Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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Ca salts in bone provide structural integrity of theskeleton.

Ca is the most abundant mineral in the body. Ca ions in extracellular and cellular fluids is essential to

normal function of a host of biochemical processes Neuromuscular excitability and signal transduction Blood coagulation Hormonal secretion Enzymatic regulation Neuron excitation

About 1000 mg of Ca is ingested per day. About 200 mg of this is absorbed into the body. Absorption occurs in the small intestine, and

requires vitamin D Milk and dairy products-Egg yolk , Fish, beans Cow’s milk 100mg/100ml Human milk 30mg/100ml

RECOMMENDED DAILY ALLOWANCE (RDA):Adults – 500 mg /dayChildren - 1200 mg /dayPregnancy & -- 1500 mg /dayLactationSITE : first part and second part of duodenum

Calcium absorbed against concentration gradientand requires energy and a carrier protein.

30 – 80 % of ingested calcium is absorbed Actively transported out of the intestinal cells with

the help of Ca 2+ dependent ATPase

A) Factors favoring calcium absorption• An acidic pH• Presence of sugar acids, organic acids and citric acid• High protein diet- Lysine and Arginine cause absorption• Presence of vitamin D• Ca : P ratio- A ratio of dietary Ca: P not more than 2:1 is

adequate for optimal absorption, ratio of less than 1:2reduces absorption

• State of health and intact mucosa- A healthy adult absorbsabout 40% of dietary calcium.

• PTH (Parathormone) stimulates the activation of vitaminD, thus indirectly increases absorption of vitamin D 5

B) Factors inhibiting absorption of calcium• Alkaline pH• High fat diet- Fatty acids form calcium soaps that can not

be absorbed• Presence of Phytates and oxalates- Insoluble calcium salts

are formed• Dietary fiber in excess inhibits absorption• Excess phosphates, magnesium and iron decrease

absorption• Glucocorticoids reduce intestinal absorption of calcium• Calcitonin reduces calcium absorption indirectly by

inhibiting the activation of vitamin D• Advancing age and intestinal inflammatory disorders

inhibit absorption of calcium

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The primary site of storage is our bones (about 1000grams).Some calcium is stored within cells (endoplasmicreticulum and mitochondria).Bone is produced by osteoblast cells which producecollagen, which is then mineralized by calcium andphosphate (hydroxyapatite).Bone is remineralized (broken down) by osteoclasts,which secrete acid, causing the release of calcium andphosphate into the bloodstream.There is constant exchange of calcium between bone andblood.

The major site of Ca excretion in the body is the kidneys.The rate of Ca loss and reabsorption at the kidney can beregulated.Regulation of absorption, storage, and excretion of Caresults in maintenance of calcium homeostasis.

4/22/2016By- Professor Namrata Chhabra(MD Biochemistry) 10

The overall action of PTH is to increase plasma Ca2+

levels and decrease plasma phosphate levels. PTH acts directly on the bones to stimulate Ca2+

resorption and kidney to stimulate Ca2+ reabsorptionin the distal tubule of the kidney and to inhibitreabosorptioin of phosphate (thereby stimulating itsexcretion).

PTH also acts indirectly on intestine by stimulating1,25-(OH)2-D synthesis.

UV B Rays (Sun)

+7- Dehydro-cholesterol (Skin)

Calcitriol regulates Calcium, muscle, bone health and blood pressure.Calcitriol having very short half life hence can not be considered as a correct indicator ofVitamin D status

The Renal metabolic pathway

LIVER

KIDNEY

1,25 -(OH)2 - D3

(Calcitriol)

Vitamin D3

(Cholecalciferol)

Calcium RegulationBONE/BLOOD

25 -(OH)- D3

(Calcidiol)Hydroxylation 1

Hydroxylation 2

Metabolism of Vitamin D

PTH increases 1-hydroxylase activity, increasingproduction of active form.This increases calcium absorption from the intestines,increases calcium release from bone, and decreases lossof calcium through the kidney.As a result, PTH secretion decreases, decreasing 1-hydroxylase activity (negative feedback).Low phosphate concentrations also increase 1-hydroxylase activity (vitamin D increases phosphatereabsorption from the urine).

Cholecalciferol was significantly, more effective thanErgocalciferol to increase serum 5(OH)D Cholecalciferolshould be the preferred drug for severe vitamin Ddeficiency.Longer half-life of D3 suggests that less frequentdosing may be needed.Alfacalcidol and Dihydrotachysterol are syntheticprodrug which are rapidly hydroxylated in liver tocalcitriol

Cholecalciferol or Ergocalciferol ?

Cholecalciferol was significantly, more effective than Ergocalciferol toincrease serum 25(OH)D (J Clin Endocrinol Meta, 2011; 96: 981–988)

Cholecalciferol should be the preferred drug for severe vitamin Ddeficiency. (Endocrine Abstracts 2012; 28:19)

Longer half-life of D3 suggests that less frequent dosing may be needed.(Mayo Clin Proc. 2010;85(8):752-758)

Group Condition Dose

Infants and childrenPrevention of vitamin D

deficiency400 IU/Day* (American academy of

Pediatrics)

>1 yr to 12 Yrs Vitamin D deficiency1000 IU-5000 IU/Day for 3 months*

(American academy of Pediatrics)

Women Pregnancy & lactation1500-2000 IU/Day from II

trimester*

Adults Maintenance 2000 IU/Day or 60 K IU/ Month*

Adults VDD 60,000 IU/ Week for 8 Weeks*

Recommended Dose of Vitamin D3

Absorption: Well absorbed from the GI tract. Decreased in patients with decreased fat

absorption.

Excretion: Mainly in the bile & faeces with only small amounts appearing in urine.

* Recommended by Dr.Michael F. Folick ( The Vitamin D Solution)

Vitamin D Deficiency: Consequences

Calcitonin acts to decrease plasma Ca2+ levels.While PTH and vitamin D act to increase plasma Ca2+--only calcitonin causes a decrease in plasma Ca2+.Calcitonin is synthesized and secreted by theparafollicular cells of the thyroid gland.

They are distinct from thyroid follicular cells by theirlarge size, pale cytoplasm, and small secretorygranules.Synthetic salmon calcitonin-sc, im

CARPOPEDAL SPAM

Obstetric hand

Laryngeal stridor Convulsions Visceral features like

intestinal spasm,bronchospasm andprofuse sweating.

CALCIUM LEVEL > 12 mg / dL

▪ Nervous system is depressed▪ Reflex activities are sluggish▪ Decreased QT interval▪ Lack of appetite

A) Cancer with bonemetastasesCarcinomaLeukemiaLymphomaMultiple myelomaB) ImmobilizationOrthopedic casting or tractionPaget's disease of boneOsteoporosis in the elderlyParaplegia or quadriplegiaYoung, growing patients

C) Parathyroid hormone excessParathyroid carcinomaPrimary hyperparathyroidismSecondary hyperparathyroidismD) Vitamin ToxicityVitamin A toxicityVitamin D toxicityE) Other disorders/causesHyperthyroidismMilk-alkali syndromeAddison's diseaseGranulomatous disordersDrug therapy such as thiazidesand lithium

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The mnemonic "stones," "bones," "abdominalmoans," and "psychic groans" describes theconstellation of symptoms and signs ofhypercalcemia

The history of hypercalcemia is dependent on itscause and the sensitivity of the individual

Mild increase :Asymptomatic,Or may have recurringproblems like kidneystones

Rapid rise or severehypercalcemia havedramatic symptoms:conusion, lethargy, maylead to death

Oral PO4 for serum Ca < 11.5 mg/dL with mildsymptoms and no kidney disease

IV saline and diuretic (furosemide) for more rapidcorrection for serum Ca < 18 mg/dL

Bisphosphonates or other Ca-lowering drugs forserum Ca < 18 mg/dL and > 11.5 mg/dL or moderatesymptoms

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CALCIUM CARBONATE Ca CITRATE GLYCEROPPHOSPHATE LACTATE GLUCONATE HEPTAGLUCONATE

To correct calcium deficiencyPost- menopausal osteoporosisRickets and osteomalaciaRemoval of parathyroid adenomaChronic kidney disease as phosphate bindersHyper-magnesemiaHyperkalemiaCardiac arrestPlacebo-calcium gluconate

Bisphosphonates –I GENERATION-ETIDRONATE, CLODRONATEII GENERATION-ALENDRONATE, PAMIDRONATE,IBANDRONATEIII GENERATION-RISEDRONATE, ZONLENDRONATE,Synthetic pyrophosphate derivativeInhibits osteoclast mediated bone resorptionPhosphorus- oxygen-phosphorus moiety is replacedwith stable phosphorus-carbon-phosphorus moietyBPNs also accelerate the osteoclastic apoptosis afterthey ingest the bone matrix

Non steroidal synthetic agents who have action onestrogen receptor is tissue selectiveRALOXIFENE-used in post menopausal osteoporosisBones- reduces vertebral fractures by 30-50%

CALCIMIMETICS-CINACALCET-calcium sensingreceptors on parathyroid gland sense the Ca levelsand reduce the PTH secretion30mg once daily

It is a ranelic acid salt of strontiumBlocks differenciation of osteoclasts and promotestheir apoptosisSEVELAMER-HYDROCHLORIDE-Posphate binding gel + calcium decreases serumphosphate levelsHyperphosphatemia due to hypoparathyroidismADR- constipation, epigastric distress

They reduce renal calcium excretionThey reduce hypercalciuria and reduce incidence ofcalcium oxalate stonesThey increase the effectiveness of PTH induced calciumreabsorptionFLUORIDES-Prophylaxis for dental cariesDose dependent toxicityIncrease risk of all types of fractures fluoroapatitegets deposited in place of hydroxyapatite losesbiomechanical strength

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