Pharm - Calcium Flashcards by Ryan Hutten

What are the essential functions of calcium?

Skeleton/Teeth structure
Neurological transmission
Muscle contraction
Second messenger signaling 
Vesicle fusion
Blood coagulation

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What channels are responsible for intracellular regulation of calcium levels?

Plasma Membrane Ca Pump
Na/Ca exchanger
SERCA
these all act to keep intracellular calcium low

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What are the general ways that serum calcium is tightly regulated?

Absorption
Excretion
Mobilization from the skeleton

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Describe what happens to dietary calcium

~1000mg/day ingested via diet
300mg is absorbed, and 100mg is lost endogenously
800 mg is excreted in feces
200 mg is excreted in urine

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Describe the endogenous process of osteoclast activation

Osteoblasts expressing RANKL activate immature osteoclast precursor cells with RANK receptor. This interaction in the presence of MCSF triggers osteoclast differentiation

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Describe the endogenous process of osteoblast activation

As bone is resorbed by osteoclasts, TGF beta, IGF1, growth factors and cytokines are released that stimulate osteoblast differentiation and activity

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What is the paradoxical role of PTH in calcium balance?

Endogenous chronic PTH stimulation increases serum Ca and decreases serum PO4. Exogenous, intermittent PTH stimulation has the opposite effect, causing bone deposition of Ca

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What are the main functions of PTH?

Increasing renal Ca resorption, PO4 excretion, and synthesis of calcitrol

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What is osteoprotegrin (OPG)?

Endogenous inhibitor of RANKL

Prevents osteoclast maturation and bone resorption

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Describe the synthesis and activation of vitamin D3

Synthesized in the skin following exposure to UV light as a pro-hormone.
Metabolized by liver (25 hydroxylase) and then kidney (1 alpha hydroxylase) to form active Calcitrol

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What is the function of Vitamin D3?

Augments Ca and PO4 absorption from the small intestine
Decreases excretion of Ca and PO4 by kidneys
Inhibits PTH production

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What is the function of calcitonin?

Secreted by parafollicular cells of the parathyroid in response to high serum Ca
Acts to decrease serum calcium and phosphate levels (bone and kidney effect)

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What disorders are treated with calcitonin?

Paget’s disease of bone
Hypercalcemia
Osteoporosis

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What are the common causes of hypercalcemia?

Primary hyperparathyroidism: parathyroid adenoma

Malignancy associated: paraneoplastic PTHrP

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What are the symptoms of hypercalcemia?

Fatigue, polyuria, polydipsia, anorexia, nausea, vomiting, abdominal pain, muscle weakness, altered mental status

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What are the common causes of hypocalcemia?

Hypoparathyroidism (PTH deficiency)

Vitamin D deficiency

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What are the common causes of hyperphosphatemia?

Chronic kidney disease

Secondary hyperparathyroidism

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What are the symptoms of hypocalcemia?

Tremor, muscle spasm, tetany, seizures, prolonged QTc interval

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What are the symptoms of hyperphosphatemia?

Hypocalcemia, decreased calcitriol, increased PTH

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What are Rickets and Osteomalacia?

Deficiencies in vitamin D intake/synthesis presenting with bone pain and symptoms of hypocalcemia
Rickets is in children; Osteomalacia is in adults

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What is the difference between Type I and Type II osteoporosis?

Type I involves loss of trabecular bone due to estrogen deficiency in postmenopausal women. Type II occurs in men and women and is related to age, increase in parathyroid axis function

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What is Paget’s disease of the bone?

Disordered sites of bone remodeling from increased bone resorption and formation
May present with bone pain, deformities and fractures

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Mechanism of action for vitamin D, calcitriol and vitamin D analogues

Agonists of vitamin D receptor causing increased Ca and PO4 intestinal absorption, renal reabsorption, and decreased PTH

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What are the clinical uses of vitamin D, calcitriol and vitamin D analogues?

Rickets, Osteomalacia
Prevent/Treat osteoporosis
Hypoparathyroidism
Chronic kidney disease (secondary hypoparathyroidism)

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What adverse effects are associated with vitamin D treatment?

Hypercalcemia due to potent effect on intestinal absorption of Ca

What are the contraindications for vitamin D treatment?

In the presence of hyperphosphatemia, Vitamin D treatment can promote metastatic calcification, hypercoaguable state, tissue infarction, skin necrosis Often fatal systemic bacterial infections due to non-healing ulcerations

How is metastatic calcification prevented in the setting of vitamin D treatment?

Phosphate levels are reduced by restricting the diet or using phosphate binders like Sevelamer

What is the mechanism of action of bisphosphonates?

Analogs of pyrophosphate that have strong affinity for bone surfaces undergoing remodeling. They bind and inhibit farnesyl pyrophosphate synthetase to inhibit osteoclast activity and function

What are the bisphosphonate drugs?

``` All end in "-dronate" Alendronate Pamidronate (IV) Risedronate Zoledronate (IV) ```

What are the clinical uses of bisphosphonates?

Osteoporosis (first line therapy) Hypercalcemia Metastatic bone disease Paget's disease of the bone

Describe the important pharmacokinetics of bisphosphonates

They are very poorly absorbed, so they must be taken on an empty stomach Maximal effect is in 2-4 days, but drug may remain in bone for lifetime

What are the adverse effects of bisphosphonate treatment?

``` Upper GI: heartburn, esophageal irritation, esophagitis Transient hypocalcemia Renal impairment Ocular side effects Osteonecrosis of the jaw ```

What is osteonecrosis of the jaw?

Painful swelling, exposed bone and infection of jaw related to bisphosphonate or denosumab treatment. Typically follows dental procedures.

What are the contraindications for bisphosphonate treatment?

Upper GI disease | Chronic kidney disease

What drugs are alternatives for bisphosphonates if they are contraindicated?

Teriparitide (PTHR agonist) Denosumab (RANKL antagonist) Raloxifene (SERM)

What is the mechanism of action of denosumab?

RANKL antagonist, prevents osteoclast differentiation and excessive bone loss

What are the clinical uses of denosumab?

Osteoporosis: reduces fracture occurence Hypercalcemia Giant cell tumor of the bone

What are the adverse effects of denosumab?

Hypocalcemia Osteonecrosis of the jaw Joint/muscle pain

What are the contraindications for denosumab treatment?

Hypocalcemia

What is the mechanism of action of teriparitide?

PTH receptor agonist | Teriparitide is actually the 34 AA of the N-terminal of PTH

What are the clinical uses of teriparitide?

Osteoporosis (paradoxical effect of intermittent PTH stimulation)

What is unique about teriparitide compared to the other osteoporosis drugs?

It is the only anabolic agent on the market. The others all decrease catabolism.

What are the adverse effects of teriparitide?

Transient hypercalcemia Increased serum uric acid Risk of osteosarcoma

What are the contraindications for teriparitide treatment?

History of gout, renal stones Children and adolescents Patients with increased risk for osteosarcoma (active bone malignancy, Paget's, increased Alk phos, prior radiation)

What is the mechanism of action of raloxifene?

SERM: agonist in bone and liver, antagonist in breast and uterus Inhibits bone loss via transcriptional regulation to decrease osteoclast function, increase osteoblast/osteocyte lifespan

What are the clinical uses for raloxifene?

Treatment of osteoporosis in postmenopausal women | Osteoporosis in women with breast cancer, history of breast/endometrial cancer

What are the adverse effects associated with raloxifene?

Venous thromboembolism | Worsened vasomotor symptoms (hot flashes/night sweats)

What is the mechanism of action of calcitonin?

Binds to osteoclast receptors to prevent bone resorption and inhibits renal reabsorption of Ca. Results in a decrease in serum Ca

What are the clinical uses of calcitonin?

Severe hypercalcemia Paget's disease Postmenopausal osteoporosis

What adverse effects are associated with calcitonin treatment?

Nausea, hand swelling, uticaria, intestinal cramping | Cancer with sustained use?

What is the mechanism of action of cinacalcet?

Calcimimetic: allosterically enhances the sensitivity of the CaSR to Ca2+ levels. This causes lower Ca levels to trigger suppression of PTH, which decreases bone turnover, decreasing serum Ca and PO4

What are the clinical uses of cinacalcet?

Secondary hyperparathyroidism due to CKD Hypercalcemia due to parathyroid carcinoma Primary hyperparathyroidism

What adverse effects are associated with cinacalcet?

Hypocalcemia | Decreased seizure threshold

What are the contraindications for cinacalcet treatment?

Hypocalcemia: Ca below 8.4 mg/dL

What are the recommended treatment options for hypercalcemia?

Volume repletion with saline Calcitonin Bisphosphonates

What are the recommended treatment options for hypocalcemia?

Vitamin D supplementation | Calcium supplementation

What are the recommended treatment options for Rickets and osteomalacia?

Vitamin D supplementation

What are the recommended treatment options for primary hyperparathyroidism?

Surgery Cincacalcet Bisphosphonates

What are the recommended treatment options for CKD, hyperphosphatemia, secondary hyperparathyroidism?

Phosphate binder: Sevelamer Cinacalcet Calcitriol

What are the recommended treatment options for osteoporosis?

``` Calcium/Vitamin D supplements Bisphosphonates Denosumab Raloxifene Calcitonin Teriparitide ```

What are the recommended treatment options for Paget's disease?

Bisphosphonates | Calcitonin