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Goar Alvarez, Pharm.D.,FASCPDirector of Pharmacy ServicesNova Southeastern UniversityPresident – Florida Pharmacy Association

Objectives

�Discuss commonly dispensed drug classes and the nutrients they may deplete

�Discuss the physiologic and biochemical rationale for nutrient depletion by commonly prescribed drugs

�Discuss possible clinical implications of nutrient depletions

�Discuss possible prevention/intervention strategies

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Centers for Disease Control and

Prevention (CDC)

�Comparing 1996 and 2006

�Patients taking at least one drug was 18% higher in 2006

�Patients taking at least three drugs nearly twice as high in 2006

� Patients taking at least five drugs was nearly three times as high in 2006

http://www.cdc.gov/nchs/data/databriefs/db32.htm

What is a Mineral?� Inorganic substances

� Participate in biochemical and physiological processes

� Essential components of enzymes and enzymatic processes

� Enzymes – molecules that catalyze or complete chemical reactions in the body

� Participate in physiological functions such as O2 transport, CNS functioning, muscle contraction and relaxation, tissue health and repair, bone health and repair

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What is a Mineral?� If body requires > 100mg/day called a mineral

� < 100mg /day called a trace mineral (or trace element)

T or F

Iron is an example of a trace mineral and Calcium is considered a mineral

What is a Vitamin?� Organic substances necessary for growth and health

� Necessary for metabolism

� Necessary for enzymatic processes

� Enzymes – molecules that catalyze or complete chemical reactions in the body

� Essential parts of hormones

� Hormones – substances that promote and protect the body, health and reproduction

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Vitamin Types� Fat Soluble (A, D, E, K)

� Require protein as carriers for absorption

� Are stored for later use (in liver and fatty tissue)

� Water Soluble (B, C)

� Easily excreted

� Not typically stored and must be supplemented frequently

Vitamin A� Necessary for vision, growth and maintenance of

epithelial tissue, growth and development of bone

� Regulates immunity and reproduction

� Deficiencies affect cell tissues and mucus linings of respiratory, urinary and secretary glands

� Deficiency:� Nyctalopia (night blindness)

� Xerophthalmia( a drying and hardening of the epithelial cell membranes in the eyes)

� Keratinization for long term deficiency ( skin becomes dry, scaly, and rough)

Vitamin A� Carotenes Retinol Vit. A

� Needs adequate levels of protein, thyroid hormone, Zn and Vit E for Carotenes to be transformed to Retinol and to active Vit. A

� As Retinol levels decrease Carotene absorption increases

� 90% of Vit. A is stored in liver

� Dose: typically 10,000-25,000 units/day

� Found in: green leafy vegetables and yellow-orange fruits and vegetables

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Vitamin B2 ( Riboflavin)� Plays a critical role in the conversion of carbohydrates

to ATP (energy production)

� Necessary in amino acid synthesis

� Necessary in enzyme functions

� Minute reserves stored in liver, kidney and heart (needs continuous replenishment)

� Deficiency:

� Affects the skin, eyes, and mucous membranes of the GI tract

Vitamin B2 ( Riboflavin)� 33% of elderly are considered “deficient”

� “Take w/Food” – (only 15% absorbed if on empty stomach)

� Dose: typically 5-100mg/day

� Found in: organ meats, chicken, cheese, almonds

Vitamin B6( Pyridoxine)� Required for the synthesis of the neurotransmitters

dopamine, serotonin and nor-epinephrine and for myelin formation

� Necessary in amino acid synthesis

� Necessary in enzyme functions

� Essential in hormonal balance

� Involved in Mg+ and Ca+ metabolism

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Vitamin B6( Pyridoxine)� Deficiency

� In adults: affects the peripheral nervous system, skin, mucous membranes, and blood cells

� In children: central nervous system is also affected

� Dose: typically 5-100mg/day

� Found in: tuna, salmon, shrimp, avocados, bananas, carrots, lentil, rice

Folic Acid (B-9)� Involved in cellular division and DNA synthesis

� Most affected are hair , skin, RBC and WBC growth and development

� Maintains nervous system, intestinal tract, organs and RBC and WBC

� Maintains cellular genetic code and transfers genetic traits between cells

� Dose: typically 400-800mcg

� Larger doses may mask B12 deficiency (may want to supplement with both folate + B12 simultaneously)

Vitamin B12(Cyanocobalamin)� Helps maintain healthy nerve cells and red blood cells

� Maintains myelin sheath (that surrounds and protects nerve cells)

� Facilitates neurotransmitter signaling

� Involved in DNA synthesis

� Necessary in carbohydrate and protein metabolism

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Vitamin B12(Cyanocobalamin)� Deficiency :

� Megaloblastic anemia

� Pernicious anemia

� Abnormal neurologic and psychiatric symptoms like ataxia ,muscle weakness, spasticity, incontinence, hypotension, vision problems, dementia, psychoses, and mood disturbances

� Dose: typically 10-100mcg/day

� Found in: meats , organ meats, dairy

Vitamin B12(Cyanocobalamin)

Vitamin C (Ascorbic acid)

� Necessary in the formation of collagen in bones, cartilage, muscle, and blood vessels and aids in the absorption of iron

� Contributes to formation of amino acid Tyrosine, precursor to neurotransmitters epinephrine and nor-epinephrine

� Necessary in amino acid metabolism and hormone synthesis

� Deficiency:� Scurvy

� Dose: typically 250-3,000mg

� Found in: citric fruit, berries, potato, brocolli

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Vitamin C� Low PH needed for Vit C absorption

� Vit C needed for Iron absorption

T or F

Vitamins like Folic Acid and B12 are typically stored in the liver and fatty tissue and are released when needed by the body

Vitamin D: Ergocalciferol (D2) and

Cholecalciferol (D3)� Maintains normal blood levels of calcium and

phosphorus

� Promotes Ca+ absorption (maintains strong bones)

� Dose: typically 400-800mg/day

� Deficiency:

� Rickets

� Osteomalacia

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Calcium�Needed for muscle contraction, blood vessel

constriction and relaxation, the secretion of hormones and enzymes, and nervous system signaling

�Deficiency: hypocalcaemia

�Sensations of tingling, numbness, and muscle twitches. In severe cases, tetany (muscle spasms) may occur

Iron� Essential mineral

� Involved in oxygen transport and metabolism.

� A cofactor in the synthesis of neurotransmitters dopamine, nor-epinephrine, and serotonin

� 3-3.5 Gm stores, 15-20mg daily maintenance dose (10% absorbed) , 1-2mg/day excreted daily in sweat and urine

� Non-heme iron absorption from the food sources is facilitated by gastric acid

� Deficiency:� Microcytic anemia� Hypochromic anemia

Magnesium� Necessary in a number of enzymatic systems (particularly in

carbohydrate metabolism)

� Involved in muscular contraction (including cardiac contractility and rhythm)

� Involved in immune system and bone structure and strength

� Involved in nerve conduction (increased Mg = depressed nervous system and skeletal muscle relaxation)

� Deficiency:� May experience twitches, cramps, muscle tension� Insomnia, anxiety, hyperactivity and restlessness� Palpitations, heart arrhythmias

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CoQ10�Protects the mitochondrial DNA

� CoQ10 is only endogenously produced coenzyme and is 90% responsible for ATP synthesis in the mitochondria

�Helps prevent the oxidation of LDL cholesterol

�Deficiency

� causes potential problems in HTN, CHF, low levels of energy and a weakened immune system

Drug classes that may induce

nutrient depletions

�Oral Contraceptives

�Antibiotics

�Acid blockers (PPI’s)

�NSAID’s

�Statins(not an all-inclusive list)

Oral Contraceptives

�OC’s may deplete :

�Folic acid

�Vitamin B6

�Vitamin A

�Vitamin B2

�Magnesium

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Oral contraceptives deplete Folic Acid� Mechanism of Action

� Possibly reduced absorption, increased excretion, increased protein binding and induction of liver enzymes which use folate

� Effect of depletion :� Decreased DNA synthesis �cause abnormal cellular development, especial in

cells with the most rapid rates of turnover (RBC,leukocytes…)� Symptoms

� Megaloblastic anemia, birth defects, cervical dysplasia, elevated homocysteine, headaches, fatigue, insomia

Some studies suggest that although a decrease in folic acid and B12 levels by as much as 40% in 1st 6 months of oral contraceptive use, there does not appear to be a need for supplementation, as there appears to be sufficient Vit B12 and folic acid in the western diet to maintain a minimal 3ng/ml (folic acid). The WHO, however, recommends prophylactic supplementation

PubMed PMID: 1921842Med Monatsschr Pharm 1991 Aug;14(8):244:7

Oral contraceptives deplete Vitamin B6�Mechanism of Action:

� Estrogen alters the metabolism and function of Vit B6�decreased levels of VitB6 �disruption of tryptophan metabolism� disruption of 5- hydroxytryptamine(serotonin) production � mood disorders

�Deficiency symptoms:� Depression, sleep disturbances, paleness, forgetfulness, PMS,

lethargy, decreased alertness, anemia, nausea, vomiting

Oral contraceptives deplete Vitamin A� Mechanism of action:

� Estrogens stimulate production of retinol binding protein, increasing the amount of vitamin A removed from liver storage and carried in blood.

� Deficiency:� The earliest symptoms is night blindness.

� Prolonged lack of vitamin A leads to deterioration of the eye tissue through progressive keratinization of the cornea (xerophthalmia)

Vitamin A is stored in the liver and deficiency of the vitamin occurs only after prolonged lack of dietary intake and it is suggested that supplementation may not be necessary

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Oral contraceptives deplete Vitamin B2� Mechanism of action:

� Possibly reduced absorption or interference with conversion to active form.

� Effect of depletion� Primarily affects skin, eyes, and mucous membranes of

the GI tract

� Symptoms:� Cracks in the corners of mouth

� Reddening, tearing, itchy eyes

Literature suggests that supplementation with Vit B2 may not be necessary as Vit. B2 is usually found in sufficient amounts in the western diet

Oral contraceptives deplete Magnesium

� Mechanism of action:

� Shifts Magnesium from plasma to tissue

� Effect of depletion

� Mg is needed for a number of enzyme systems

� Altered muscular contractions

� Altered nerve conduction

It is recommended that Magnesium levels be monitored in patients with other risk factors for hypomagnesimiaand prophylactic supplementation is not usually recommended

Oral Contraceptives - Suggestions

� Supplementation with folic acid and B6 supplement while on OCs may be beneficial

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Proton Pump Inhibitors�Proton pump inhibitors (PPI) are commonly

prescribed for the treatment of GI ulcers and gastroesophageal reflux disease (GERD)

� Lowering the amount of stomach acid, which can relieve the pain associated with heartburn, acid indigestion and ulcers.

�However, the level of acidity in the gastrointestinal tract is a critical factor that regulates the absorption of many nutrients

Proton Pump Inhibitors� Third largest category of drugs sold

� $13.5 billion in sales

� 119 million Rx’s dispensed in 2009 in USA alone

Outline � FDA approved PPIs

� Physiology of gastric acid secretion

� Effect of PPIs on the absorption of

�Vitamins

� Iron

� Calcium and Magnesium

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FDA approved PPIs� Esomeprazole (Nexium)

� Dexlansoprazole(Dexilant)

� Omeprazole (Prilosec, Zegerid)

� Lansoprazole (Prevacid)

� Pantoprazole (Protonix) and

� Rabeprazole (Aciphex)

Physiology of Gastric acid secretion

PPIs & Vitamin B12�Acid blockers have been linked to significant increases

in the risk of vitamin B12 deficiency

�Mechanism of Action:

�Decreased gastric acid reduces cleavage of protein-bound dietary vitamin B12, reducing the amount available for absorption

�Deficiency mostly when dietary intake of vitamin B12 is poor, or when PPIs are taken continuously (in high doses) >2 years

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PPIs & Vitamin C�Mechanism of Action:

�Decreased vitamin C level possibly due to destruction of vitamin C at higher PH levels

� With resulting decreased Iron absorption

PPIs & Iron�Mechanism of Action:

�Reduced iron absorption due to lack of gastric acid (increased PH)

PPIs & Calcium� Mechanism of Action:

� Acidic environment in the GI tract facilitates the release of ionized calcium from insoluble calcium salts (especially the carbonate salt)

� Hypochlorhydria resulting from PPIs causes calcium malabsorption

� PPIs used > one year increase fracture risk

� In May 2010, FDA issued a warning of the possible increased risk of fractures of the hip, wrist, spine with high doses or long term use of PPIs

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PPIs & Magnesium� Mechanism of Action:

� Unknown at present (believed to be GI magnesium loss but currently unproven)

� < 25 cases reported as of 2010� In 10 cases with av of 8.3yrs on PPI

� Severe symptomatic hypomagnesaemia (fatigue, unsteadiness, tetany, seizures, cardiac arrhythmias)

Curr Gastroenterol Rep (2010) 12:448-457

The following minerals are affected by long term use of PPI’s

A. Calcium, Iron and Selenium

B. Calcium, Iron and Magnesium

C. Vitamin A and D

D. Vitamin C and B12

The following vitamins are affected by long term use of PPI’s

A. Calcium, Iron and Selenium

B. Calcium, Iron and Magnesium

C. Vitamin A and D

D. Vitamin C and B12

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PPI’s - Suggestions� Supplementation with calcium citrateand magnesium

while on PPIs may be beneficial

� Supplementation with sublingual or intranasal B12 while on PPIs may be beneficial

� Increased doses of Vit C while on PPIs may be beneficial

� Monitor Iron, Ferritin & s/s of anemia

Statins� An estimated 36 million Americans are candidates for statin therapy

Therapeutic use

� Lowers TC and LDL Cholesterol “ bad cholesterol” by blocking endogenous biosynthesis of cholesterol from acetyl-CoA

Adverse effects

� Muscle cramps

� Liver enzyme derangement

� Myopathy

Commonly dispensed StatinsGeneric name Brand name

Atorvastatin Lipitor

Lovastatin Mevacor

Pravastatin Pravachol

Rosuvastatin Crestor

Simvastatin Zocor

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Statins�Commonly deplete Coenzyme Q10

�Mechanism of Action:� Statins inhibit HMGCoA reductase, which decreases

cholesterol synthesis by inhibiting the conversion of acetyl CoA to mevalonate (but also inadvertently inhibits intrinsic synthesis of coenzyme Q10 (CoQ10))

� CoQ10 is indispensable for cardiac function

�Mevalonate is necessary in the production of CoQ10.

�Statin drug therapy decreases plasma levels of CoQ10.

The mevalonate pathway. Inhibition by HMGCoA reductase by statins leads to depletion in

products of the pathway including cholesterol and possibly CoQ10.

Clin Biochem Rev. 2008 May; 29(2):71-82

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Co enzyme Q10� First isolated from beef heart mitochondria by Frederick Crane of

Wisconsin in 1957.

� An essential co-factor in the mitochondria for electron transport pathway (and ATP formation)

� Lipid soluble antioxidant. The only one endogenously produced.

� Synthesized via the mevalonate pathway.

� Meat product is the largest source in western diet.

Therapeutic importance• Necessary for ATP production

• Shown to correlate to plasma LDL and Cholesterol levels.

• Levels decrease up to 54% plasma /serum concentration in patients on statin therapy

• Reference level 0.5-1.7µmol/L

Proc Natl Acad Sc USA.1989 Apr.86(7):2379-82

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CoQ10 and statin myopathy

• Mitochondria dysfunction through the depletion of CoQ10 which is essential for normal muscle function.

• Postulated underlying pathophysiology of statin induced myopathy .

• Post marketing surveys 13.6% of statin treated patients will experience some degree of myopathy

Clin Biochem Rev. 2008 May; 29(2):71-82

CoQ10 and Heart Failure� It’s depletion has been postulated to compromise

myocardial energy and lead to “energy starvation” of the myocardium1.

� Considered a pathogenic mechanism of congestive heart failure1.

� CoQ10 as an adjunctive therapy in congestive heart failure treatment1.

� The myocardial CoQ10 is reversed with CoQ10 supplementation therapy2.

1. Biofactors 2003;18(1-4):79-89 2. Proc Natl Acad Sc USA.1985 Apr.82(3):901-4

T or F

Cholesterol synthesis follows the Mevalonate pathway and statins selectively block TC and LDL and thereby improves mitochondrial ATP formation in the heart

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Statins - Suggestions

� Supplementation with CoQ10 while on Statins may be beneficial

What we do to remind us to recommend supplements

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References1. Thomson ABR, Sauve MD, Kassam N et al. Safety of the long-term use of

proton pump inhibitors. World J Gastroenterol 2010 May 21; 16(19): 2323-23302. Rozgony NR, Fang C, Kuczmarski MF. Vitamin B12 Deficiency is Linked with

Long-Term Use of Proton Pump Inhibitors in Institutionalized Older Adults: Could a Cyanocobalamin Nasal Spray be Beneficial?. Journal of Nutrition for the Elderly, 2010,29:87–99

3. Ito T, Jensen RT. Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium. Curr Gastroenterol Rep (2010) 12:448–457

4. Ali T, Roberts DN, Tierney WM. Long-term Safety Concerns with Proton Pump Inhibitors. The American Journal of Medicine (2009) 122, 896-903

5. McColl KEL. Effect of Proton Pump Inhibitors on Vitamins and Iron. Am J Gastroenterol 2009; 104:S5 – S9;

6. Laine L,Ahnen D, Mcclain C et al.Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14: 651-668.

7. Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors – a review. Journal of medicine. May 2009; 67(5):169-172

Sandhya Rani Emmadi & Dr. Lafferty Lynn

References

Molyneux SL, Young JM, Florkowski CM. Coenzyme Q10: is there a clinical role and a case for measurement? Clin Biochem Rev. 2008 May;29(2):71-82.

Folkers K, Vadhanavikit S, and Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci U S A. 1985 February; 82(3): 901–904.

Ogasahara S, Engel AG, Frens D, and Mack D. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A. 1989 April; 86(7): 2379–2382.

Martesen SA. Overview on coenzyme Q_{10} as adjunctive therapy in chronic heart failure. Rationale, design and end-points of "Q-symbio" - A multinational trial . Biofactors 2003;18(1-4):79-89

Chew GT and Watts GF. Coenzyme Q10 and diabetic endotheliopathy: oxidativestress and the ‘recoupling hypothesis’.Q J Med 2004; 97:537–548

Rosenfeldt FL, Haas SJ, Krum H, et al. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trialsCoenzyme Q10 and hypertension. J Hum Hypertension.2007;21:297-306

References1.Stargrove,M.,Treasure,J.,Mckee,D.,

(2008).Herb,Nutrient,and Drug Interactions Clinical Implications and Therapeutic Strategies.Mosby Elsevier

2.Pelton,R.,LaValle,J.,Hawkins,E.,Krinsky,D.(1999-2000)Drug-Induced Nutrient Depletion Handbook.

3.Natural Standard Available at www.naturalstandard.comAccessed in Nova Library

4. American Diabetes Association Available at http://www.diabetes.org

5. Pubmed Available at http://www.ncbi.nlm.nih.gov/pubmed

6.Pharmacist Letter Available at http://pharmacistsletter.therapeuticresearch.com