This presentation provides knowledge about Calcium, its role in human body, homeostasis, factors affecting calcium absorption, drugs affecting calcium regulation, various endogeneous & exogeneous substances, recent research. This ia an assignment in the subject Advanced Pharmacology -II, 1st year M.Pharm, 2nd semester.

1. ADVANCED PHARMACOLOGY - II
“Drugs Affecting Calcium Regulation”
By
Chetan A., M.Pharm 1st Year (Pharmacology)
K.K. College of Pharmacy
Chennai, TamilNadu

2. Learning Objective
• Introduction
• Calcium Homeostasis
• Factors affecting calcium absorption
• Drugs affecting calcium regulation
• Drugs stimulating Bone formation
• Drugs inhibiting Bone resorption
• Other Drugs
• Recent Research
• Facts
• Reference

3. Calcium
• Calcium is the most abundant mineral in the body (bone & teeth),
providing integrity of the skeleton
• Calcium ions (Ca2+) contribute to the physiology and biochemistry of
organisms cell.
• They play an important role in signal transduction pathways, where they
act as a second messenger, in neurotransmitter release from neurons, in
contraction of all muscle cell types, and in fertilization.
• Parathyroid hormone secreted by the parathyroid gland regulates the
resorption of Ca2+ from bone, reabsorption in the kidney back into
circulation, and increases in the activation of vitamin D3 to calcitriol.

4. Physiological Role of Calcium
• Controls excitability of nerves & muscles
• Maintains integrity and regulates permeability of cell membrane
• Essential for muscle contraction (Skeletal, Cardia)
• Formation of milk, bone & teeth
• Necessary for blood coagulation
• Necessary for release of some neurotransmitters from storage vesicles of
the nerve terminal.
• Impulse generation and conduction in heart
• Intracellular messanger for hormones, autocoids and transmitters

5. Plasma Calcium Level
• Regulated by three hormones , Parathyroid hormone, Calcitonin and
Calcitriol (active Vit. D)
• Recommended Dietary Allowances (RDAs) for calcium is 800-1500 mg.
• Normal Plasma Level is 9-11 mg/dL, <8 mg/dL - Hypocalcaemia and
>12 mg/dL - Hypercalcaemia
• 40% is bound to plasma protein, Albumin, 10% to citrate, carbonate and
Phosphate and 50% is free ionized and important form.
• Calcium metabolism is connected to Phosphorous and Magnesium
metabolism.

6. Absorption & Excretion of Calcium
• Absorbed by facilitated diffusion and carrier mediated active transport in
duodenum by Ca2+ dependent ATPase.
• Absorption occurs in the small intestine and require vitamin D, filtered
through glomerulus but mostly reabsorbed.
• Phosphates, Oxalates and Tetracyclines complexes with calcium in gut
and inhibits its absorption
• Vitamin D and Parathyroid hormone (PTH) increases the reabsorption of
calcium, while Calcitonin decreases reabsorption in kidney.
• About 300 mg is excreted daily in urine and faeces, while 30-80% of
ingested calcium is absorbed.

7. Calcium Homeostasis
• The plasma ionized calcium (Ca2+) concentration is very tightly controlled by a pair
of homeostatic mechanisms.
1. The Parathyroid glands, where the chief cells sense the Ca2+ level by means of
specialized calcium receptors in their membranes & secrete parathyroid hormone
(PTH) in response to a fall in the plasma ionized calcium level. Other substance
released are Calcitriol (Vit. D3) & Fibroblast growth hormone.
2. The Parafollicular cells of the thyroid gland secrete calcitonin, in response to a rise
in the plasma ionized calcium level. Other substance released are glucocorticoids &
estrogen
 In the absense of any of these process, bone becomes brittle or Hypercalcemia

8. Calcium Homeostasis
https://en.wikipedia.org/wiki/Homeostasis#/media/File:625_Calcium_Homeostasis.jpg
There are two types of cells in
bone,
Osteoblast - Responsible for the
synthesis and mineralization of bone
during both initial bone formation and
later bone remodeling.
Osteoclast - A cell that nibbles at and
breaks down bone and is responsible
for bone resorption

9. Factors affecting Calcium absorption
• Factors favouring calcium absorption
1. Body needs - Growth, Pregnancy, Lactation
2. Presence of Vitamin D
3. Parathyroid Hormone (PTH) stimulates the activation of vitamin D, thus
indirectly increases absorption of vitamin D
4. Milk lactose
5. Acid environment - Hcl, citric acid, ascorbic acid (Vit. C)
6. Protein intake and amino acids such as lysine and glycine
7. Fat intake
8. Excercise
9. Phosphorous balance

10. Factors affecting Calcium absorption
• Factors inhibiting absorption of Calcium
1. Vitamin D deficiency
2. High fat diet - Fatty acids form calcium soaps that cannot be absorbed.
3. Hypochlorhydria (low stomach acid)
4. Lack of excercise
5. Presence of Phytates and Oxalates - Insoluble calcium salts are formed.
6. Dietary fiber in excess inhibits absorption
7. Excess Phosphates, Magnesium and Iron decrease absorption
8. Glucocorticoids, advancing age & intestinal inflammatory disorders
reduce intestinal absorption of Calcium

11. Drugs affecting calcium regulation
Drugs stimulate bone formation
Calcium Preparations
1. Calcium
phosphate/Carbonate/Lactate
/Lactobionate
2. Hydroxyapatite
Vitamin D Preparation
1. Ergocalciferol (Vit. D2)
2. Cholecalciferol (Vit. D3)
3. Alfacalcidol (1α (OH) D3)
4. Doxercalciferol (1α (OH) D2)
5. Paracalciferol (19 Nor 1,25 (OH) D2)
Parathyroid hormone Preparation
1. Teriparatide (Recombinant PTH)
2. Abaloparatide

12. Drugs affecting calcium regulation
Drugs inhibiting bone resorption
Resorption - Bone resorption is the process by which the bones are absorbed and
broken down by the body. Osteoclast cells are responsible for the breakdown of bone
minerals thus releasing calcium and phosphorous into the bloodstream. This occurs
when the body has insufficient calcium from an individual’s diet.
Miscellaneous
1. Calcitonin
2. Cinacelcet
3. Denosumab
4. SERM
5. Gallium nitrate
Bisphosphonates
1. Pamidronate
2. Risedronate
1. Fluorides
2. Glucocorticoids
3. Estrogen
4. Strontium ranelate
Other Drugs

13. Drugs stimulating bone
formation

14. I. Calcium Preparation
• Calcium carbonate (40% Ca)
• Calcium citrate (as tetrahydrate, 21% Ca2+)
• Calcium gluconate (9% Ca)
• Calcium lactate
• Calcium dibasic phosphate (23% Ca)
• Calcium chloride (27% Ca)
Side effects:
• Constipation, Bloating and excess gas

15. 1. Calcium gluconate
• It contains 9% calcium
• Non-irritating to GI mucosa & preferred for parentral route in tetany
2. Calcium dibasic phosphate
• It contais 23% calcium & it is insoluble
• With HCl it form soluble chloride in stomach
• Used as antacid and calcium supplement
3. Calcium lactate
• It contains 13% of calcium
• Orally administered
• Non-irritant & well tolerated

16. Use of Calcium Preparations
1. Tetany
• For immediate treatment of severe cases 10–20 ml of Cal. gluconate (elemental calcium 90–
180 mg) is injected i.v. over 10 min, followed by slow i.v. infusion.
• A total of 0.45- 0.9 g calcium (50 to 100 ml of cal. Gluconate solution) over 6 hours is
needed for completely reversing the muscle spasms.
2. As dietary supplement
In growing children, pregnant, lactating and menopausal women.
3. Calcium gluconate i.v. has been used in dermatoses, paresthesias, weakness and other
vague complaints.
4. As Antacid

17. II. Vitamin D
• Vitamin D is a fat-soluble vitamin. It is a prohormone. It has three forms,
• D1 : ergocalciferol - mixture of antirachitic substances found in food—only of
historic interest
• D2 : calciferol—present in irradiated food— yeasts, fungi, bread, milk.
• D3 : cholecalciferol — synthesized in the skin under the influence of UV rays.
• Well absorbed from intestine in presence of bile salts, bound to specific α globulin &
stored mostly in adipose tissues. It is hydroxylated in liver to active & inactive
metabolites which are excreted in bile. Calcitriol is cleared rapidly from body
• Source of Vit. D for body - synthesized from 7-dehydrocholestrol in presence of UV
light or absorbed from the diet in natural form (Vit. D3) or the plant form (Vit. D2).
• The t1/2 of different forms varies from 1-18 days.
• 1 μg of cholecalciferol = 40 IU of Vit. D. RDA is 400 IU/day

18. Synthesis of Vitamin D
7-DEHYDROCHOLESTEROL ERGOSTEROL
UV light
CHOLECALCIFEROL (Vit D3) CALCIFEROL (Vit D2)
liver
CALCIFEDIOL (25-OH-D3) 25-OH-D2
kidneys
CALCITRIOL (1,25 (OH)2D3) 1,25 (OH)2D2

19. Action of Vitamin D

20. Disorders related to Vitamin D
• Vitamin D Deficiency:
Plasma Ca2+ & phosphate falls due to inadequate intestinal absorption. PTH is
released which increases resorption. Bone formation fails and bone becomes soft -
rickets in childrens & Osteomalacia in adults.
• Hypervitaminosis D
Due to high doses of Ca2+ (~50000 IU/day) or due to increased sensitivity of
tissues to Vit. D. It causes hypercalcaemia, weakness, fatigue, vomitting, diarrhoea,
polyuria. Treated by Corticosteroids, low calcium diet, withholding vitamin
supplements.

21. Analogs of Vitamin D
There are 2 analogs of Vit. D
1. Alfacalcidol - 1α-OHD3 - a prodrug
• Effective in renal bone disease, Vit. D dpendent rickets, Vit. D resistant rickets,
hypoparathyroidism, osteoporosis
• Dose - 1-2 μg/day, children < 20 kg 0.5 μg/day
2. Dihydrotachysterol:
• Directly mobilizes calcium from bone after 25 - hydroxylation in liver & does not
require PTH dependent activation in the kidney
• Used in hypoparathyroid & renal bone disease
• Dose - 0.25-0.5 mg/day

22. III. Parathyroid Hormone (PTH)
• PTH is a single chain 84 amino acid polypeptide, synthesized from cheif cells of
parathyroid gland vis calcium-sensing receptor (CaSR) & regulated by plasma Ca2+
concentration.
• Injection s.c 20μg once daily, it acts only for 2-3 hours.
• PTH has four actions that increase the extracellular calcium concentration. First, it
stimulates resorption of calcium by renal tubules.
• Second, it decreases resorption of phosphate by renal tubules. This decreases the
extracellular phosphate concentration, which in turn tends to increase the
extracellular calcium concentration.
• Third, PTH stimulates the hydroxylation of vitamin D in the kidneys.
• Fourth, PTH increases bone resorption by stimulating osteoclast activity, which
enables bone calcium to enter the extracellular pool.

23. Parathyroid Hormone (PTH)
• The active form of Vit.D (Calcitriol)
inhibits expression of PTH gene in
parathyroid cells reducing PTH
production.
• Low plasma Ca2+ stimulates PTH
release. PTH plasma half life is 2-5
mins.
• Two disorders in PTH
1. Hypoparathyroidism - Low levels
of Ca2+ , tetany.
2. Hyperparathyroidism -
Parathyroid tumour
Action of PTH

24. Mechanism of Action of PTH

25. Parathyroid Hormone Analogs
There are two PTH analogs - Teriperatide, Abaloparatide
Teriperatide
• Recombinant preparation of human PTH. It duplicates all the actions of long (1-84)
PTH. Increase bone mineral density in osteoporotic women. It stimulates bone
formation with plasma t1/2 of 1hr.
• The effects are faster & marked then that produced by estrogen & bisphosphonates
(BPNs)
• Side effects - dizziness, leg cramps, risk of Osteosarcoma
• Contraindications - Pagets disease & Hypercalcaemia
• Treatment beyond 2 years is not recommended.

26. Drugs Inhibiting Bone Resorption

27. I. Bisphosphonates (BPNs)
• BPNs are pyrophosphate analogues.
• Two phosphonate groups are linkded to C atom.
• They decrease osteoclast-mediated bone resorption.
• Prevent loss of bone density & decrease the risk of fractures.
• Also impart antitumour action on bony metastasis.
• BPNs are given orally, except Zolendronate, Pamidronate.
• Poorly absorbed in body & produce gastric irritation, Esophagitis
• Food interaction causes poor absorption, hence to be taken on empty stomach.
• They are contraindicated in gastroesophageal reflux, peptic ulcer and renal
impairment.

28. Classes of Bisphosphonates
• First generation BPNs
1. Etidronate
2. Tiludronate
3. Medronate
4. Tiludronate
• Second generation BPNs
1. Pamidronate
2. Alendronate
3. Ibandronate
• Third generation BPNs
1. Risedronate
2. Zoledronate
3. Neridronate
4. Oxidronate
Less potent, Rarely used now
10-100 times more potent, Contains ‘N’ in side chain
Upto 10,000 times more potent, Contains ‘N’ in heterocyclic c ring

29. Mechanism of Action of BPNs
Bisphosphonates
Stimulate osteoclast apoptosis Inhibit cholestrol synthesis
pathway
Decrease in osteoclast number Decrease in osteoclast function
Decrease in bone resorption
Exerted by only 2nd &3rd
generation BPNs

30. Uses of BPNs
1. Osteoporosis - first choice of drug is BPNs. 2nd & 3rd gen BPNs are
effective in preventing & treating postmenopausal osteoporosis.
2. Paget’s disease - arrest osteolytic lesions, reduce bone pain. BPNs are
more effective than calcitonin.
3. Hypercalcaemia of malignancy - is a medical emergency with altered
consiousness. Vigorous i.v hydration is instituted first. Pamidronate
(60-90 mg i.v over 2-4 hr) or Zoledronate (4 mg i.v over 15 min) are
effective & taken for 24-48 hrs
4. Osteolytic bone metasis - Parentral pamidronate/Zoledronate are
effective.

31. Bisphosphonates (BPNs)
1. Pamidronate - (Second generation potent BPN)
• Dose - 60-90 mg over 2-4 hours weekly or monthly only by i.v
• Uses - Paget’s disease, hypercalcaemia of malignancy & in bone metastatis
• Adverse effects - thrombophlebitis of injected vein, bone pain, fever &
leukopenia
2. Risedronate - (third generation BPN)
• More potent than alendronate with oral bioavailability of 1%
• Use - In Osteoporosis & Paget’s disease
• Dose - 35 mg/week oral in morning with water

32. II. Miscellaneous
1. Calcitonin
• Calcitonin is the hypocalcaemic peptide hormone, secreted by parafollicular ‘C’ cells
of thyroid gland
• Synthesis and secretion of calcitonin is regulated by plasma Ca2+ concentration itself,
rise in plasma Ca2+ increases calcitonin levels, while fall in plasma Ca2+ decreases
calcitonin release
• The plasma t1⁄2 of calcitonin is 10 min, but its action lasts for several hours
• Synthetic salmon calcitonin is used clinically, because it is more potent and longer
acting due to slower metabolism. Human calcitonin has also been produced.
• 1 IU = 4 μg of the standard preparation

33. Actions of Calcitonin

34. Uses of Calcitonin
1. Used in Hypercalcaemic of malignancy, hypervitaminosis D, Osteolytic bone
metastasis, Hyperparathyroidism - 4-8 IU/Kg i.m, 6-12 hr for 2 days.
2. Used in Postmenopausal osteoporosis
3. To treat Paget’s disease
4. Diagnosis of medullary carcinoma of thyroid
Side effects
1. Nausea, flushing & tingling of fingers
2. Bad taste, flu-like symptoms, allergic reactions & joint pain

35. 2. Calcimimetics (Cinacalcet):
• These are also called as Calcium Sensing Agonists.
• They mimic the stimulatory effects of calcium on the calcium sensing receptors (CaSR),
which are present on Parathyroid glands
• MOA- bind on parathyroid receptors & decrease PTH secretion which causes fall in
serum Ca2+ levels.
• Used in hypercalcemia associated parathyroid carcinoma
3. Denosumab:
• It is a human monoclonal antibody which inhibits osteoclast differentiation and function
as well as promotes their apoptosis.
• It is a treatment option for postmenopausal osteoporosis when no other drug is
appropriate
• It is a Rank Ligand (RANKL) Inhibitor
• ADR - Osteonecrosis of Jaw, Femoral fractions, Flu like syndroms

36. 4. SERM (Selective Estrogen Receptor Modulator):
• Non-steroidal synthetic agent that act as estrogen agonist in bones (Increase
resorption) & blood (better lipid profile) and as antagonist in breast & endothelial
tissues
• Used for treatment & prophylaxis of postmenopausal osteoporosis breast cancer etc.
Eg, Raloxifene, Tamoxifene
5. Gallium nitrate:
• It is a potent inhibitor of bone resorption;
• Acts by depressing ATP-dependent proton pump at the ruffled membrane of
osteoclasts.
• Indicated in resistant cases of hypercalcaemia,
• It is given by continuous i.v. infusion daily for 5 days.
• It is nephrotoxic and only a reserve drug.

37. Other drugs
1. Fluorides
• For prophylaxxis of dental caries & to prevent osteoporosis.
• Sodium fluoride enhances osteoblasts & increase bone volume
• Generally stimulate osteoblasts at low doses and suppress at higher doses
2. Glucocorticoids:
• High doses of prednisolone (and others)
• Enhance calcium excretion, decrease calcium absorption and
• Have adjuvant role in hypercalcaemia due to lymphoma, myeloma, leukaemia,
carcinoma breast, etc.
• Used to treat Hypercalcaemia

38. 3. Estrogen
• Produced by ovaries.
• Natural estrogens include estradiol which can directly inhibit osteoclast
• It plays important role in growth& maturation of bones & regulate bone turnover in
adult bones
• In young age, estrogen deficiency cause increased osteoclast formation & enhanced
bone resorption
4. Strontium ranelate:
• It suppresses bone resorption as well as stimulates bone formation, and has been
introduced as a reserve drug for elderly women >75 years age who have already
suffered osteoporotic fracture and are unable to tolerate BPNs.
• Used for Osteoporosis

39. Recent Research
• Calcium Regulation of Bacterial Virulence - Michelle M. King et,al. (2019)
Calcium (Ca2+) is a universal signaling ion, whose major informational role shaped the evolution
of signaling pathways, enabling cellular communications and responsiveness to both the intracellular and
extracellular environments. Elaborate Ca2+ regulatory networks have been well characterized in
eukaryotic cells, where Ca2+ regulates a number of essential cellular processes, ranging from cell division,
transport and motility, to apoptosis and pathogenesis. However, in bacteria, the knowledge on Ca2+
signaling is still fragmentary. This is complicated by the large variability of environments that bacteria
inhabit with diverse levels of Ca2+. Yet another complication arises when bacterial pathogens invade a
host and become exposed to different levels of Ca2+ that (1) are tightly regulated by the host, (2) control
host defenses including immune responses to bacterial infections, and (3) become impaired during
diseases. The invading pathogens evolved to recognize and respond to the host Ca2+, triggering the
molecular mechanisms of adhesion, biofilm formation, host cellular damage, and host-defense resistance,
processes enabling the development of persistent infections. In this review, we discuss: (1) Ca2+ as a
determinant of a host environment for invading bacterial pathogens, (2) the role of Ca2+ in regulating
main events of host colonization and bacterial virulence, and (3) the molecular mechanisms of Ca2+
signaling in bacterial pathogens.

40. Facts
• Calcium is also found in cartilage - the softer connective tissue
located between different joints, the ear, nose, and the rib cage.
• Calcium is opaque to X-rays.
• 99% of the body's calcium is found in bones.
• Vitamin D can also be considered as a Hormone as it is
synthesized in body, transported via blood & works by
feedback mechanism
• Calcium oxalate stones are the most common type of kidney
stone

41. Reference
• Wikipedia.com
• Google search
• Slideshare.net
• King M.M., Kayastha B.B., Franklin M.J., Patrauchan M.A. (2020) Calcium
Regulation of Bacterial Virulence. In: Islam M. (eds) Calcium Signaling. Advances in
Experimental Medicine and Biology, vol 1131. Springer, Cham

42. Quote
~“All that we are is the result of what we have thought”
- Gautama Buddha

43. Thank You