Dr. Mohamed KhedrProf. of Clinical Pharmacology

Faculty of Medicine-Beirut Arab University

Calcium homeostasis refers to the regulation of the concentration of calcium ions in the extracellular fluid [Ca++]

Calcium Homeostasis

Bone CaCa++ ++ 99%99% PO4PO4¯ ¯ 85%85% (1-2Kg/ body wt.) ( 1 Kg/ body wt.)(1-2Kg/ body wt.) ( 1 Kg/ body wt.)

↓↓Major source ofMajor source of

Serum CaSerum Ca++++ & Phosphate & Phosphate

↓↓ Free ionized CaFree ionized Ca++++ only only ( 50% of blood level )( 50% of blood level )

..Blood coagulationBlood coagulation..

..Normal cardiac functionNormal cardiac function....Normal skeletal m. contractionNormal skeletal m. contraction..

..Release of neurotransmittersRelease of neurotransmitters..

Bone MassBone Mass

↓ ↓ ContinuousContinuous Remodeling →Bone building. →Bone building.

Bone lossBone loss . .

young→↑ building.young→↑ building. Old →↑ lossOld →↑ loss..

controlledcontrolled

byby

Osteoblasts Osteoclasts) ) Bone matrix forming (Bone matrix Bone matrix forming (Bone matrix

destructingdestructing cells) cellscells) cells ( (

BalanceBalance

Remodeling

Schematic representation of bone remodeling.

Regulation of Bone-Mineral HomeostasisRegulation of Bone-Mineral Homeostasis

Hormonal Regulation

Non-hormonal Regulation

Bone MassBone Mass ↑) ↑) blood Cablood Ca++++ level level((

Bone MassBone Mass ↓) ↓) blood Cablood Ca++++ level level((

..PTHPTH....Vit. DVit. D..

..CorticosteroidsCorticosteroids..

㊉㊉ osteoclastsosteoclasts..

Θ osteoblastsosteoblasts..

..CalcitoninCalcitonin....AndrogensAndrogens....OestrogensOestrogens..

..G.HG.H....Thyroid HThyroid H..

㊉㊉ osteoblastsosteoblasts..

ΘΘ osteoclastsosteoclasts..

Bisphosphonates

Parathormone(PT) Parathormone(PT) Single polypeptide H.

Secreted from parathyroid gland.

Parathormone (PT) Parathormone (PT)

Release Release → → regulated by level of blood Caregulated by level of blood Ca++++ & PO4 & PO4.¯.¯ ↑ ↑ ➣ ➣when when →→ Ca Ca++++ ↓ & ↑ PO4 ↓ & ↑ PO4.¯.¯

↓Through effects onThrough effects on

Bone Kidney GIT. rate rate

of Resorptionof Resorption

. Ca Ca++++ reabsorption reabsorption... PO4¯ excretion by PO4¯ excretion by

renal tubulesrenal tubules..

Action:Action: → → Tends to Tends to Ca Ca++++ level in blood level in blood..

IndirectIndirect㊉㊉ synthesis ofsynthesis of

calcitirolcalcitirol) ) active vit. Dactive vit. D(.(.➣➣

absorptabsorptnn of Ca of Ca.++.++

Uses of PT . Uses of PT . →→ Was used for hypocalcaemia, Was used for hypocalcaemia,

( PT→ immunological agent )( PT→ immunological agent )

Treatment of hypocalcaemiaTreatment of hypocalcaemia

1-Hypocalcaemic tetany 1-Hypocalcaemic tetany

→→ Calcium gluconate I.V.Calcium gluconate I.V.

2-Long R/ of hypo-para-thyroidism:2-Long R/ of hypo-para-thyroidism:

→→Vitamin D + Calcium gluconate or LactateVitamin D + Calcium gluconate or Lactate

..

1-Hypocalcaemic tetany 1-Hypocalcaemic tetany

→→ Calcium gluconate I.V.Calcium gluconate I.V.

2-Long R/ of hypo-para-thyroidism:2-Long R/ of hypo-para-thyroidism:

→→Vitamin D + Calcium gluconate or LactateVitamin D + Calcium gluconate or Lactate

..

Vitamin DVitamin DSteroid HormoneSteroid Hormone Vit.D2Vit.D2-Ergocalciferol-Ergocalciferol..

Vit.D3Vit.D3-Cholecalciferol-Cholecalciferol..Human) Pro D3=7 dehydrocholestrol(

↓UVR

Vit.D3 (Chole-calciferol)

KidneyKidney

25) OH(

2525))OHOH ( (Vit.DVit.D33

LiverLiver

1,251,25))OHOH((22 D D33 (Calcitriol) (Calcitriol)

) )ActiveActive((

Complete hydroxylation

Two forms:

Vitamin D synthesis and activation.

ActionAction:: →→

↓Through effects onThrough effects on

.↑↑ resorption & Formationresorption & Formation.. (Normal→ resorption.)Normal→ resorption.) (Rickets→ formation.) Rickets→ formation.)

Bone Kidney GIT

.↑ Ca↑ Ca++++ &↑ PO4¯ &↑ PO4¯ absorption .absorption .

Tends to Tends to Ca Ca++++ & &PhosphatesPhosphates

.↑ Ca↑ Ca++++ &↑ PO4¯ &↑ PO4¯ reabsorptionreabsorption byby renal tubules.renal tubules.

Uses of vit.DUses of vit.D

..Prevention & treatment of Rickets & osteomalaciaPrevention & treatment of Rickets & osteomalacia..

..Treatment of hypoparathyroidismTreatment of hypoparathyroidism..

.Osteoporosis..Osteoporosis.

.

The boy pictured here has rickets, a disease resulting from a lack of calcium and/or vitamin D in the diet. Rickets weakens the long bones, so that they are not strong enough to support the body; they bend outwardly under the body’s weight.( the skeleletal and muscluar systems Gregory Stewart)

Radiograph of the scapula of a 58-year-old woman with osteomalacia. The presence of a pseudofracture, or Looser's zone, is indicated by an arrow.

CalcitoninFrom parafollicular (C) cells of thyroid glandsFrom parafollicular (C) cells of thyroid glands

↓↓ Hypercalcaemia & Hypercalcaemia & vitamin D vitamin D..

Action:Action: → → Tends to ↓ CaTends to ↓ Ca++++ &Phosphates &Phosphates

↓Through effects onThrough effects on

Bone Kidney

Θ Osteoclast activity.

Tends to Tends to Ca Ca++++ &Phosphates &Phosphates

as a result ofas a result of

.Θ Ca Ca++++ & PO4¯ reabsorption & PO4¯ reabsorption by renal tubules.by renal tubules.

Uses of CalcitoninUses of Calcitonin: : → → As it As it Θ bone Resorption.

Diseases in which Diseases in which active or chronic loss of bone massactive or chronic loss of bone mass::

.Post menopausal osteoporosis..Post menopausal osteoporosis. .Hypercalcaemia of malignancy..Hypercalcaemia of malignancy. .Paget’s disaese.Paget’s disaese..

PreprationsPreprations::

Human calcitoninHuman calcitonin → t½ 10 min → t½ 10 min..Calcitonin-salmonCalcitonin-salmon→ long t½ , more potent→ long t½ , more potent,,

))miacalcinmiacalcin ,( ,(s.c , I.M, nasal sprays.c , I.M, nasal spray . .

PTH Vitamin D CalcitoninPTH Vitamin D Calcitonin

Bone: Bone: ↑ resorption. ↑ resorption & ↓ resorption↑ resorption. ↑ resorption & ↓ resorption..

formationformation..

Kidney: Kidney: ↑ tubular Ca↑ tubular Ca++ ++ ↑ tubular Ca↑ tubular Ca++++&& ↓ tubular Ca↓ tubular Ca ++ ++&& reabsorption. POreabsorption. PO44¯reabsorpt¯reabsorptnn PO PO44¯ reabsorpt¯ reabsorptnn..

↑ ↑tubular POtubular PO44¯̄ excretionexcretion..

G.I.T. G.I.T. Indirect through ↑ CaIndirect through ↑ Ca++++ &PO &PO44¯̄ calcitriol reabsorptioncalcitriol reabsorption..

↑) ↑) CaCa++++&PO&PO44¯̄ reabsorptionreabsorption.(.(

SerumSerum CaCa++++

POPO44¯̄

-

Bisphosphonates

Θ Bone ResorptionBone Resorption

Non-hormonal Agents affectingNon-hormonal Agents affecting Bone-Mineral HomeostasisBone-Mineral Homeostasis

..ΘΘ Osteoclast activityOsteoclast activity ) ) by by ΘΘ osteoclast proton-pump osteoclast proton-pump , ,

so so ΘΘnn of dissolution of hydroxy of dissolution of hydroxy-- apatite; the ground substanceapatite; the ground substance

matrix of bonematrix of bone.(.(

.. ㊉㊉ osteoclst apoptosis (cell death)osteoclst apoptosis (cell death)..

.. ㊉㊉ osteoblast activityosteoblast activity..

↓. ↓.calcitriol activity (active vit.D)calcitriol activity (active vit.D)↓ → ↓ → GIT absorption of CaGIT absorption of Ca.++.++

Pharmackinetics of Bisphosphonates:

Absorption: → orally , only Absorption: → orally , only 10%10% & interfered with food & interfered with food..) ) empty stomachempty stomach((

Distribution → Bone ( 50% of the dose )Distribution → Bone ( 50% of the dose )..Excretion → RenalExcretion → Renal..

Therapeutic Uses

..Postmenopausal osteoporosisPostmenopausal osteoporosis....Paget’s diseasePaget’s disease..

..Malignancy associated with hypercalcaemiaMalignancy associated with hypercalcaemia..

PreparationsPreparations

..Alen-dronate Alen-dronate ( fosamax )( fosamax ) Orally one tab./ w Orally one tab./ w.. ) ) patient is upright with glass of waterpatient is upright with glass of water,,

to prevent oesophageal ulcerationto prevent oesophageal ulceration.(.(

..Eti-dronate. Eti-dronate. Orally & parenterallyOrally & parenterally..

..Rise-dronateRise-dronate..

Side effectsSide effects

G.I.T irritations

ContraindicationsContraindications

.Kidney diseases..Peptic ulcer.

Drugs used for treatment ofDrugs used for treatment of

osteoporosisosteoporosis

11--Bisphosphonates. Bisphosphonates. → → ΘΘ Bone resorption Bone resorption..

22--Oestrogen. Oestrogen. → ↑ Bone mass (→ ↑ Bone mass (ΘΘoseoclast activity)oseoclast activity)..

33--Vitamin D & CaVitamin D & Ca++++..

44--Calcitonin.Calcitonin.→→ΘΘ Bone resorption Bone resorption..) ) ΘΘ osteoclast activity osteoclast activity.(.(

Cumulative proportions of women with osteoporosis who suffered clinical fracture (vertebral, hip, or wrist) during 3 years of treatment with alendronate or placebo (FIT 1). (From DM Black et al: Lancet 348:1535, 1996.)