weakness, muscle cramps, and muscle tiredness compared to placebo in patients diagnosed with statin-induced myopathy. The doses of coenzyme Q10 used in clinical trials ranged from 100 mg to 600 mg daily. Based on these data, supplementation with coenzyme Q10 appears to be a reasonable option for preventing or treating statin-related muscle symptoms due to coenzyme Q10 depletion.

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Diabetes Drugs

Metformin is a first-line choice for most patients with type 2 diabetes. As a result, many diabetes patients are taking this medication chronically for many years. Metformin can reduce levels of vitamin B12 and folic acid. Metformin may reduce levels through several mechanisms including decreased intrinsic factor secretion, decreasing gastrointestinal tract motility, and bacterial overgrowth. As many as 30% of people who take metformin long-term can have decrease vitamin B12 serum levels.

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Some patients can also develop megaloblastic anemia while taking metformin long-term; however, this is uncommon in patients with adequate dietary intake of vitamin B12 (see Table 6). Patients who take higher metformin doses, are elderly, and those who don’t eat meat are more likely to develop clinically meaningful vitamin B12 deficiency. Patients on long-term metformin treatment should be monitored for vitamin B12 deficiency. Vitamin B12 supplements are usually adequate for preventing or treating deficiencies.

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Table 6. Vitamin B12-rich foods

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Summary

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Many drugs from a variety of different drug classes have been implicated in drug-induced nutrient depletion. The challenge in evaluating these concerns is determining which issues are clinically significant. Clinically significant drug-induced nutrient depletion can vary substantially among patients due to patient-specific factors. For example, while many drugs decrease levels of certain nutrients a clinically significant deficiency may not develop unless the patient also has other risk factors such as inadequate dietary intake of the nutrient.  Additionally, in many cases, research in this arena is rapidly growing and as a result recommendations may change over time. Therefore, its primarily important to understand which drugs have the potential to affect nutrient status. This knowledge and understanding will provide the necessary red flag to signal that nutrient monitoring may be necessary in certain patients.

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Active Learning

Many drug-induced nutrient deficiencies can be prevented, at least in part, by adequate dietary intake of nutrients. An important part of helping patients avoid these problems is teaching patients about healthy eating. The US Department of Health and Human Services has developed helpful recommendations to support healthy eating. Review below link for some helpful tips that you may be able to use to help counsel your patients in health eating. https://health.gov/dietaryguidelines/2015/guidelines/

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