The document discusses the significance of calcium balance, including its physiological roles and the various disorders associated with its imbalance such as hypercalcemia and osteoporosis. It outlines the physiology of calcium absorption, excretion, and the effects of drugs like bisphosphonates and vitamin D on calcium metabolism. The regulatory mechanisms involving calcitonin and parathyroid hormone are also explained, highlighting their importance in maintaining calcium homeostasis.

1. Drugs affecting Calcium Balance
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Why such drugs?
HYPERCALCEMIA
HYPOCALCEMIA--Hypoparathyroidism
HYPERVITAMINOSIS D— Hypercalcemia
VITAMIN D DEFICIENCY
• SPECIFIC DISORDERS OF BONE
– Rickets
– Osteoporosis
– PAGET’S DISEASE
– OSTEOMALACIA AND RENAL OSTEODYSTROPHY

4. CALCIUM
• Composition: ~2% TBW,
1-1.3 kg/ healthy adult
• Bone: 99%
• Normal plasma level: 9-11 mg/dl
• Plasma protein bound: 40%
• Un-dissociable complex: 10%
• Ionized: 50%

6. DAILY REQUIREMENT
• Adolescents: 1.3 g/day
• Adults: 1 g/day
• >50yrs: 1.2 g/day
• <9 yrs: 865-625 mg/day

7. Physiological importance of Calcium
• Calcium salts in bone provide structural integrity of
the skeleton
• Calcium ions in extracellular and cellular fluids is
essential to normal function of a host of biochemical
processes
– Neuro-muscular excitability
– Blood coagulation
– Hormonal secretion
– Enzymatic regulation

8. Regulation of Calcium Metabolism
• Organ systems that play an import role in Ca2+
metabolism
– Skeleton
– GI tract
– Kidney
• Calcitropic Hormones
– Parathyroid hormone (PTH)
– Calcitonin (CT)
– Vitamin D (1,25 dihydroxycholecalciferol)
– Parathyroid hormone related protein (PTHrP)

9. ABSORPTION & EXCRETION
• Ca2+
enters the body only through the intestine.
• Active vitamin D-dependent transport occurs in the proximal
duodenum, whereas facilitated diffusion throughout the
small intestine accounts for the majority of total Ca2+
uptake.
• This uptake is counterbalanced by an obligatory daily
intestinal calcium loss of about 150 mg/day.
• The efficiency of intestinal Ca2+
absorption is inversely
related to calcium intake. Thus, a diet low in calcium leads to
a compensatory increase in fractional absorption owing partly
to activation of vitamin D. In older persons, this response is
considerably weak.

10. ABSORPTION & EXCRETION
• Disease states associated with steatorrhea, diarrhea, or
chronic malabsorption promote fecal loss of calcium
• Drugs such as glucocorticoids and phenytoin depress
intestinal Ca2+
transport.
• Urinary Ca2+
excretion =quantity filtered -amount reabsorbed
at the nephrons.
• About 9 g of Ca2+
is filtered each day. Tubular reabsorption is
very efficient, with more than 98% of filtered Ca2+
returned to
the circulation. The efficiency of reabsorption is highly
regulated by PTH but also is influenced by filtered Na+
, the
presence of non-reabsorbed anions, and diuretic agents.

11. ABSORPTION & EXCRETION
• Sodium intake, and therefore sodium excretion, is directly
related to urinary calcium excretion.
• Diuretics that act on the ascending limb of the loop of Henle
(e.g., furosemide) increase calcium excretion.
• By contrast, thiazide diuretics uncouple the relationship
between Na+
and Ca2+
excretion, increasing sodium excretion
but diminishing calcium excretion.
• Dietary protein is directly related to urine Ca2+
excretion,
presumably owing to the effect of sulfur-containing amino
acids on renal tubular function.

12. Calcium turnover

13. USES
• Tetany
• Dietary Supplement
• Osteoporosis
• Antacid (Calcium Carbonate)

14. PREPARATIONS OF CALCIUM
• Calcium chloride (27% Ca)
• Calcium gluconate (9% Ca)
• Calcium lactate (13%) Ca
• Calcium dibasic phosphate (23% Ca)
• Calcium carbonate (40% Ca)

15. Calcium Balance Modulators
• Bisphosphonates
• Vitamin D
• Calcitonin
• PTH

16. BISPHOSPHONATES
• Derivatives of Pyrophosphate in which O of the P-O-P is replaced
by carbon
– Etidronate, Pamidronate, Alendronate
• Mechanism is not fully understood but theories have been
proposed for their actions:
– They localize in the acidic regions of bone matrix below
osteoclasts and are taken up by osteoclasts in exchange for
Ca2+
resulting in:
• Accelerated apoptosis of osteoclasts
• Disruption of cytoskeleton and border of osteoclasts
– Also affect osteoclast precursors by inhibiting their
differentiation by suppressing IL-6
– Interferes with certain steps of mevalonate pathway required
for prenylation of certain GTP-proteins involved in maturation
of cytoskeletal maturation

17. ETIDRONATE
• Also interferes with bone mineralization; should be used
intermittently with a 3 months gap
USES:
• Paget’s Disease, hypercalcemia
Side effects are GI irritation, bone pain, headache, metallic
taste, pyrexia, hypersensitivity
Precaution:
Continuous therapy  Osteomalacia

18. ALENDRONATE
• More potent, orally active
• Patients must be advised not to lie down after medication to
reduce chances of esophagitis
• USES: Prevention and treatment of Osteoporosis
• S/E: gastric erosion, flatulence, body-ache, initial fall in serum-
Ca2+
level
• Calcium ions, iron, fruit juice, tea, coffee, mineral water
interferes with its absorption
• NSAIDs use is discouraged

19. Common USES of BPN
• Osteoporosis
• Paget’s Disease
• Osteolytic Bone Metastasis
• Hypercalcemia of Malignancy

20. Other BPN
• Tiludronate
• Risedronate
• Ibandronate
• Zolendronate

21. VITAMIN D
• Antirachitic compounds
– D1
– D2 (Calciferol)
– D3 (Cholecalciferol)
• Biologically active derivative of
D3  Calcitriol
• D3 is synthesized from
cholesterol underlying the skin,
transported by blood to act on
specific receptors on target sites
and synthesis has negative
feedback regulation based on
Ca2+ concn.  Hormone

22. HUMAN REQUIREMENTS/DAY
• Infants & Children: 400 IU or 10 mcg
• Adult: 200 IU or 5 mcg
• Pregnant & Lactating: > 1000 IU

23. ABSORPTION, FATE & EXCRETION
• Both vitamins D2 and D3 are absorbed from the small
intestine, D3 may be absorbed more efficiently.
• Appears first within chylomicrons in lymph and bile is
essential for adequate absorption of vitamin D
• The primary route of vitamin D excretion is the bile; only a
small percentage is found in the urine
• Absorbed vitamin D circulates in the blood in association with
vitamin D-binding protein, a specific a-globulin with a t1/2
=19 to 25 hours
• Stored in fat depots for prolonged periods
• Two successive hydroxylations give biologically active
Calcitriol, first in liver and the next in PCT of nephron
• Calcitriol itself undergo hydroxylation before elimination

24. MECHANISM OF ACTION
• Increases absorption and retention of Ca2+
and phosphate
and maintain normal concn. of these ions by facilitating their
absorption in the small intestine, by interacting with PTH to
enhance their mobilization from bone, and by decreasing
their renal excretion.
• It also exerts direct physiological and pharmacological effects
on bone mineralization.
• The mechanism is mediated by the interaction of calcitriol
with the vitamin D receptor (VDR)
• Calcitriol binds to cytosolic VDRs (Steroidal type) within
target cells, and the receptor-hormone complex translocates
to the nucleus and interacts with DNA to modify gene
transcription.

25. PHYSIOLOGICAL FUNCTIONS
Intestinal Absorption of Ca2+
:
• Increases the transcellular movement of Ca2+
from the
mucosal to the serosal surface of the duodenum involving
three processes:
– Ca2+
entry across the mucosal surface,
– diffusion through the cell, and
– energy-dependent extrusion across the serosal cell membrane
• Calcium is also secreted from serosal to mucosal
compartments. Thus net calcium absorption occurs.
• Calcitriol also up-regulates the calcium-binding protein
calbindin-D9K

26. PHYSIOLOGICAL FUNCTIONS
Mobilization of Bone Minerals:
• Physiological doses of vitamin D promote mobilization of Ca2+
from bone, and large doses cause excessive bone turnover
• Increases bone turnover by multiple mechanisms  Mature
osteoclasts apparently lack the VDR and thus acting by a
non-VDR mechanism, it moves the osteoclast precursor cells
to resorption sites, as well as the development of
differentiated functions
• Osteoblasts express the VDR, and calcitriol induces their
production of several proteins, including osteocalcin, a
vitamin K-dependent protein and interleukin-1 (IL-1), a
lymphokine that promotes bone resorption

27. PHYSIOLOGICAL FUNCTIONS
Renal Retention of Ca2+
& PO4
-
• The effects of calcitriol on the renal retention of Ca2+
and
phosphate are of uncertain importance.
• Calcitriol increases retention of Ca2+
(DCT) independently of
phosphate (PCT)
Other Effects:
• Affects maturation and differentiation of mononuclear cells
cytokine production and immune function
• Inhibits epidermal proliferation and promotes epidermal
differentiation  potential treatment for psoriasis vulgaris
• Affects the function of skeletal muscle and brain

28. USES
• Prophylaxis of Vit. D Deficiency
• Metabolic Rickets:
1. Vit. D Resistant Rickets: High dose of Calcitriol or Alfacalcidiol with
phosphate
2. Vit. D Dependent Rickets: Calcitriol or Alfacalcidiol
3. Renal Rickets: Calcitriol or Alfacalcidiol
• Senile or postmenopausal Osteoporosis : Vit. D3 + Calcium or
Calcitriol or Alfacalcidiol for Vit. D3
• Hypo-PTH: Calcitriol or Alfacalcidiol (expensive than Vit. D2 or
D3)
• Psoriasis
• Fanconi’s Syndrome (Expired Tetracyclines- Kidney)

29. Rickets- Russia-Yesteryears
• School kids getting their dose of
Vitamin D in Russia in yesteryears
when rickets was seen as a
prominent problem there,
government made it compulsory
for school kids to get exposed to
UV lamps to help the rid of rickets.

31. CALCITONIN
• Hypocalcemic hormone whose actions generally oppose
those of PTH, secreted by C cells of Thyroid glands
• Secretion is regulated by plasma levels of Ca2+; increases
with hypercalcemia and vice-versa
• Secretion is stimulated by a number of agents, including
– catecholamines,
– glucagon,
– gastrin, and
– cholecystokinin
• Mechanism produced via CTR, a GPCRs

32. PHYSIOLOGIC FUNCTIONS
• The hypocalcemic and hypophosphatemic effects of
calcitonin are caused predominantly by direct inhibition of
osteoclastic bone resorption
• Although calcitonin inhibits the effects of PTH on osteolysis,
it inhibits neither PTH activation of bone cell adenylyl cyclase
nor PTH-induced uptake of Ca2+ into bone
• Calcitonin interacts directly with receptors on osteoclasts to
produce a rapid and profound decrease in ruffled border
surface area, thereby diminishing resorptive activity
• Depressed bone resorption reduces urinary excretion of
Ca2+, Mg2+, and hydroxyproline

33. PHYSIOLOGIC FUNCTIONS
• Plasma phosphate concentrations are lowered owing also to
increased urinary phosphate excretion
• Direct renal effects of calcitonin vary with species
• Acute administration of pharmacological doses of calcitonin
increases urinary calcium excretion, whereas calcitonin
inhibits renal calcium excretion at physiological
concentrations
• In humans, calcitonin increases fractional urinary calcium
excretion in a dose-dependent manner in subjects given a
modest calcium load

34. USES
• Hypercalcemic states associated with or without:
– hyper-PTH,
– HyperVitaminosis D,
– osteolytic bony metastasis
• Postmenopausal Osteoporosis
• Paget’s Disease

35. PARATHYROID HORMONE (Parathormone)
• Polypeptide hormone that helps to regulate plasma Ca2+
by
– affecting bone resorption/formation,
– renal Ca2+
excretion/reabsorption, and
– calcitriol synthesis (thus GI Ca2+
absorption)
• PTH exerts its action via at least two receptors;
– PTH-1 receptor (PTH1R or PTH/PTHrP receptor) and
– PTH-2 receptor
– found in vascular tissues, brain, pancreas, and placenta.
• These are GPCRs that can couple with Gs and Gq in cell-type
specific manners; thus, cells may show one, the other, or
both types of responses.
• Also can activate phospholipase D

36. Regulation of PTH Secretion
• Plasma Ca2+
is the major factor regulating PTH secretion. As
the concentration of Ca2+
diminishes, PTH secretion
increases.
• Sustained hypocalcemia induces parathyroid hypertrophy
and hyperplasia
• The active vitamin D metabolite (calcitriol), directly
suppresses PTH gene expression
• Severe hypermagnesemia or hypomagnesemia can inhibit
PTH secretion

37. Physiologic Functions
Effects on Bone:
• Increases bone resorption and thereby increases Ca2+
delivery to the extracellular fluid
• Allows osteoclast precursor cells to form new bone
remodeling units
• Direct in vitro effects of PTH on osteoblasts are inhibitory 
reduced formation of type I collagen, alkaline phosphatase,
and osteocalcin
• PTH in vivo increases total number of active osteoblasts
owing to initiation of new remodeling units.
• Thus plasma levels of osteocalcin and alkaline phosphatase
activity actually may be increased

38. Physiologic Functions
Effects on Kidney:
• Enhances the efficiency of Ca2+
reabsorption, inhibits tubular
reabsorption of phosphate, and stimulates conversion of
vitamin D to its biologically active form, calcitriol
• Net Result  Hypercalcemia and Hypophosphatemia
• However, the increase excretion of Ca2+
may occur in
hyperparathyroidism and vice-versa due to direct prominent
effect on tubules
• Newly synthesized calcitriol interacts with specific high-
affinity receptors in the intestine to increase the efficiency of
intestinal Ca2+
absorption, thereby also increasing the plasma
Ca2+
concentration

39. Physiologic Functions
Calcitriol Synthesis:
• The final step in the activation of vitamin D to calcitriol
occurs in kidney proximal tubule cells. Three primary
regulators govern the activity of the 25-hydroxyvitamin D3-1a-
hydroxylase that catalyzes this step: Pi, PTH, and Ca2+
• Reduced circulating or tissue phosphate content rapidly
increases calcitriol production, whereas hyperphosphatemia
or hypercalcemia suppresses it
• PTH powerfully stimulates calcitriol synthesis. Thus, when
hypocalcemia causes a rise in PTH concentration, both the
PTH-dependent lowering of circulating Pi and a more direct
effect of the hormone on the 1a-hydroxylase lead to
increased circulating concentrations of calcitriol

40. Physiologic Functions
Other Ions:
• Reduces renal excretion of Mg2+ 
the net result is increased renal Mg2+
reabsorption and increased mobilization of the ion from bone
• Increases excretion of water, amino acids, citrate, K+
, bicarbonate, Na+
, Cl-
,
and SO4
2-
, whereas decreases the excretion of H+
Other Actions:
• Decreases Ca2+
in milk, saliva and ocular lens

41. Calcium homeostasis and its
regulation by PTH
• PTH has stimulatory effects on
bone and kidney, including the
stimulation of 1 alpha-
hydroxylase activity in kidney
mitochondria leading to the
increased production of the
biologically active hormone
1,25-dihydroxyvitamin D
(calcitriol) from 25-
hydroxyvitamin D.
Solid lines indicate a positive effect; dashed lines refer to negative feedback

42. USES
• To differentiate pseudo-hyper-PTH from true
one.
• No therapeutic value as such
• Problems associated with Ca2+
deficiency can
be overcome by affordable Ca2+
preparations
and Vit. D

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