2. Contents:
• Introduction
• Distribution of calcium
• Biochemical functions
• Daily requirement and sources of calcium
• Calcium homeostasis
• Parathyroid hormone
• Calcitriol
• Calcitonin
• Disease states
• Hypercalcemia
• Hypocalcemia
3. Introduction
• Calcium is the most abundant mineral in the body. Calcium
contribute to the physiology and biochemistry of organisms. They
play an important role in signal transduction, in contraction of
muscles and in fertilization.
• The total content of calcium in an adult man is about 1 to 1.5 kg.
As much as 99% of it is present in the bones and teeth. The rest 1%
is present in extracellular fluid(mainly blood).
• Plasma calcium levels are tightly regulated in mammals(including
humans) with bone as the major storage site. Parathyroid hormone,
calcitriol and other factors regulate plasma calcium levels.
4. In bones:
• 99% of body calcium is present in bones.
• Bone is composed of a tough organic matrix
that is greatly strengthened by deposits of
calcium salts. Average compact bone
contains by weight about 30 percent matrix
and 70 percent salts. Newly formed bone
may have a considerably higher percentage
of matrix in relation to salts.
• The crystalline salts deposited in the
organic matrix of bone are composed
principally of calcium and phosphate.
• Major crystaline salt is calcium
hydroxyapatite{Ca10(PO4)6(OH)2]
Distribution of calcium
5. Plasma calcium:
• Most of the blood Ca is present in the plasma since the blood cells contain very
little of it. The normal concentration of plasma or serum Ca is 9-11 mg/dl (4.5-5.5
mEq/l).
50% ionized form = 5mg/dl
40% protein bound = 4-5mg/dl
10% complexed with = 1mg/dl
citrate, phosphate
6. Calcium in cells:
• Intracellular Ca2+ concentration= 2mEq/l
• Calcium influx into the cell is by Na+/Ca2+ exchange mechanism. This mechanism is
rapid but has low affinity for calcium.
• Entry of Ca2+ into mitochondria is by a calcium uniport system. But calcium exit by a
Na+-Ca2+ system which in turn is dependent on the Na+-H+ ATPase pump.
7. Biochemical Functions
1. Development of bones and teeth:
Calcium alongwith phosphate is required
for the formation(hydroxyapatite) and
physical strength of skeletal tissue.
Bones are in dynamic state and serve as
reservoir of calcium.
2. Muscle contraction: Ca2+ interacts with
troponin C to trigger muscle contraction.
Calcium also activates ATPase, increases
the interaction between actin and
myosin.
3. Blood coagulation: Several reactions in
cascade of blood clotting process are
dependent on Ca2+ (factor IV).
Figure: Biochemical functions of Calcium
8. 4. Nerve transmission: Ca2+ is necessary for the transmission of nerve impulse.
5. Membrane integrity and permeability: Ca2+ influences the membrane structure and
transport of water and several ions across it.
6. Activation of enzymes: Ca2+ is needed for the direct activation of enzymes such as
lipase(pancreatic), ATPase and succinate dehydrogenase.
7. Calmodulin mediated action of Ca2+ : Calmodulin is a calcium binding regulatory protein.
Ca-calmodulin complex activates certain enzymes e.g., adenylate cyclase, Ca2+ dependent
protein kinases, myosin kinase, phospholipase C, glycogen synthase.
Figure: Mechanism of action of calcium mediated calmodulin
9. 4. Calcium as intracellular messenger:
Certain hormones exert their action
through the mediation Ca2+ (instead of
cAMP). Calcium is regarded as a second
messenger for such hormonal action e.g.
epinephrine in liver glycogenolysis.
Calcium serves as a third messenger for
some hormones e.g. antidiuretic
hormone(ADH) acts through cAMP), and
then Ca2+ .
10. 5. Release of hormones: The release of certain hormones(insulin, PTH, calcitonin) from the
endocrine glands is facilitated by Ca2+ .
6. Secretory processes: Ca2+ regulates microfilament and microtubule mediated processes such
as endocytosis, exocytosis and cell motility.
7. Contact inhibition: Calcium is believed to be involved in cell to cell contact and adhesion of
cells in a tissue. The cell to cell communication may also require Ca2+ .
8. Action on heart: Ca2+ acts on myocardium and prolongs systole.
11. Calcium homeostasis
Calcium homeostasis refers to the maintenance of a constant concentration
of calcium ions in the extracellular fluid. It includes all of the processes that
contribute to maintaining calcium at its “set point.” Because plasma [Ca2+]
rapidly equilibrates with the extracellular fluid, ECF [Ca2+] is kept constant
by keeping the plasma [Ca2+] constant.
12. Factors regulating plasma Calcium level
The major Hormones that
regulate plasma calcium
level are:
1) Parathyroid hormone
2) Calcitriol
3) Calcitonin
Figure: Overview of calcium homeostasis
13. Principle organ systems
for Calcium homeostasis:
1) Intestine
2) Bone
3) Kidney
Figure: Organs of calcium homeostasis
14. Parathyroid hormone(PTH)
• Parathyroid hormone (PTH) is secreted by two pairs of parathyroid glands that
are closely associated with thyroid glands.
• Parathyroid hormone (mol. wt. 95,000) is a single chain polypeptide, containing
84 amino acids.
15. Synthesis of PTH:
PTH is originally synthesized as preproPTH
which is degraded to proPTH and, finally, to
active PTH. The rate of formation (by
degradation of proPTH) and the secretion of
PTH are promoted by low Ca2+ concentration.
Thus, the release of PTH from parathyroid
glands is under the negative feedback
regulation of serum Ca2+
Figure: Structure of preproparathyroid hormone
16. Control of Parathyroid Secretion by Calcium
Ion Concentration:
Even the slightest decrease in calcium ion
concentration in the extracellular fluid causes the
parathyroid glands to increase their rate of
secretion within minutes. Changes in extracellular
calcium ion concentration are detected by a
calcium-sensing receptor(CaSR).
Figure: Effects of parathyroid hormone
17. Mechanism of action of PTH :
PTH binds to a membrane receptor protein on the target cell and activates adenylate cyclase to
liberate cAMP
. This, in turn, promotes the phosphorylation of proteins (by kinases) which, finally
brings about the biological actions. PTH has 3 independent tissues-bone, kidneys and intestine-to
exert its action. The prime function of PTH is to elevate serum calcium level.
Figure: Mechanism of action of PTH
18. Action of PTH on Bones:
In the bone, PTH causes demineralization or decalcification. The number of osteoclasts are also
increased . Osteoclasts release lactate into surrounding medium which solubilizes calcium. PTH
also causes secretion of collagenase from osteoclasts. This causes loss of matrix and bone
resorption.
19. Action of PTH on intestine:
Parathyroid stimulates 1-hydroxylation
of 25-hydroxycholecalciferol in kidney
to produce calcitriol. This indirectly
increases calcium absorption from
intestine.
Figure: Organs of calcium homeostasis
20. Action of PTH on kidney:
In kidney, PTH causes decreased renal excretion of calcium and increased
excretion of phosphates. The action is mainly through increase in reabsorption of
calcium from kidney tubules.
Figure: Action of PTH on kidney
21. Calcitriol
• The physiologically active form
of vitamin D is a hormone,
namely calcitriol or 1,25-
dihydroxycholecalciferol (1,25
DHCC).
22. Action of calcitriol:
Calcitriol induces the synthesis of a specific calcium binding protein, Calbindin, in the intestinal cells. This
protein increases the intestinal absorption of calcium as well as phosphate. Thus blood Ca level is increased
by calcitriol (the active vitamin D). Furthermore, calcitriol stimulates calcium uptake by osteoblasts of bone
and promotes calcification or mineralization (deposition of calcium phosphate) and remodeling
Figure: Action of calcitriol
24. Calcitonin
• Calcitonin is a peptide containing 32 amino acids. It is secreted by
parafollicular cells of thyroid gland. The action of CT on calcium
metabolism is antagonistic to that of PTH. Thus calcitonin
promotes calcification by increasing the activity of osteoblasts.
Further, calcitonin decreases bone resorption and increases the
excretion of Ca into urine. CT, therefore, has a decreasing
influence on blood calcium.
25.
26. Disease states
The blood Ca level is maintained within a narrow range by the homeostatic
control, most predominantly by PTH. Hence abnormalities in Ca metabolism
are mainly associated with alterations in PTH
27. HYPERCALCEMIA
• Elevation in serum Ca level (normal 9-11
mg/dl) is hypercalcemia. Hypercalcemia is
associated with hyperparathyroidism caused
by increased activity of parathyroid glands.
Decrease in serum phosphate (due to
increased
28. CAUSES OF HYPERCALCEMIA:
Overactive parathyroid glands
(hyperparathyroidism): This most common
cause of hypercalcemia
Cancer: Lung cancer and breast cancer, as
well as some blood cancers(multiple
myeloma). Metastatic carcinoma of bones
Other diseases: Certain diseases, such as
tuberculosis, sarcoidosis, Paget’s disease
Hereditary factors: Familial hypocalciuric
hypercalcemia.
Thyrotoxicosis and Addison’s disease
Severe dehydration: A common cause of mild or transient
hypercalcemia
Medications: Certain drugs — such as lithium, used to
treat bipolar disorder
Supplements:
Milk alkali syndrome:- Taking supplements of calcium.
Excess vitamin A and vitamin D
Figure: Hyperparthyroidism
29. Symptoms of hypercalcemia:
1. Anorexia, nausea, vomiting
2. Polyuria and polydipsia
3. Confusion, depression, psychosis
4. Renal stones
5. Ectopic calcification and pancreatitis
6. Blood alkaline phosphatase is increased
30. HYPOCALCEMIA
• Hypocalcemia is a more serious and life
threatening condition. lt is characterized by
a fall in the serum Ca to below 7 mg/dl,
causing tetany. The symptoms of tetany
include neuromuscular irritability, spasms
and convulsions.
Figure: Carpopedal spasm in Tetany
31. CAUSES OF HYPOCALCEMIA:
•Deficiency of Vitamin D:
Decreased exposure to sunlight
Melabsorption, dietary deficiency
Hepatic diseases
Decreased renal synthesis of calcitriol
•Deficiency of parathyroid
Hypoparathyroidism(primary, secondary)
•Increased calcitonin
Medullary carcinoma of thyroid
•Deficiency of calcium
Intestinal melabsorption
Alkalosis decreasing ionized calcium
•Deficiency of magnesium
•Increase in posphorus level
Renal failure
•Hypoalbuminemia
