Transcript Slide 1

Phar 722
Pharmacy Practice III
MineralsCalcium
Spring 2006
Calcium Learning Objectives
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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 1,25diOH-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
Changes in Calcium Flux with Age
10 year old
Female Male
18 year old
Female Male
Body Ca (gm)
290
360
630700
820900
Rate of
Deposition in
Bone (mg/day)
100150
100150
50
100
0
1,300
1,300
1,300
1,000
AI (mg/day)
1,300
Mature
Female Male
9201,000
60 year old
Female
1,200
820
0
-20*
1,000
1,200
* An early postmenopausal female loses 30 – 100 mg/day from bone.
Mean Calcium Intake by Age and Gender
1400
1997 DRI
Calcium (mg) per day
1200
1000
1989 RDA
800
Males
600
Fem ales
400
200
0
0
10
20
30
40
50
Age (years)
60
70
80
90
Top number: adolescent female
Bottom number: adult female
Distribution of Calcium in the Body
• Assume 1000 g
– Skeleton & teeth 990 g (99%)
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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 calciumbinding protein.
• Bone: Calcium reservoir
• Kidney: Maintains
calcium homeostasis.
Normally, calcium
undergoes tubular
reabsorption, but calcium
is excreted when tubular
reabsorption decreases.
Blood
Ca+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.
1,25-diOH-D3
Blood
Ca+2
1,25-diOH-D3
Parathyroid
Hormone
Hormonal Control of Calcium Flux-2
• 1,25-diOH-D3
– Increases blood calcium
concentrations.
– PTH required to activate
the oxidation of 25-OHD3 in the kidney to 1,25diOH-D3.
– Increases calcium
absorption from the
small intestine.
– With PTH, it enhances
fluxes of calcium out of
the bone
1,25-diOH-D3
Blood
Ca+2
1,25-diOH-D3
Parathyroid
Hormone
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
Calcitonin
osteoporosis.)
Promotes.
Blood
Ca+2
Calcitonin
inhibits
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
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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
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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
% Fraction
Absorbed
Calcium
Content
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
126
258
31
80
1.2
Tofu
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
Ca glubionate
6.5
Ca gluconate
9
Ca lactate
13
Ca citrate
21
Ca acetate
25
Tricalcium phosphate 39
Ca carbonate
40
mEq Ca++/g mg Ca/1000 g
3.3
65
4.5
90
6.5
130
10.6
210
12.6
250
19.3
390
20
400
There are various combinations including:
Calcium with fluoride
Calcium with vitamin D
Calcium with vitamins D and K
Calcium Supplements
Calcium 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
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MW 430
9% Ca (9.3% anhydrous)
4.5 mEq Ca++/ g
90 mg/1000 g salt
Ca++
O
C
O-
H
C
OH
HO
C
H
H
C
OH
H
C
OH
CH2OH
2
Calcium Supplements
• Calcium lactate
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MW 308
13% Ca
6.5 mEq Ca++/ g
130 mg/1000 g salt
H3C
OH
O
CH
C
5 H2O
Ca++
O- 2
Calcium Supplements
O
• Calcium citrate
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–
–
–
MW NA
21% Ca
10.6 mEq Ca++/ g
210 mg/1000 g salt
O
-O
C
CH2
C
C
OH
CH2
C
O
OxCa++
On
Calcium Supplements
• Calcium acetate
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–
–
–
MW 158
25% Ca
12.6 mEq Ca++/ g
250 mg/1000 g salt
Ca++
O
H3C
C
O-
2
Calcium Supplements
• Tricalcium Phosphate
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Ca3(PO4)2
MW 310
39% Ca
19.3 mEq Ca++/ g
390 mg/1000 g salt
Calcium Supplements
• Calcium Carbonate
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CaCO3
MW 100
40% Ca
20 mEq Ca++/ g
400 mg/1000 g salt
Calcium Supplements
Potential 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
– Infants 7 – 12 months
– Child 1 – 3 years
– Child 4 – 8 years
– Boys & Girls 9 – 18 yrs
– Men & Women 19 – 50 yrs
– Men & Women 51- 70+ yrs
– Pregnancy & Lactation
210 mg
270 mg
500 mg
800 mg
1,300 mg
1,000 mg
1,200 mg
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.