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PHarm > Calcium homeostasis > Flashcards

Calcium homeostasis Flashcards

1
Q

PTH

A

A peptide- secreted by the parathyroid gland in response to low serum calcium
Binds with PTH receptors in the bones and the kidneys, leads to increase in cAMP level

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2
Q

PTH actions

A

In bone, PTH can increase both the rate of bone formation and the rate of bone resorption -
pulsatile exposure and low dose- results in net bone formation (increases osteoblastic activity)
continuous exposure results in net bone resorption (increases osteoclastic activity)

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3
Q

Teriparatide

A

Recombinant analog of human PTH (34 AA)

Administered once a day
this intermittent exposure results in net bone formation (increases the osteoblastic activity).

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4
Q

Teriparatide use

A

the treatment of osteoporosis (increases spinal bone density and decreases the risk of vertebral fracture and its recurrence).

First approved treatment for osteoporosis that stimulate bone formation (osteoblastic activity)

treatment of glucocorticoid-induced osteoporosis

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5
Q

Teriparatide ADR

A

Major adverse effects: Hypercalcemia (transient)

Frequent adverse effects: nausea, vomiting, dizziness, depression, limb pain, headache and leg cramps

Report of increased risk of osteosarcoma in rats.
should be reserved for patients at high risks of fractures or who can not tolerate other osteoporosis therapies

Must not be used for more than 2 years

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6
Q

Abaloparatide

A

An analog of parathyroid hormone-related peptide

Increases the osteoblastic activity

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7
Q

Abaloparatide use

A

treatment of postmenopausal women with osteoporosis at high risk for fracture, or patients who have failed or are intolerant to other agents
Abaloparatide reduced the risk of new vertebral and non-vertebral fractures over a period of 18 months

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8
Q

Calcitonin

A

Peptide secreted by parafollicular cells of the thyroid gland in response to elevated Ca2+

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9
Q

Calcitonin actions

A

Reduces serum Ca2+ and PO4

Antagonizes the actions of PTH through independent mechanism:

Interacts with specific receptors on osteoclasts to decrease net resorption of bone. May also stimulate bone formation.

Increases renal excretion of Ca2+, Na+, and PO4

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10
Q

Calcitonin pharmalogical properties

A

Synthetic salmon calcitonin differs from human calcitonin by 13 of 32 amino acids and has a longer half-life
Route- intranasal
Reduces bone resorption and improves bone architecture, relieves bone pain*** (unique property) associated with osteoporotic fracture and, increases function
Decreases serum Ca2+ in 2 hours that persists for 6-8 hours

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11
Q

Therapeutic uses of calcitonin

A

treat hypercalcemia due to Paget’s disease, hyperparathyroidism, idiopathic juvenile hypercalcemia, vitamin D intoxication, osteolytic bone disorders

Used for prevention of osteoporosis (in women who are postmenopausal for>5 years***)

Tolerance develops to the action of calcitonin when it is administered continuously over a long period of time (due to the production of anticalcitonin antibodies).

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12
Q

Vitamin D is a derivative of?

A

7-dehydrocholesterol
Considered as a pro-hormone

Hydroxylation in the liver → 25-hydroxyvitamin D

Then Hydroxylation in kidneys yields 1,25-dihydroxyvitamin D

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13
Q

Vitamin D actions

A

Increases calcium and phosphate absorption from the intestine

Increases calcium and phosphate reabsorption from kidneys

Decreases calcium and phosphate excretion by kidneys

Net result: increases serum calcium as well as phosphate
Increases bone formation

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14
Q

Forms of Vitamin D

A

Calcifediol (25-hydroxy)
Calcitriol (1,25 dihydroxy)***

Other analogs
Calcipotriene: used in psoriasis topically
Doxercalciferol
Paricalcitol

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15
Q

Bisphosphonates

A

P-C-P bond which is non-hydrolyzable compared to Pyrophosphate
P-O-P bond found in bone hydroxyapatite.

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16
Q

Bisphosphonate MOA

A

They bind directly to hydroxyapatite crystals in bone and impair resorption

Increase bone density and reduce fractures

Inhibit osteoclastic proton pump (necessary for dissolution of hydroxyapatite crystals)

Inhibit the activity of farnesyl pyro-phosphate synthase (mevalonic acid biosynthetic pathway) important for osteoclastic function (esp. amino biphosphonates)

increase osteoclastic apoptosis

17
Q

Etidronate, Tiludrontate

A

First gen bisphosphonates

18
Q

Alendronate, pamidronate, Ibandronate

A

Second gen bisphosphonates

19
Q

Risedrontate, Zoledronate

A

3rd gen bisphosphonates

20
Q

Bisphosphonate indications

A

Paget’s disease

Osteoporosis: For prevention and treatment (preferred in postmenopausal osteoporosis)

Hypercalcemia

Cancer metastases to bone

Other bone diseases with high bone resorption

21
Q

Pharmacokinetics of Bisphosphonates

A

VERY poor oral absorption <10% (all bisphosphonates); Pamidronate given IV

Food significantly interferes with absorption (hence administered on empty stomach with 6-8 Oz of water at least 1 hr before breakfast) and patient should remain upright at least for 30 minutes (to prevent esophagitis)

Nearly half of the absorbed drug accumulates in bone

Elimination solely through renal clearance (should not be given to individuals with severe renal impairment)

22
Q

Bisphosphonate ADR

A

GI disturbances including GI bleeding, diarrhea, abdominal pain

Esophageal ulceration and erosion*** (esp. with oral bisphosphonates (risedronate, alendronate and Ibandronate)
to minimize the risk of esophageal irritation, patients should remain upright for at least 30 mins (60 mins for Ibandronate)

Osteomalacia and bone pain (esp Etidronate on prolonged treatment)

Fracture of femoral shaft (“Chalk stick fracture”)

Musculoskeletal pain and chest pain

Osteonecrosis of Jaw (ONJ)- esp with zoledronate on high IV dose

23
Q

Bisphosphonate contraindication

A

Women who are pregnant or planning pregnancy (although no concrete evidence in human available)
Renal insufficiency
Low serum calcium
Osteomalacia

24
Q

Oral bisphosphonates should not be used by?

A

patients with serious esophageal diseases

patients at bed rest who can not stay upright for an hour

25
Q

Bisphosphonates don’ts:

A

Not with food in your stomach

Not with a little sip of water (drink at least 4 oz)

Not within 1 hour before you go to bed

26
Q

Cinacalcet

A

Calcium sensing receptor activators/calcimimetics

CaSR is widely distributed but has its greatest concentration in parathyroid gland

Inhibits PTH secretion and hence is approved for use in patients with hyperparathyroidism secondary to renal disease and for the treatment of parathyroid carcinoma

Primary hyperparathyroidism in patients unable to be managed surgically

Hypocalcemia- major adverse effect

27
Q

Calcium and Vit D supplements

A

Calcium and Vitamin D: essential for optimal bone formation in children and prevention of and treatment of osteoporosis in adults

Also used for prevention and treatment of Hypocalcemia

by ingesting optimal calcium and vitamin D, young adults can have increased bone mass and older adults can have decreased rate of bone loss.

28
Q

Calcium carbonate

Calcium citrate

Calcium gluconate

A

Calcium carbonate requires stomach acidity for absorption.

Calcium citrate does not require acidity.

Calcium gluconate is the preferred i.v. preparation

29
Q

Calcium supplement ADR

A

constipation and hypercalcemia (with long-term use)

30
Q

Denosumab

A

Recombinant humanmonoclonal antibody against RANKL

First RANKL inhibitor to be approved by the FDA

Inhibits maturation of osteoclasts by binding to and inhibiting RANKL

31
Q

Denosumab treats

A

osteoporosis, bone metastases (from breast cancer), multiple myeloma, drug induced osteoporosis andgiant cell tumor of bone

SC injection every 6 months for osteoporosis
Patient should use it along with Calcium and vitamin D

32
Q

Denosumab ADR

A 
Joint and muscle pain in the arms/legs
Increased risk of infections
Hypocalcemia
Hypersensitivity, allergic reactions, 
Osteonecrosis of the jaw
Atypical hip fractures
33
Q

Secondary agents affecting Ca homeostasis

A

Thiazide diuretics: decrease the renal excretion of Ca2+ and the incidence of kidney stone formation in patients with idiopathic hypercalciuria

Loop diuretics: Furosemide increases the renal excretion of Ca2+

Estrogens: Effective therapy for the prevention of postmenopausal bone loss

34
Q

Estrogen receptors found?

When estrogen initiated immediately in postmenopausal …?

A

receptors are found in bone and have direct effects on bone remodeling.

When initiated immediately in postmenopausal period, prevent osteoporosis and reduce the risk of hip fracture
Reduce the bone resorbing action of PTH
Increase bone density

35
Q

Why are estrogens no longer the used

A

increased risk of breast cancer, endometrial cancer, stroke, venous thromboembolism, and coronary disease

36
Q

Estrogen deficiency

A

Increases the release of IL-1, IL-6 and IL-7 from stroma cells in bone marrow. IL-7 increases the proliferation of T-cells and TNF
Decreases the production of osteoprotegerin (OPG), increases the production of RANKL and facilitates its binding to RANK (osteoblast secrets RANK L and binds to osteoclast RANK to activate it)

The net result is increase in the osteoblast apoptosis and augmentation of the activity of osteoclasts

37
Q

Raloxifene

A

SERM: approved for the prevention and treatment of osteoporosis
It protects against fractures of spine but not hip

alternative for postmenopausal osteoporosis in women who are intolerant to bisphosphonates or denosumab

increases bone density without increasing risk of endometrial cancer and reduces the risk of invasive breast cancer

38
Q

Raloxifene ADR

A

Hot flashes, inc of pulmonary embolism, leg cramps, inc risk of deep vein thrombosis

39
Q

Strontium ranelate

A

being used in Europe for the treatment of osteoporosis
Acts on both osteoblasts and osteoclasts (Dual action bone agent-DABA)
appears to block osteoclast differentiation while promoting their apoptosis and thus inhibits bone resorption
also promotes bone formation

PHarm (7 decks)

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