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Endocrine > Cook - Bone Mineral Drugs > Flashcards

Cook - Bone Mineral Drugs Flashcards

1
Q

Teriparatide (hPTH)

A
  • Short half-life; INJECTABLE subcu (daily)
  • Exogenous PTH in low doses directly stimulates bone formation w/o stimulating resorption
  • Important for women with osteoporosis after bisphosphonate therapy
  • May stimulate IGF-1
  • AEs: hypercalcemia and hypercalciuria
  • REMEMBER: excess endogenous PTH causes bone resorption
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2
Q

What 3 calcitropic hormones control Ca in the body?

A
  • PTH
  • Calcitonin
  • Calcitriol (active form of Vitamin D)
  • Coordination of these 3 hormones controls Ca concentration in the blood
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3
Q

Where is the Ca in the body? How much?

A
  • Tightly regulated: 2.5mM = 5mEq/L = 10mg/dL
  • IC: mostly in mito and ER (fluctuates greatly)
  • Blood and ECF: 40% protein-bound, 10% complexed (citrate, phosphate), 50% diffusable, ionic, or free Ca
    1. Ionized, free Ca in this compartment almost always 1mM (concentration of phosphorous in the blood about the same)
  • Bone: vast majority -> 99% in mineral phase, and 1% in pool that can rapidly exchange with EC Ca
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4
Q

What are the 3 major sites of action for blood Ca regulation?

A
  • BONE: Ca and phosphate in blood are in equilibrium w/hydroxyapatite of bone -> allows resorption of bone Ca into blood
  • KIDNEY: excretion of Ca by kidney about 100mg/d
  • GI TRACT: total dietary intake about 1,000mg/d, and 900mg/d excreted in feces
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5
Q

Why do we only absorb about 10% of the Ca we consume each day?

A
  • Low bioavailability bc absorbed in brush border of the duodenum only (via Vitamin D regulation)
  • Not an active transport system (facilitated diffusion) because Ca moving down the conc gradient (from bowel to IC)
  • If you get too much Ca in the cell, it will apoptose because mitochondria take it up
  • Vitamin D stimulates production of calbindin inside the cell, which binds Ca to prevent cellular damage
  • What is regulating Ca uptake is how much that cell can hold
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6
Q

How much Ca and Vitamin D needs to be consumed each day?

A

This is controversial, and no one really agrees about these

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7
Q

What is the primary action of Vitamin D?

A

Uptake of Ca

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8
Q

Describe how PTH, Vit D, Calcitonin, and FGF23 affect Ca/P in bone, kidney, and GI tract (image).

A
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9
Q

Briefly describe the actions of 1,25-OH2D (image).

A
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10
Q

What mediators are important in osteoclast/blast activity (image)?

A
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11
Q

What are the 3 major actions of PTH?

A

– Synthesized by parathyroid gland, and functions to INC plasma Ca

  1. INC bone resorption
  2. INC kidney resorption
  3. INC active form of Vit D
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12
Q

How does the Ca-sensing receptor work?

A
  • Activation has 2 major signal-transducing effects:
    1. Activation of phospholipase C, leading to generation of 2nd messengers: diacylglycerol and inositol triphosphate (GQ)
    2. INH of adenylate cyclase, suppressing IC concentration of cAMP
  • Allows both PTH and Calcitonin-secreting cells to respond to EC Ca
  • In both parathyroid glands and parafollicular cells of thyroid
  • Also expressed in several cell types in kidney, osteoblasts, and a variety of hematopoietic cells in bone marrow and GI mucosa
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13
Q

Cinacalcet

A
  • Activates CaSR by INC sensitivity (CALCIMIMETIC)
    1. Binds allosterically to CaSR and allows PTH suppression at lower Ca
  • DEC PTH (effectively lowers circulating PTH)
  • Allows parathyroid gland to stop PTH production at lower Ca levels
  • This is for hyperparathyroidism (NOT osteoporosis) in pts with parathyroid carcinoma
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14
Q

What are the 3 major actions of Calcitonin?

A
  • Synthesized by parafollicular C cells of thyroid gland, and functions to DEC plasma Ca
    1. DEC bone resorption
    2. DEC kidney reabsorption
    3. DEC active form of Vit D
  • In general, Calcitonin opposes PTH actions
  • Also synthesized in lung and intestinal tract
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15
Q

Calcitriol

A
  • Active form of Vit D -> functions to INC plasma Ca
  • Synthesized in skin and transported in blood
  • Most important physiological action:
    1. INC Ca (+ phosphate) uptake from GI tract -> induces synthesis of Calbindin by binding to transcription factor to INC mRNA and protein synthesis (nuclear receptor)
  • Other actions:
    1. INC kidney reabsorption (pharma dose)
    2. INC bone resorption (pharmacologic dose): paradoxical, but true, and INC dose promotes more resorption (Ca can reverse this effect)
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16
Q

What are 6 things that can lead to a loss of Ca homeostasis?

A
  • Estrogen deficiency (post-menopausal osteoporosis)
  • Glucocorticoid excess
  • Growth hormone deficiency
  • Insulin deficiency
  • Primary hyperparathyroidism
  • Cancer
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17
Q

What is the body’s response to low Ca?

A
  • Detected by parathyroid, causing INC PTH synthesis, which causes:
    1. INC absorption of Ca by kidney
    2. INC synthesis of Calcitriol -> INC GI absorption of Ca
    3. INC resorption of bone
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18
Q

What is the body’s response to high Ca?

A
  • Detected by parafollicular C cells of thyroid, causing INC Calcitonin synthesis, which causes:
    1. DEC synthesis and secretion of PTH -> INC excretion of Ca
    2. DEC resorption of bone (opposing PTH)
    3. Shift to inactive form of Vitamin D
19
Q

How is PTH synthesized?

A
  • Goes through Golgi (can’t take these orally bc they would be digested)
20
Q

What is the MOA of PTH?

A
  • Binds plasma membrane receptor
  • Activates adenylate cyclase -> INC cAMP
  • cAMP activates protein kinases
  • INC urinary cAMP, a test for parathyroid function
21
Q

Hypoparathyroidism? Tx?

A
  • Autoimmune disease rare; more common from thyroid surgery or parathyroid cancer
  • Very serious, but treatable
  • TX: hPTH (Teriparatide): short half-life -> daily, injectable form
    1. More comonly treated with VIt D, with or w/o dietary Ca supplements
22
Q

Raloxifene

A
  • Selective estrogen receptor modulator (SERM): for prevention and treatment of OSTEOPOROSIS in post-menopausal women (ORAL)
    1. Partial agonist effect on bone
  • Antagonist effects in breast tissue, and reduces incidence of breast cancer in F at very high risk
  • No estrogenic effects on endometrial tissue
  • AEs: hot flushes (an antagonist effect) and INC risk of venous thrombosis (an agonist effect)
23
Q

Denosumab

A
  • MAb to RANKL
  • Subcu 60mg dose/6 mos
  • Blocks stimulation of osteoclast formation by RANKL and DEC osteoporosis
  • INC bone mass in pts w/breast or prostate cancer
  • At least as effective as the bisphosphonates
  • Could be INC risk of infection due to RANKL’s role in the immune system
24
Q

FGF-23

A
  • INH production of 1,25-OH2D3, opposing PTH action in the kidney
  • Produced by osteoclasts and blasts
25
Q

Synthesis of calcitonin (image)

A
26
Q

What is the MOA of Calcitonin?

A
  • Binds to plasma mem receptor, and DEC ruffled border surface area on osteoclasts
    1. Osteoclasts start from monocytes, and merge (several nuclei), but one side of cell has ruffled, brush border that lays down bone, resorbs Ca
  • Not a global INH of PTH
  • Has direct renal effects
27
Q

Calcitonin therapeutics

A
  • Acts through calcitonin receptors to INH resorption of bone
  • Used in tx of osteoporosis and Paget’s -> very effective for short-term tx
    1. Ab devo with long-term use (even w/hCT)
  • Subcu injection or intranasal
  • Can get rhinitis with the nasal spray
28
Q

How is calcitriol synthesized (image)?

A
  • He said we don’t need to memorize all of this
29
Q

What are the major uses of Calcitriol in therapeutics?

A
  • Prophylaxis and cure of nutritional ricketts
  • Treatment of metabolic ricketts and osteomalacia
  • Treatment of hypoparathyroidism
  • Prevention and tx of osteoporosis
30
Q

Cholecalciferol/Ergocalciferol

A
  • Cholecalciferol: Vitamin D3
    1. Found in fish and liver oils, and takes effect in 12 to 24 hours
    2. Remains in lipid stores for months
  • Ergocalciferol: Vitamin D2
  • Regulate gene transcription via Vit D receptor to produce the effects of Calcitriol
  • Used to tx Vit D deficiency
  • Oral admin; require metabolism in liver and kidney to active forms
  • AEs: hypercalcemia, hyperphosphatemia, hypercalciuria
31
Q

Ergosterol

A
  • Plant form of Vit D -> similar to cholesterol
32
Q

Calcipotriol

A
  • Analog of Calcitriol
  • Used in tx of psoriasis -> more effective than GCS
33
Q

Dihydrotachysterol

A
  • Reduced Vit D2, DHT
  • 0.002x as active as Calcitriol, but more effective in high doses
  • Now used in tx of OSTEOPOROSIS
  • Injection and nasal spray
34
Q

Paricalcitol

A
  • Analog of Calcitriol used for mgmt of 2o hyperPTH in pts with CKD
  • Reduces PTH via different mechanism than Cinacalcet (agonist for the Vit D receptor
35
Q

22-Oxacalcitriol

A

Suppresses PTH gene expression

36
Q

Bisphosphonates basics

A
  • Nonhydrolyzable analogs of inorganic pyrophosphate -> INH of bone resorption
    1. Bind to bone, killing osteoclasts
  • First used in Paget’s, but effective in tx of osteoporosis
  • Oral Etidronate and Pamidronate are NOT effective in mgmt of hypercalcemia, but 4-24 hr infusion effective in lowering Ca for several weeks
  • Can cause esophageal irritation and osteonecrosis of the jaw
37
Q

Which bisphosphonates are used for Paget’s? Osteoporosis? How are they taken?

A
  • Paget’s: Etidronate, Alendronate, risedronate
  • Osteoporosis: Alendronate
  • All absorbed very poorly in intestine -> must be taken after overnight fast with full glass of H2O
    1. No food for 30 minutes
  • Now have weekly dosage form (newer forms are more potent)
  • Most common side effect is esophageal irritation
    1. Osteonecrosis of the jaw also possible
38
Q

Name the bisphosphonates (incl. gens).

A
  • 1st gen: Etidronate (Paget’s)
  • 2nd gen: 10-100x more potent
    1. Pamidronate
    2. Aledronate (osteoporosis, Paget’s)
    3. Ibandronate
  • 3rd gen: 1,000-10,000x more potent; used to prevent cancer metastases to bone
    1. Risedronate (Paget’s)
    2. Zoledronate
39
Q

What is a serious complication of bisphosphonate therapy?

A
  • Osteonecrosis of the jaw:
    1. Bone under the teeth exposed, often painfully
    2. Swelling, loosening of teeth
    3. Surgical correction makes lesions worse
    4. 80% of cases follow dental extraction
    5. Many cases complicated by infection
    6. Mainly in pts w/cancer after prolonged tx
    7. Much more common w/3rd-gen drugs
  • Some pts started having breaks in their femur (at the strongest point because this bone is very brittle; will not bend, but break)
  • Very effective drugs, but only for a certain period of time -> can’t take these for more than 5 years
40
Q

How does bone mineral density change with menopause? Mediators (graph)?

A
  • Estrogen: effective in preventing osteoporosis
    1. Replacement therapy trials have shown INC risk of thrombosis
41
Q

How do GCS affect bone?

A
  • Common cause of osteoporosis in adults
  • Antagonize Ca uptake in intestine
  • Useful in reversing lymphoma-induced hypercalcemia
42
Q

Plicamycin

A
  • AB used for Paget’s disease and hypercalcemia in the past
  • Don’t think we need to know this one
43
Q

Strontium ranelate

A
  • Used in Europe for osteoporosis (like a bisphosphonate)
  • Blocks differentiation of osteoclasts and promotes apoptosis
  • Also promotes bone formation
  • INC bone mineral density and DEC fractures
  • Don’t think we need to know this one
44
Q

Fluoride

A
  • Dental carries prevention: associated w/mottled enamel, but high resistance to decay
  • F- binds Ca, and can be used to prevent blood clotting
  • Potential agent in preventing osteoporosis
  • Toxicity: osteosclerosis (hydroxyapatite replaced by fluoroapatite), mottled enamel (fluorosis)

Endocrine (12 decks)

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