Phar 722Pharmacy Practice III

Minerals-Calcium

Spring 2006

Calcium Learning Objectives• What are symptoms of hypercalcemia and hypocalcemia?• What are causes of hypercalcemia and hypocalcemia?• Be able to list the various roles of calcium.• How efficient is absorption of dietary calcium and how does it

vary with age?• Be able to describe the distribution of calcium throughout the

body in terms of percentages.• To the extent covered in lecture, describe the functions of 1,25-

diOH-D3, PTH and calcitonin in terms of regulating calcium.• Be able to differentiate between bone diseases covered in

lecture.• Differentiate between osteoblast and osteoclast cells.• Given a molecular weight, be able to calculate the amount of

elemental calcium in tablet of a calcium salt. (Most times the empirical formula will be given, but, as a pharmacy student, you should know the formula of calcium carbonate.)

• Know the adult AI and UL for calcium.

Calcium and Phosphate Homeostasis

• It is critical to maintain blood calcium concentrations within a tight normal range.

• Hypocalcemia: – Increased neuromuscular excitability including

muscle spasm, tetany and cardiac dysfunction.– Decreased growth and increased osteoporosis.

• Hypercalcemia: – Normal blood Ca and phosphate concentrations

are near saturation. – Loss of appetite, nausea, vomiting, constipation,

confusion, delirium, coma, death

10 year old 18 year old Mature 60 year oldFemale Male Female Male Female Male Female

Body Ca (gm) 290 360 630- 820- 920- 1,200 820700 900 1,000

Rate of 100- 100- 50 100 0 0 -20*Deposition in 150 150Bone (mg/day)

AI (mg/day) 1,300 1,300 1,300 1,300 1,000 1,000 1,200

* An early postmenopausal female loses 30 – 100 mg/day from bone.

Changes in Calcium Flux with Age

Mean Calcium Intake by Age and Gender

0

200

400

600

800

1000

1200

1400

0 10 20 30 40 50 60 70 80 90

Age (years)

Calc

ium

(m

g)

per

day

1997 DRI

1989 RDA

Females

Males

Top number: adolescent femaleBottom number: adult female

Distribution of Calcium in the Body• Assume 1000 g

– Skeleton & teeth 990 g (99%)• Skeleton: 40% Ca & 60% P (textbook)

• Bone consists of a mixed salt Ca(OH)(PO4)

• Osteoblast cells: deposit Ca salts onto bone• Osteoclast cells: remove Ca from bone

– Intracellular Ca 10 g (1%)– Extracellular Ca 1 g (0.1%)

• Ionized Ca+2 450 mg (45%)• Bound Ca

– Plasma proteins 450 mg (45%)

– Ions (lactate, HCO3-1, HPO4

-2, H2PO4-1)

Calcium Pools• Bone Calcium

– 99% as hydroxyapatite [Ca5(PO4)3OH]– 1% in a pool that rapidly exchanges with

extracellular calcium

• Intracellular Calcium– Majority sequestered in the mitochondria and

endoplasmic reticulum.– Its concentration is dynamic because of release

from cellular stores or influx from extracellular fluid.

• Extracellular Calcium Including Blood– 45 - 50% bound to protein– Ionized calcium about 10,000 times the

concentration of free calcium within cells.

Phosphate Distribution

• 85% in the mineral portion of the bone

• Remaining distributed in a variety of inorganic (HPO4

-2/H2PO4-1 buffer system) and organic compounds (ATP, GTP, DNA, RNA, phosphoproteins, etc.)

• Total blood concentration is similar to that of calcium.

Regulation of Calcium Levels• Parathyroid glands

– Contains cells that sense blood calcium levels.– Produces parathyroid hormone (PTH).

• Kidney– Regulates calcium levels either by tubular

reabsorption or excretion.

– Produces 1,25-(OH)2-D3

– Hormonal regulation includes PTH and calcitonin

• Thyroid gland– Produces calcitonin

Calcium Flux

• Small Intestine: Site of dietary calcium absorption – requires expression of a calcium-binding protein.

• Bone: Calcium reservoir• Kidney: Maintains

calcium homeostasis. Normally, calcium undergoes tubular reabsorption, but calcium is excreted when tubular reabsorption decreases.

BloodCa+2

Hormonal Control of Calcium Flux-1

• Parathyroid Hormone (PTH):– Activates 1,25-diOH-D3

production in the kidney– Mobilizes calcium and

phosphate from the bone by activating osteoclasts.

– Maximizes tubular reabsorption of calcium from the kidney.

BloodCa+2

1,25-diOH-D3

ParathyroidHormone

1,25-diOH-D3

Hormonal Control of Calcium Flux-2

• 1,25-diOH-D3

– Increases blood calcium concentrations.

– PTH required to activate the oxidation of 25-OH-D3 in the kidney to 1,25-diOH-D3.

– Increases calcium absorption from the small intestine.

– With PTH, it enhances fluxes of calcium out of the bone

BloodCa+2

1,25-diOH-D3

ParathyroidHormone

1,25-diOH-D3

Hormonal Control of Calcium Flux-3

• Calcitonin– Produced in the thyroid

gland.– Reduces blood calcium levels

in response to hypercalcemia.

– Suppresses renal tubular reabsorption of calcium which enhances calcium excretion into the urine.

– Inhibits bone resorption which minimizes fluxes of calcium from bone into blood.

– (It is not considered a practical therapy for osteoporosis.)

BloodCa+2

Calcitonininhibits

CalcitoninPromotes.

Role of Calcium

• Teeth

• Bones

• Triggering or Impeding a Cell’s Function

• Cofactor for Enzymes and Proteins

Role of Calcium

• Teeth– In contrast with the that seen with bones, there is

no calcium or phosphate exchange with teeth.– Drugs that interfere with calcium during infancy

and early childhood can interfere with formation of the permanent teeth.

– Fluoride, in proper amount, can strengthen teeth. – Fluoride, in excessive amounts, can discolor and

possibly damage teeth.– Fluoride does not seem to strengthen bone, nor

does it damage bone.– There be may genetic traits that either reduce the

risk or increase the risk of developing dental caries.

Role of Calcium-1• Bones

– Contains 99% of body calcium and is the body’s storage organ for calcium.

– Dynamic tissue that is serviced by an excellent blood supply or vascularization.

– The large bones house the bone marrow, site of myeloid (erythrocytes, platelets, granulocytes, and monocytes), lymphoid (B cells , T cells) cells, natural killer cells, and dendritic cells.

– Because bone is dynamic, it is subject many diseases including ricketts, osteosarcomas, osteoarthitis, osteoporosis, osteomalacia and Pagets Disease.

– Healthy bone needs a balance between the bone forming osteoblast and calcium removal osteoclast cells.

Osteoarthritis

Healthy vertebrae

Osteoporotic vertebrae

Osteoporosis in the spine

Osteoporosis-fractured vertebral column

Osteonecrosis

Role of Calcium-2

• Triggering or Impeding a Cell’s Function (Cell Signaling)– It is essential that the flow of calcium into

the cell be regulated. Otherwise the cell will “overreact.”

– Note the role of calmodulin, one of many regulators of calcium flow through the cell membrane calcium channels.

– Many time, a calcium channel will be coupled to the channel of another cation such as potassium

Role of calcium in insulin release from the pancreas.

Integrated role of calcium in release of insulin from the pancreas

Examples of Cell Signaling• Vasoconstriction and vasodilation• Nerve impulse transmission• Muscle contraction• Secretion of hormones including

insulin• NOTE:

– Recent studies indicate that calcium with vitamin D does not reduce the risk of colon cancer.

– Calcium may increase the risk of prostate cancer (See vitamin D notes)

Role of Calcium-3• Cofactor for enzymes and proteins.

– Stabilizes many proteins and enzymes.

– Required for the clotting cascade• See phytonadione notes this vitamin’s role in

producing a protein’s ability to bind calcium.

Causes of Hypocalcemia

• Rarely caused by diet.

• Abnormal parathyroid gland function.

• Kidney failure leading to dialysis.

• Vitamin D deficiency

• Low blood magnesium levels from severe alcoholism– Decreases osteoclast response to PTH.

Implications of Hypocalcemia• Impaired growth

• Increased severity of osteoporosis.

Calcium Bioavailability from Food

Food Serving

Size

Calcium Content

% Fraction

Absorbed

Ca/serving

Absorbed

Servings = 1 glass of milk

Milk 240 300 32.1 96.3 1.0

Dried beans

177 50 15.6 7.8 12.3

Broccoli 71 35 61.3 21.5 4.5

Cabbage 85 79 52.7 41.6 2.3

Kale 65 47 58.8 27.6 3.5

Spinach 90 122 5.1 6.2 15.5

Tofu 126 258 31 80 1.2

Calcium Supplements

• There are a large number of OTC calcium salts.

• They vary by the anion.• The anion determines the amount of

elemental calcium per tablet.• Information you need to calculate the amount

of elemental calcium:– mEq wt of Ca++ 20 mg– At. Wt of Ca 40

• Insufficient evidence that coral or oyster calcium is better.

Calcium Supplements % Ca mEq Ca++/g mg

Ca/1000 g Ca glubionate 6.5 3.3 65Ca gluconate 9 4.5 90Ca lactate 13 6.5 130Ca citrate 21 10.6 210Ca acetate 25 12.6 250Tricalcium phosphate 39 19.3 390Ca carbonate 40 20 400

There are various combinations including:Calcium with fluorideCalcium with vitamin DCalcium with vitamins D and K

Calcium SupplementsCalcium glubionate

(Calcium complex with gluconogalactogluconic acid)

C18H32O19 Ca++ H2O (approximate formula)

- MW 610

- 6.5% Ca

- 3.3 mEq Ca++/g

- 65 mg/1000 g salt

Calcium Supplements

• Calcium gluconate– MW 430– 9% Ca (9.3% anhydrous)– 4.5 mEq Ca++/ g– 90 mg/1000 g salt

C

C

C

C

C

CH2OH

OHH

HHO

OHH

OHH

O

O-

2

Ca++

Calcium Supplements

• Calcium lactate – MW 308– 13% Ca– 6.5 mEq Ca++/ g– 130 mg/1000 g salt

H3C CH C

OH O

O-2

Ca++

5 H2O

Calcium Supplements

• Calcium citrate – MW NA– 21% Ca– 10.6 mEq Ca++/ g– 210 mg/1000 g salt

CH2

C

CH2

OHC

O

-O

C

C

O

O

O-

O-

n

xCa++

Calcium Supplements

• Calcium acetate – MW 158– 25% Ca– 12.6 mEq Ca++/ g– 250 mg/1000 g salt

H3C C

O

O-

2

Ca++

Calcium Supplements

• Tricalcium Phosphate– Ca3(PO4)2

– MW 310– 39% Ca– 19.3 mEq Ca++/ g– 390 mg/1000 g salt

Calcium Supplements

• Calcium Carbonate– CaCO3

– MW 100– 40% Ca– 20 mEq Ca++/ g– 400 mg/1000 g salt

Calcium SupplementsPotential Interactions

• Calcium Salts and Iron Salts– GI absorption of iron may be reduced.– Separate administration times if feasible.

• Calcium Carbonate and Quinolones– Norfloxacin appears to be the most sensitive– Give CaCO3 6 hours before or 2 hours after the

quinolone.

• Calcium Salts and Tetracycline– Ca++ complexed by most tetracyclines.

• Calcium Salts and Verapamil– Clinical effects of toxicities of verapamil may be

reversed.

Drugs Targeting Calcium or Processes involving Calcium

• Calcium Channel Blockers– Verapamil, Nifedipine, Amlodipine, Felodipine,

Isradipine, Nicardipine, Nimodipine, Diltiazem

• Slow Resorption of Bone (bisphosphonates)– Etidronate, Alendronate, Pamidronate, Risedronate,

Tiludronate, Zoledronic Acid, Ibandronate

• Hormones (must be injected)– Calcitonin-Salmon; Teriparatide (amino acids 1-34)

• Asthma– Cromolyn Sodium, Nedocromil Sodium

• Block calcium flux in mast cells preventing degranulation including histamine release.

Calcium Supplements and Reducing the Risk of Osteoporosis

• Current evidence concludes that it is crucial to consume adequate calcium in childhood and adolescence.– The more bone mass, the longer it will take

for osteoporosis to develop.

• High impact exercise with adequate calcium intake increases bone mass.– Much of this work has been done at OSU.

Calcium DRIs-1• Why AI rather than RDA?

– Difficult to determine an RDA for calcium intake that will result in:

• Optimal accumulation AND retention of calcium in the skeleton.

– Factors that affect calcium accumulation AND retention:

• Genetics• Hormones• Physical activity

Calcium DRIs-2• AI

– Infants 0 – 6 months 210 mg– Infants 7 – 12 months 270 mg– Child 1 – 3 years 500 mg– Child 4 – 8 years 800 mg– Boys & Girls 9 – 18 yrs 1,300 mg– Men & Women 19 – 50 yrs 1,000 mg– Men & Women 51- 70+ yrs 1,200 mg– Pregnancy & Lactation no change

Hypercalcemia-1• Causes

– Excessive intake of calcium supplements.– Increased intake of calcium supplements

or vitamin D supplements– Hyperparathyroidisms– Malignancies.

Hypercalcemia-2• Nephrolithiasis (kidney stones)

– Mixed conclusions. Some studies report that decreased intake of dietary calcium increases the risk of stone formation.

• Milk-Alkali Syndrome– It was first reported when the treatment of

peptic ulcer included milk and calcium carbonate antacid. The result was renal insufficiency with metabolic alkalosis.

• UL – Infants: dietary sources only– Age 1 year and older: 2,500 mg.