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ENDO 2 Exam II (2017) > Bone mineral pharm > Flashcards

Bone mineral pharm Flashcards

1
Q

drug list: minerals

A

calcium

phosphate

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2
Q

drug list- hormones

A

calcitonin

teriparatide

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3
Q

drug list: vitamin D, metabolites and analogs

A
  • calcitriol
    *cholecalciferol (vitamin D3)
  • ergocalciferol (vitamin D2)
    calcipotriene
    doxercalciferol
    paricalcitol
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4
Q

drug list- selective estrogen receptor modulators (SERMs)

A

raloxifene

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5
Q

drug list- bisphosphonates

A 
* alendronate
etidronate
ibandronate
pamidronate
risedronate
tiludronate
zoledronic acid
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6
Q

drug list- calcium receptor agonists

A

cinacalcet

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7
Q

other drugs

A
  • Denosumab
    estrogens
    glucocorticoids
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8
Q

Bone Remodeling

A

Osteoblast-derived cytokines
RANKL binds RANK, induces osteoclast formation
Osteoprotegerin acts as decoy ligand for RANKL
Completion of resorption followed by preosteoblast invasion
Remodeling cycle ~ 6 months

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9
Q

Calcium and Phosphate

A

Calcium (Ca2+) and Phosphate (PO43-), major mineral constituents of bone
Human Adult: 1-2 kg Ca2+ and 1 kg PO43-
- 95% of Ca2+ stored in bone
- 85% of PO43- stored in bone

Absorption:

  • 600-1000 mg/day of Ca2+ with 100-250 mg absorbed (net)
  • Similar amount of PO43- but absorbed more efficiently

Kidney Reabsorption:

  • 98% of filtered Ca2+
  • 85% of filtered PO43-

Extracellular Concentrations:

  • Ca2+ 8.5-10.4 mg/dL
  • PO43- 2.5-4.5 mg/dL
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10
Q

Parathyroid Hormone (PTH)

A

Polypeptide hormone produced in parathyroid gland

  • Activity Results:
      • Increased serum calcium
      • Decreased serum phosphate

Actions on Bone:

  • Indirectly increases activity and number of osteoclasts
  • Acts on osteoblasts  induces RANKL
  • RANKL increases osteoclast activity and number
  • Increases bone remodeling
    • Net effect = bone resorption (but low, intermittent doses increase bone formation)

Actions in Kidney:

  • Increases reabsorption of calcium; inhibits reabsorption of phosphate
  • Stimulates 1,25(OH)2D (calcitriol) production
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11
Q

Vitamin D

A

Applied to natural cholecalciferol (vitamin D3) and plant-derived ergocalciferol (vitamin D2)

** Activity Results:
- Increased calcium and phosphate
- Increased bone turnover
Actions in Intestine:
Augmented absorption of calcium and phosphate
Actions on Bone:
Promotes recruitment of osteoclast precursors
Induces RANKL

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12
Q

Biotransformation of Vitamin D

A

Ultraviolet light
Hydroxylation in liver
Hydroxylation in kidney

consider impact of liver/ renal failure on Vitamin D

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13
Q

PTH effects on Intestine, kidney, bone

A

Intestine- inceased calcium and phosphate absorption (by increased 1,25 OH2D production)

Kidney: decreased calcium excretion, increased phosphate excretion

bone: calcium and phosphate resoprtion increased by high doeses; low doses may increase bone formation

Net effect: serum calicum increased, serum phosphate decreased

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14
Q

Vitamin D effects on intestine, kidney, and bone

A

intestine: increased calcium and phosphate absorption by 1,25(OH)2D
kidney: calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D

Bone: increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D

Net effect: serum calcium phosphate both increased

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15
Q

FGF23 effects on intestine, kidney, bone

A

intestine: decreased calcium and phosphate absorption by decreased 1,25(OH)2D
kidney: increased phosphate excretion
bone: decreased mineralization due to hypophosphatemia

net effect: decreased serum phosphate

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16
Q

Teriparatide

A

Synthetic, recombinant PTH
Increases BMD and reduces risk or vertebral and non-vertebral fractures
MOA: intermittent PTH promotes bone growth
Therapeutic Use:
- Women – with history of osteoporotic fracture, multiple risk factors for fracture, or those intolerant or failed other drug therapy
- Men – primary or hypogonadal osteoporosis
ADRs: orthostatic hypotension, hypercalcemia, dizziness, nausea, angina
CI: those patients at increased risk of osteosarcoma

don’t give longer than 2 years

17
Q

Vitamin D

A

MOA: increases intestinal absorption of calcium and phosphate
- Also increases bone turnover

Therapeutic Use:

  • Nutritional rickets
  • Metabolic rickets and osteomalacia (especially in CKD)
  • Hypoparathyroidism
  • Osteoporosis

Choice of Preparation:

  • Otherwise healthy patients – ergocalciferol or cholecalciferol may be used
  • Liver disease – 25-hydroxyvitamin D (does not require hepatic hydroxylation)
  • Kidney disease +/- liver disease – calcitriol

ADRs: hypercalcemia (+/- hyperphosphatemia), nausea, vomiting, constipation

18
Q

Calcitonin

A

Excreted by parafollicular cells of thyroid; single-chain peptide
MOA: inhibits osteoclastic bone resorption (with time also inhibits formation)
- Decreases calcium and phosphate reabsorption in kidney
Net Effects: decreased serum calcium and phosphate
PK:
- Human calcitonin t1/2 10 min; salmon calcitonin t1/2 40-50 min

Therapeutic Use:
- Disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)

ADRs: nausea, hand-swelling, urticaria, intestinal cramping (rare)

19
Q

Glucocorticoids

A

Actions Related to Bone Mineral Homeostasis:

  • Antagonize vitamin D stimulated intestinal calcium transport
  • Stimulate renal calcium excretion
  • Block bone formation

Net Effect: decrease total body calcium stores

Therapeutic Use:

  • Hypercalcemia (associated with lymphomas and granulomatous diseases)
  • Vitamin D intoxication
20
Q

Estrogens

A

MOA: prevent maturation of osteoclast precursors to mature osteoclasts
Therapeutic Use:
- Primary hypogonadism
- Post-menopausal hormone replacement therapy
- Hirsutism and amenorrhea
- Prevention of osteoporosis

ADRs: increased risk of heart disease and breast cancer, uterine bleeding, cancer (breast, endometrial), nausea, breast tenderness, hyperpigmentation, migraines, cholestasis, gallbladder disease, hypertension

CIs:

  • Estrogen-dependent neoplasms
  • Undiagnosed genital bleeding
  • Liver disease
  • History of thromboembolism
  • Heavy smokers
21
Q

Raloxifene

A

Selective Estrogen Receptor Modulator (SERM)
MOA: partial agonist in bone but does not stimulate endometrial proliferation
Therapeutic Use:
- Treatment and prevention of post-menopausal osteoporosis
ADRs: hot flashes, leg cramps, thromboembolism
CIs:
- Active or past history of thromboembolism
- Coronary heart disease or risk factors for major coronary event

22
Q

Bisphosphonates: agents, MOA and PKs

A

Agents: alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, zoledronate

MOA: analogs of pyrophosphate
- P-O-P bond replaced with non-hydrolyzable P-C-P
- Concentrate at sites of active remodeling
- Decreases formation and dissolution of hydroxyapatite
- Directly inhibits osteoclasts
PK:
Food decreases absorption –> take on an empty stomach
under 10% of dose absorbed; nearly half of absorbed accumulates in bone

23
Q

Bisphosphonates: therapeutic use and ADRs

A

Therapeutic Use:

  • Osteoporosis
  • Hypercalcemia associated with malignancy
  • Paget’s disease

ADRs:

  • Esophageal and gastric irritation (oral formulations)
  • Hypocalcemia and musculoskeletal pain
  • Osteonecrosis of the jaw (dentists won’t want to treat these patients)
  • Subtrochanteric fractures

“Drug Holidays”

24
Q

Denosumab

A

Fully human monoclonal antibody
MOA: binds and prevents action of RANKL. Mimics effects of osteoprotegerin.
Blocks osteoclast formation and activation

PK:
- Administered subcutaneously every 6 months

Therapeutic Use:

  • Post-menopausal osteoporosis
  • Cancer (prostate and breast)

ADRs: concern for immune suppression, osteonecrosis and fractures, hypocalcemia

25
Q

Cinacalcet

A

MOA: activates calcium sensing receptor (CaSR), highest concentration in parathyroid gland, which leads to inhibition of PTH secretion
PK:
- t1/2 30-40 hours; eliminated by renal excretion
- CYP3A4, CYP2D6, and CYP1A2 metabolism

Therapeutic Use:

  • Secondary hyperparathyroidism in CKD
  • Vitamin D deficiency

ADRs: hypocalcemia

DDIs:

  • Drugs which inhibit calcium homeostasis
  • Those that inhibit drug absorption
  • Those that interfere with metabolism
26
Q

treating hypercalcemia

A

isotonic saline- restores intravascular volume, increases urinary calcium excretion (hours)

calcitonin- inhibits bone resorption via intererence with osteoclast function, promotes urinary calcium excretion (4-6 hours)

bisphosphonates- inhibit bone resorption via interference with osteoclastr recruitment and function (24-72 hours)

loop diuretis- increase urinary calcium excretion via inhibition of calcium reabsorption in the loop of henle (hours)

glucocorticoids- decrease intestinal calcium absorption, decrease 1,25 dihydroxyvitamin D production by activated mononuclear cells in patients with granulomatous diseases or lymphoma (2-5 days)

Calcimimetics- calcium sensing receptor agonist, reduces PTH (parathyroid carcinoma, secondary hyperparathyroidism in CKD) (2-3 days)

dialysis- low or no calcium dalysate (hours)

27
Q

equation for corrected calcium

A

4-plasma albumin (g/dL) * .8 + serum calcium

28
Q

treating Hypocalcemia

A

Treatment Approach: calcium and vitamin D

Oral Calcium:
Calcium carbonate (40% calcium) – preferred 
Calcium lactate (13% calcium)
Calcium phosphate (25% calcium)
Calcium citrate (21% calcium)

Intravenous Calcium:
Calcium gluconate – preferred
Calcium chloride- has to be given IV and can cause tissue necrosis

29
Q

Vitamin D Deficiency

A

Optimal Vitamin D Level: controversial

  • IOM sets lower limit at 20 ng/mL
  • Endocrine society lower limit is 30 ng/mL

Causes of Deficiency:

  • Decreased intake or absorption
  • Reduced sun exposure
  • Increased hepatic catabolism
  • Decreased endogenous synthesis (↓ 25-hydroxylation in liver or ↓ 1-hydroxylation in kidney)
  • End-organ resistance to vitamin D

Treatment Approach:

  • Vitamin D2 or D3 in high doses for several weeks followed by maintenance dosing
  • Diet should contain adequate amount of calcium
30
Q

best agent for osteoporosis

A

teriparatide

other agents don’t do as well AND tend to plateau after a while

31
Q

what supplemental MOA causes constipation, inestinal bloating, and excess gas?

A

calcium

32
Q

what is the MOA of Teriparatide?

A

synthetic PTH, enhances remodelling

33
Q

what is the MOA of calcitonin?

A

inhibits osteoclastic bone resorption

34
Q

What enhances intestinal absorption of calcium and phosphate but has adverse effectsof hypercalcemia, nausea, and constipation?

A

Vitamin D

35
Q

what are the adverse effects of raloxifene? it is an estrogen receptor agonist in bone

A

hot flash
leg cramps
thromboembolism

36
Q

What adverse effects of alendronate? It inhibits osteoclasts, inhibits dissolution of hydroxyapatite

A

esophageal and gastric irritation

37
Q

what is the MOA of enosumab, which has the adverse effects of hypocalcemia, potentially increasing the risk of infection and osteonecrosis?

A

binds and prevents action of RANKL

ENDO 2 Exam II (2017) (19 decks)

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