Phar 722Pharmacy Practice III

Vitamins-Introduction

(Nutrition ScienceVersus

Nutrition Policy)

Spring 2006

STUDY GUIDE FOR THE UNIT ON VITAMINS-INTRODUCTION

1. Understand the different philosophies between nutrition science and nutrition policies.

2. Be able to explain how nutrient deficiencies can develop and how nutritional requirements are determined.

3. Know the following items associated with the DRIs.A. For each type of DRI know (1) their definition. (2) how they are determined generally. (3) which ones can be used for diet planning.

B. The adult male and female range and units used for the RDA (the AI

when a vitamin does not have a RDA) for each vitamin.

4. Know the definition or characteristics of a vitamin.

5. Know the source of the Daily Values versus the Dietary Reference Intakes.

6. Know the items mentioned under each of the vitamins. (There will be a set of learning objectives with each vitamin.)

Should we recommend vitamins?

Nutrition Science versus Nutrition Policy-1

• Nutrition Science– The emphasis is on science which uses the scientific

method to reach conclusions. This requires a hypothesis, proper experimental design, and conclusions based on the experimental results. Among other things, nutrition science will

• 1. determine the dose to prevent a nutritional deficiency.• 2. determine the dose to cause a toxic response.

• Unfortunately, the experiments required to obtain the necessary information for proper dosing of nutrients can be a long, expensive process. Thus there is a lot of extrapolation. In the case of the Dietary Reference Intakes (DRI), the doses are based on retrospective studies, animal models and surveys. More will be stated on this later.

Nutrition Science versus Nutrition Policy-2

B. Nutrition Policy– This is the approach used to determine the dose

required to maintain well being. – It has become a very political process, particularly

with ascorbic acid (Vitamin C) and α-tocopherol (Vitamin E).

• These two vitamins are hypothesized to provide some protection against certain malignancies and artereosclerosis.

• Thus, some believe that the RDAs should be greater than that required to prevent a nutritional deficiency.

– This controversy so split that panel that was charged with developing the 1985 RDAs that it had to be disbanded.

– In other words, nutrition policy can become very political.

Causes of Nutrient Deficiencies-1• Inadequate ingestion usually from a poor diet.

– economic deprivation;

– self-imposed reducing diets;• A 1,200 Calorie diet professionally selected from the four

major food groups (dairy, fruits and vegetables, grains, and meat) containing no fried food nor added sugar has been considered the least amount of food not requiring a vitamin supplement.

– chronic disease.• This usually is due to loss of appetite from such

conditions as cancer chemotherapy, depression and eating disorders.

Causes of Nutrient Deficiencies-2• Inadequate absorption

– Diseased intestinal tract such as chronic inflammatory conditions (Crohn’s Disease) and parasites.

– Lipase inhibitors (Xenicol®, Alli®; orlistat)• The undigested triglycerides in the small intestine can

disolve the oil-soluble vitamins (retinol (A), cholecalciferol/ergocalciferol (D), α-tocopherol (E), phytonadione( K) from food where they will be excreted with the feces.

– Ion exchange resins (colestipol, colestyramine, wellchol) • These cholesterol lowering drugs complex with the bile

salts and can interfere with the absorption of the oil soluble vitamins. A vitamin supplement can be taken one hour before or two hours after taking the resin.

Causes of Nutrient Deficiencies-3• Inadequate absorption-continued

– Cystic fibrosis • This genetic disease can cause fat

malabsorption (steatorrhea) due to inadequate production or secretion of pancreatic lipases. This can lead to malabsorption of the fat soluble vitamins: retinol (A), cholecalciferol (D3), α-tocopherol (E), and phytonadione (K1).

– Gastric Bypass• Decreased absorption of cyanocobalamin (B12)

possibly requiring nasal or parenteral dosage forms.

Causes of Nutrient Deficiencies-4• Inadequate utilization

– genetic disease• Examples include variants of maple syrup urine disease

which will respond to thiamine (B1) supplements and homocystinuria which will respond to pyridoxine (B6).

– drug antagonists and interactions• Isoniazid and pyridoxine (B6) (covalent chemical

combination)• Phenobarbital and cholecalciferol (D3) (possibly induce

metabolism)• Methotrexate and folic acid (inhibit conversion to the

coenzyme form)• Phenytoin and folic acid (inhibit folate uptake)• Warfarin (coumadin) and phytonadione (K) (inhibit re-

conversion to coenzyme form)

Causes of Nutrient Deficiencies-5

• Increased requirements– Strenuous exercise– Disease

• Examples include recovery from a debilitating illness, severe burn injuries, cancer, etc. Nutritional assessments are becoming a more common part of medical treatment.

• Chronic alcoholism– Interferes with the uptake of some vitamins —

folic acid, thiamine (B1) — or, due to liver disease, proper processing and/or storage of vitamins.

Determination of Nutritional Requirements

Dose

Ou

tcom

e

Death Death

Deficiency Toxicity

Marginal deficiencysymptoms

Marginal toxicities

Optimum Dosing

• Vitamin Dose Response Curve

Toxicities and possiblydeath require high dosesover long time periods.

Dietary Reference Intakestry to address marginal deficiencies.

Methods for Obtaining a Dose Response Curve-1

• Extrapolate from animal studies.– This will be dependent on the species. The

vitamin requirements differ among the common laboratory animals.

• Ascorbic acid (C) is not a vitamin in most animals. • α-Tocopherol (E), biotin, and pantothenic acid cause

definitive deficiency syndromes not seen in humans.

• Metabolic balance studies in humans.– This usually involves a seven day period on a

defined diet in which the urine and feces are monitored.

• The problem is that corrections have to be made for the vitamins are stored.

• The pharmacokinetics of most vitamins have not been carefully determined.

Methods for Obtaining a Dose Response Curve-2

• Compare nutrient intake in areas with and without the deficiency disease. – First, not all vitamin deficiencies lead to a defined deficiency state. – Second, rarely does one find an area deficient in only one nutrient.

• Most common deficiencies are due to inadequate diet which means several nutrient deficiencies will result.

• Poor sanitation is usually coordinated with a poor economy. This leads to intestinal disease and its malabsorption of nutrients.

• Saturation of biochemical function.– A reliable biochemical indicator is required.

• Niacin: Which NAD+ or NADP+ containing enzyme should be selected? • Pyridoxine (B6): Which transaminase will be the indicator? • Retinol (A): Is vision in the rods or cell differentiation a reliable measure?

• Serum levels– This probably is the most reliable, but it does require very sensitive

assay methods for those vitamins required in μg (10-6) amounts.

Dietary Reference Intakes (DRI)compared with

Recommended Dietary Allowances (RDA)

• The last official set of reference values were the 1989 Recommended Dietary Allowances (RDAs) for the United States and 1990 Recommended Nutrient Intakes for Canada.

• The DRIs are published by the Food and Nutrition Board of the National Academy of Sciences National Research Council.

Dietary Reference Intakes (DRI)• How do the DRIs differ from RDAs?• There is one set of reference values for both Canada and the

United States.

– There will be clear documentation on how reference values are selected.

– A goal will the "the promotion of nutrient function and biologic-physical well-being” based on peer reviewed science.

– Evidence concerning the prevention of disease and developmental disorders will be examined in addition to the traditional of how much nutrient is needed to prevent a deficiency symptom.

– Data supporting food components that, up to this time, have not been considered essential nutrient will be examined.

• Anti-oxidants• Omega-3 fatty acids

– There will be recommendations for future research.

Uses of Dietary Reference Intakes-1

• Uses of Dietary Reference Intakes– The DRIs consist of four components.

• Estimated Average Requirement (EAR)• Recommended Dietary Allowance (RDA)• Adequate Intake (AI)• Tolerable Upper Intake Level (UL)

– Each type of reference value is calculated from daily intakes averaged over time (usually one or more weeks).

– Nutrition labeling • Uses the FDA’s Daily Values (DV) on vitamin

and nutrition lables.

Uses of Dietary Reference Intakes-2

• Estimated Average Requirement (EAR)– The intake that meets the estimated

nutrient need of 50 percent of the individuals in that group (i.e. infants, children, adult males, adult females, pregnant women, nursing women, the elderly, etc.)

• It is used to evaluate the adequacy of nutrient intakes of population groups and for planning intakes for group.

• It can be used in diet planning. • The EAR is based on a median rather than a

mean.

Uses of Dietary Reference Intakes-3

Uses of Dietary Reference Intakes-4• Recommended Dietary Allowance (RDA)

– The intake that meets the nutrient need of almost all (97 to 98 percent) individuals in that group.

– They can function as a guide to achieve adequate nutrient intake.

– By themselves, they are not generally recommended for diet planning for specific groups of individuals.

– Diet planning must take into account extensive physical activity, type of body build including lean versus adipose tissue, general life style, etc.

– If the sampling and end points are well defined, the RDA can be calculated from the EAR.

– RDA = EAR + 2 SDEAR

– Where• SDEAR = standard deviation above the EAR

Uses of Dietary Reference Intakes-5

Uses of Dietary Reference Intakes-6

• Adequate Intake (AI)– Average observed or experimentally

derived intake by a defined population or subgroup that appears to sustain a defined nutritional state, such as normal circulating nutrient values, growth, or other functional indicators of health.

– It is derived from mean intakes of groups (rather than individuals).

– The AI is used when a reliable EAR is not available.

• (vitamins D, K, Biotin, Pantothenic Acid and infants)

Uses of Dietary Reference Intakes-7

• Tolerable Upper Intake Level (UL)– The maximum intake by an individual that is

unlikely to pose risks of adverse health effects in almost all (97 to 98 percent) individuals. It includes intake of a nutrient from all sources (food, fortified food, water and supplements). Water can include fluoride and minerals depending on the source of water.

– "Tolerable" is used to "avoid implying any possible beneficial effect." The amount can be "tolerated.“

• (A, D, E, Niacin, Pyridoxine, Folic Acid)

Uses of Dietary Reference Intakes-8

Dose

Out

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Death Death

Deficiency Toxicity

Marginal deficiencysymptoms

Marginal toxicities

Optimum Dosing

UL

Uses of Dietary Reference Intakes-9

What is a Vitamin?• Naturally occurring.

– This does not mean that a synthetic copy will not be as effective.

• Essential.– What about niacin?

• Produced from tryptophan in most mammals including humans• People living in sunny areas may not need vitamin D supplements.

• Organic– A trace element cannot be a vitamin.

• Fe, Ca, Mg, Zn, etc are not vitamins.

• “Normal” constituent of the diet.– Cholecalciferol (D3) is found on fish, not a common component of many diets, particularly

those who live inland.

• Required in minute amounts.– This is arbitrary but ranges from 2.0 μg (10-6 gm) for cyanocobalamin to 90 mg for ascorbic

acid. Other essential nutrient like amino acids generally are required in larger amounts. Even ascorbic acid's RDA is about 30 times greater than any other vitamin.

• Aids in maintaining the normal activities of the tissues.– Most vitamins function either as a hormone/chemical messenger, structural component in

some metabolic process, or a coenzyme.

• Why aren’t these other essential nutrients classified as vitamins.

• Tradition?– Discoveries of what we call vitamins was

based on discovering deficiency diseases mostly in animals caused by defined diets.

– There is more effort on dosing for vitamins.

– Amino acids and omega-3 acids are required in large amounts.

• Omega-3 RDAs: 650 mg to 2.22 gm depending on the omega-3 acid.

Very Brief History-1• There originally were two vitamins.

– Fat soluble A reported in 1913.– Water soluble B reported in 1915 by McCollum and Davis

who reported a water-soluble B factor that restored growth in rats.

• The vitamin B complex, of which thiamine is considered the first one, generally includes the group of water soluble vitamins found in rice polishings, bean extracts, yeast, and liver. – There are no chemical relationships in the B complex. The

nomenclature is very confusing. The common name originally implied something about the chemical nature of the vitamin.

– Even the concept of water soluble is somewhat misleading as some of the vitamins in this group would be considered poorly soluble by most pharmaceutical standards.

– The one thing the B complex have in common is that nearly all function either as a cofactor or a structural component of a cofactor.

Very Brief History-2• D was discovered during the search for a cure for

rickets.• Vitamins E and K were discovered later and by

accident.– The fat-soluble vitamins have a variety of roles including:

• hormonal (A and D)• an integral part of a biochemical process (A, D, K)• general antioxidant (E)

• The term vitamin was coined by Funk who isolated thiamine from rice polishing and called it vitamine because chemical analysis indicated an amine was essential for life. Of course there is no consistent chemical structure among the many vitamins and not all are humans.

Few Manufacturers of Raw Materials• Until late 2002, Roche (Switzerland) has controlled

70% of the free world's bulk vitamin production. Roche sold its vitamin business to DSM for $2.24 billion. The exception has been cyanocobalamin, the calciferols, and niacin. DSM is followed by Takeda (Japan), BASF and Lonza. Rhône-Poulenc is leading producer of cyanocobalmin.

• A few years ago, European prosecutors convicted mid-level executives for conspiring to fix prices.

• There are 100s of formulators who take the bulk vitamins and develop the products. Many formulators manufacture vitamins under several labels.

Limits to Vitamin Labeling• Unfortunately, vitamins fall under the Food portion of the Food

and Drug Cosmetic Act. Therefore, as long as no false medical claims are made and the product actually contains what is stated on the label, there is little to stop anyone from getting into the highly profitable vitamin business.

• Much vitamin labeling is ambiguous. – Vitamin C with rose hips only implies that there is some rose

hips in the product. There is no requirement that the rose hips is the source of the vitamin in the tablet.

• All Natural does not mean that 100% of the vitamin is from natural sources. There is no legal definition of natural. – Vitamin C is manufactured from glucose. Therefore it is

natural.– Natural vitamin E may actually contain both the synthetic and

the vitamin from wheat germ.

• Read vitamin labels carefully, particularly those in the health food stores or sections of pharmacies.

Daily Values (DV) – Nutrition Labels

Nutrient DV RDA/AI Nutrient DV RDA/AI

Vit A 1500 μg 700-900 μg Thiamine 1.5 mg 0.9-1.2 mg

Vit C 60 mg 25-90 mg Riboflavin 1.7 mg 0.9-1.3 mg

Calcium 1000 mg 800-1200 mg Niacin 20 mg 12-16 mg

Iron 18 mg 10-18 mg Vit B6 2.0 mg 1-1.7 mg

Vit D 400 IU 200-600 IU Folate 400 μg 200-400 μg

Vit E 30 mg 7-15 mg Vit B12 6.0 μg 1.8-2.4 μg

Vit K 80 μg 55-120 μg Biotin 300 μg 20-30 μg

Pantothenic Acid

10 mg 20 mg