Pharmacology PPT

1. Drug affecting calcium
metabolism
Dr Chintan Doshi

2. Calcium –
Physiological Roles
 Excitability of nerves and muscles and regulates
permeability of cell membranes. Also integrity of cell
menbanes
Ca++ essential forexcitation and coupling of all types of
muscles
Excitation and secretion of endocrine and exocrine glands
and release of neurotransmitters from nerve endings
Intracellular messenger for hormones, autacoids and
transmitters
Impulsegeneration and conduction in heart
Coagulation of Blood
Structural function of Bone and Teeth - hydroxyapatite
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2

3. Plasma Calcium Level
 Regulated by 3 hormones Parathormone, calcitonin
and Calcitriol (active vit. D)
 Normal plasma level = 9-11 mg/dl
 40% is bound to plasma protein – albumin,
3

5. Circulating Calcium
 Ionized calcium (free calcium)
 Responsible forcalcium function
 Can be directly measured
 Hypoalbuminemia – total Ca++ may be low but conc.
of Ca++ is usually normal
Acidosis – favours ionization
Alkalosis – disfavours ionization – hyperventilation
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precipitates
deficiency
tetany and laryngospasm in Calcium
5

6. Calcium - Uses
Tetany: Severe cases Calcium gluconate 10 to 20 ml IV
over 10 minutes followed by 50 to 100 ml of Ca gluconate
solution over 6 Hrs
 Oxygen inhalation, IV fluids thenoral therapy
2. Dietarysupplement: growing children, pregnant,
lactating and meopausal etc. Also in men and women
reduce the bone loss
3. Osteoporosis: Prevention ant treatment of
osteoporosis with HRT/raloxifene/Alendronate – to
ensure Ca++ deficiencydoes not occur
1.
Calcium and Vit. D3 used as adjuvant

4. Empirically in dermatoses, parathesia and weakness
5. Antacids

7. Vitamin D
 Mainly D3 (cholecalciferol) and D2 (calciferol)
 Both are equallyactive in man
 Calcitriol (active form of D3) is more important
physiologically
 Released from liver in blood and binds tospecificvit D
binding globulin

8. VITAMIN D SYNTHESIS
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL VITAMIN D3
25-HYDROXYLASE
25(OH)VITAMIN D
1-HYDROXYLASE
h
25(OH)VITAMIN D 1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
VITAMIN D3
TISSUE-SPECIFIC VITAMIN D RESPONSES 11

9. Vitamin D
 The body can supply its own Vitamin D via the
synthetic pathways
 Alternatively, Vitamin D may be supplied byVitamin
D - enriched foods.
multiplevitamins.
The classic examples are milk and
12

10. Actions of calcitriol
 Enhancementof absorption of Ca and PO4 from
intestine
 By increasing the synthesis of calcium channels and a
carrier “calcium binding protein (CaBP)” or calbindin
 Analogous to stroid hormones – binds to cytoplasmicvit
D receptor (VDR)-translocation-increased synthesis of
mRNA-regulation of protein synthesis
13

11.  Calcitriol also enhances recruitment and
differentiation of osteoclast precursor for
remodelling – resorption of Calcium and PO4 from
Bone
•Also enhances tubular reabsorption of Calcium

13. Vit D - Uses
 Prophylaxis (400 IU/day ) and treatment(3000 -4000
IU/day) of rickets & osteomalacia
 Metabolic Rickets
 Vit D resistant rickets: PO4 with high doses of
 Vit D dependent rickets
 Renal rickets
 Senile or postmenopausal osteoporosis
 Hypoparathyroidism: calcitriol/alfacalcitriol
 Fanconi like syndrome
 Calcipotriol : Vitamin D analog used topically in psoriasis
calcitriol

14. •
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Deficiency of vitamin D leads to:
 Rickets in small children.
 Osteomalacia in adult
Vitamin D deficiency

15. Vitamin
•
D - Sources
Sunlight is the most
important source
Not found naturally in
foods
Synthesized in body
Plants (ergosterol)
– Sun-cured forages
• many
•
•
• Fluid milk products are fortified
with vitamin D
Oily fish & Fish liveroil
Egg yolk
Butter
Liver
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16. • is
TOXICITY
D
Hypervitaminos
causes hypercalcemia, which manifest as:
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Nausea & vomiting
Excessive thirst , polyuria
Severe itching
Joint & muscle pains
Disorientation & coma.
Calcificationof soft tissue
& anorexia
– Lungs, heart, blood vessels
Hypercalcemia
– Normal is ~ 10 mg/dl
– Excess blood calcium leads
kidneys
,
•
to stone formation in

17. Parathyroid Hormone
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Location : Posterior to thyroid gland
Secreted by principal cells
27
•Hypocalcemia is a principal factor regulating
PTH
synthesis & release, mediated through activation
of adenylatecyclase & subsequent increase in
cAMP level

18.  Rapidly metabolised in liver & kidney
 T1/2 is 2-5 min
 Actions
 Bone
 Kidney
 Intestine
28

19. PTH receptor  G protein coupled receptor on activation increases
cAMP formation
are osteoblast
& intracellular Ca++ in target cells, in bone target cells
29

20. CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS
SUPPRESS PTH
RISING BLOOD Ca
NORMAL BLOOD Ca
STIMULATE PTH
31
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
FALLING BLOOD Ca
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION

21. Calcitonin

22.  Calcitonin, peptide hormone secreted by the
thyroid gland, tends
and,
to
in
decrease plasma Ca
concentration general, has effects
opposite to those of PTH
 Parafollicular cells, or C cells, lying in
of
the
the
interstitial f luid between the follicles
thyroid gland
32-amino acid
about 3400
 peptide with a molecular weight of

23.  The primary stimulus for calcitonin
secretion is increased plasma Ca ion
concentration
 calcitonin decreases blood
within
Ca ion
concentration rapidly, minutes
after injection of the calcitonin

24.  Inhibit bone resorption by directaction on
Osteoclasts
 Also inhibits the proximal tubular reabsorption of
calcium and phosphate by directaction on kidney
 Action is mediated through G- protein coupled
calcitonin receptor & increased cAMP formation
but target cells are different from that of PTH

25. Uses
• Hypercalcemia states (e.g associated with
neoplasia)
Pagets disease of bone:
•
• Postmenopausal osteoporosis &
induced osteoporosis:
corticosteroid
• Salmon calcitonin is used as nasal spray along with
Vit D supplements 200 IU /day

26. Bisphophonates (BPNs)

27. Introduction
 Non-hormonal agent in Ca++ homeostasis
 Recentlyattracted considerable attention
 Preventosteoporosisand useful in metabolic bone
diseases and hypercalcaemia
 Mosteffective “antiresorptive” drug at present
 BPNs are analogousof pyrophosphates – Carbon atom
replacing “P-O-P skeleton”
 BPNs have selectiveaffinity for Calcium phosphate –
so calcified tissues

28. Bisphosphonates have two side
chains:
R1 affects binding affinity to
bone;
R2 affects antiresorptive capacity
and, possibly,Side-effect profile.
Bisphosphonates vary in potency
Based
chains.
on these specific side

29. Generations of Bisphosphonates
 With each successivegeneration, there has been
increased potency, with more selectivity for inhibition
of resorption and less inhibition of bone formation.
 First-generation bisphosphonates, such as etidronate
and clodronate, inhibit bone formation and bone
resorption equally.
 Second-generation bisphosphonates include
pamidronateand alendronate
 The third generation includes the highly potent
risedronateand zolendronate.

30. BPNs - MOA
 BPNs have selective affinity for Calcium phosphate – so calcified
tissues
 2 main componentof Bone – Bone matrixand Solid mineral phase
(hydroxyapatite)
Results in
 Accelerated apoptosis of osteoclastsreducing their number
 Disruption of the cytoskeleton of the ruff led boarderof osteoclasts
•Inhibit their differentiation by suppressing IL-6
•Second and third generation potent aminoderivatives
important metabolic effects in the mevalonate pathway
for isoprenoid lipid synthesis
•Inhibit prenylation of certain GTP-binding proteins
involved in cytoskeleton organization

31. Therapeutic Uses
Osteoporosis: Alendronate>HRT or raloxifene
1.
Prevention and treatmentof post-manaupasal osteoporosis
Both Men and Women – age related, steroid induced and
idiopathicosteoporosis
I.
II.
Oestrogen prevents only vertebral fracture, BNPs 5 years protection
Pagetsdisease: Honeycomblike bonearchitecture – arrest
osteolytic lesions, reduce bonepainand improvesecondary
symptoms. Alendronate, Risedronate, Pami and Zoleare used.
Calcitonincombination better
Hypercalcaemiaof Malignancy: Medical emergencywith
altered consciousness – Pamidronate IV or
Zoledronate.
2.
3.
4. Osteolytic Bone Metastasis

32. Individual Drugs
Etidronate: Not used anymore
1.
2. Pamidronate: Only IV 60-90 mg for 2-4 Hrs, weekly
or monthly in Pagets disease and hypercalcaemia
3. Alendronate: Available in oral form 5, 10, 35, 70 mg
tabs. Prevention of osteoporosis in man and woman.
In empty stomach with glass of water
a.
b. Do not allow to lie down or eat till 30 minutes –
oesophagitis; Tea, coffee, mineral water, Juice, NSAIDs
ADRs: Gastric errosion, retrosternal pain, f latulence
c.
d. Bioavailability 1%, 50% goes to Bone, terminal
elimination half-life 10.5 years

33. Individual Drugs – contd.
4. Risedronate: Similar to Alendronate, but
potent
more
Used in osteoporosis and Paget`s disease
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5. Zolendronate: Prenterally effective, highly potent
Suppression of osteoclastic activity and additional
antitumor effect (mevalonate pathway)
Proliferation of bony metastasis of Prostate and breast
cancer cells are suppressed
Can be infused in 15 minutes
ADR: Flu-like symptoms due to cytokine release
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34. Adverse effects
 Oral bisphosphonates causes Gastrointestinal
complications such as gastritis oresophagitis,
abdominal pain, nausea, vomiting, diarrhea, and
constipation.
To minimize gastrointestinal inflammation And
ulcer,
patients should remain upright (sitting or standing)
forat least 30 minutesafter taking the medication
Bisphosphonate-related osteonecrosis of the jaw
Phossy jaw
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36.  Disadvantages
 Risk of gastrointestinal
sx
 ex dosing instructions
 Contraindicated in
ESRD; need toadjust
dose according to
creatinineclearance
 Advantages
 Increases BMD by 1-4%,
decreases fracture risk
by 41-44%
 No increased risk of
breast, uterine ca or
thromboembolic
 Weeklydosing
events
Bisphosphonates

37. THANK YOU