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therapeutics > Lecture 39 + 40: cant make me > Flashcards

Lecture 39 + 40: cant make me Flashcards

1
Q

Note about serum Ca2+

A

-50% ionized (DIFFUSABLE)
-10% complexed (DIFFUSABLE)
-40% protein bound

-total Ca+: 10mg/dL
-diffusable Ca+: ~5mg/dL

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2
Q

Body distribution of calcium

A

-99% in bone and teeth
-1% in ECF and cytoplasm

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3
Q

Calcium state in bone

A

-crystalline form
-hydroxyapatite (Ca10(PO4)6(OH)2

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4
Q

Osteoblasts

A

-bone forming cells
-inc Ca and PO4 from plasma INTO bone

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5
Q

Osteoclasts

A

-bone resorption cells
-RELEASE Ca+ and PO4 into PLASMA

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6
Q

Osteocytes

A

-release factors that regulate osteoblast/clast activity

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7
Q

Osteocytes are stimulated by

A

-mechanical force detected by cell process that extend into canaliculi forming a network involving ACTIN and CONNEXIN 43 connection channels

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8
Q

positive regulators of osteoblasts/neg of osteoclasts

A

-sense inc load
-inc BMD
-osteonectin
-Nitric oxide
-Dentin Matrix Protein 1

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9
Q

negative regulators of osteoblasts/postitive regulators of osteoCLASTS

A

-sense dec in load
-dec BMD
-sclerostin
-DKK-1
-RANKL

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10
Q

Regulation of Ca homeostasis by

hormone

A

-Parathyroid Hormone (PTH)

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11
Q

Parathyroid hormone (PTH)

A

-peptide hormone secreted from parathyroid gland
-84aa cleaved from 115aa
-aa 1-34 have full activity
-deletion of aa 1 and 2 eliminates activity

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12
Q

PTH effect on calcium

A

-inc Ca in ECF (PLASMA!)

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13
Q

PTH mech of action

A

-inc Ca reabsorption from collecting tubules (kidney)(ECaC1/TrpV5)
-inc Ca reabsorption from bone (inc osteoCLAST # and activity)
-inc PO4 loss in urine
-inc 1,25(OH2) D3 production by kidney

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14
Q

PTH secretion triggered by

2 things

A

-low serum Ca++ levels
-low levels of CSR (GPCR that binds Ca++)

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15
Q

First step of Vitamin D synthesis

A

-7-dehyrocholesterol (Provitamin D) to Cholecalciferol (Vitamin D3) by UV irradition of skin

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16
Q

Cholecalciferol

A

-Vitamin D3
-can be obtained in diet or by exposure to sunlight

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17
Q

Vitamin D3 fate

A

-transport to liver
-then to kidmey

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18
Q

Vitamin D binding protein

A

-transports vitamin D3 to liver
-adds OH to the top branch
=25 hydryoxyvitamin D3

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19
Q

25 hydroxyvitamin D3 transport to kidney

A

-1-a-hydroxylase (if PTH present)
-24-hydroxylase (normal Ca and PO4 levels)

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20
Q

1-a-hydroxylase

A

-converts 25OH-vitamin D3 to 1,25diOH vitamin D3 calcitriol
-kidney
-only if PTH is present (low Ca and PO4)
-24hydroxylase if no PTH
-adds OH under CH2 on bottom ring

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21
Q

24-hydroxylase

A

-25-OHvitamin D3 to 24,25 diOH vitamin D3
-secalciferol
-if no PHT present/Ca and PO4 levels ok
-inactive form
-adds OH to top branch

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22
Q

1,25 Dihydroxy Vitamin D3

A

-Calcitriol
-active form of vit D
-1-a-hydroxylase in kidney

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23
Q

Actions of Vitamin D

A

-inc Ca and PO4 absorption from small intestine
-inc reABsorption
-indirect effect on calbindins and vitamin D binding protein
-feedback inhibition of PTH

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24
Q

How does Vit D inc Ca and PO4 absorption from small intestine?

A

-direct, rapid effect on brush border of intestinal mucosal cells
-ECaC2/TrpV6

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25
Q

Absorption of Ca++ from intestine

A

-Ca2+ enters cell via TrpV6 on brush border
-exists in cell bound to calbindin-D9k
-released from cell by Ca2+ ATP-ase (requires ATP)

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26
Q

Vit D3 upregulates

A

-TrpV6
-calbindin
-Ca2+ATPase

-also NPt2b which enhances PO4 absorption

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27
Q

Fibroblast Growth Factor 23 (FGF23)

A

-32kDa protein
-STIMULATES PO4 excretion (supress Npt2a and c)
-INHIBITS PTH secretion
-INHIBITS 1,25(OH)2D3 synthesis (=less P absorption by intestine)

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28
Q

FGF23 secreted by

A

-osteocytes and osteoBLAsts
-in response to elevated serum PHOSPHATE

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29
Q

FGF23 Auto/paracrine effect on osteoctyes

A

-inhibits bone mineralization

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30
Q

High levels of FGF23 correlate w

A

-poor prognosis in pts w CKD on dialysis

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31
Q

Protease-resistant mutant of FGF23

A

-causes autosomal dominant hypophosphatemic rickets
-excreting too much phosphate

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32
Q

Inhibitors of PTH secretion

A

-1,25-(OH)2 Vit D3
-FGF23
-High Ca2+

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33
Q

Calcitonin

A

-negative regulator of serum Ca++
-secreted by C-cells in thyroid gland
-32aa peptide

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34
Q

Calcitonin actions

A

-INHIBIT osteoCLASTs
-INCREASE Ca++ and PO4 excretion in urine

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35
Q

Calcitonin stimulated by

A

high serum Ca++

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36
Q

Paget’s Disease

A

-uncontrolled osteoCLASTIC bone resorption and secondary bone formation that is poorly organized

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37
Q

Paget’s Disease characteristics

A

-bone pain
-bone deformities
-loss of hearing, HYPERcalcemia
-may be caused by slowly acting virus

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38
Q

Osteoporosis

A

-shift in bone balance toward resorption
-more osteoCLASTs
-spontaneous or minimal trauma fractures
-hip, vertebrae ribs

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39
Q

causes of osteoporosis

A

-postmenopause: dec in estrogen levels dec bone mass
-age related dec in osteoBLAST activity

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40
Q

Vertebral complications of osteoporosis

A

-fragility fracture
-pain
-height loss
-kyphosis
-activity limitations
-restrictive lung disease
-psychological symptoms

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41
Q

Risk factors for osteoporosis

A

-physical INactivity
-age
-low Ca++ intake in early years
-long term glucocorticoid therapy

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42
Q

Hypercalcemia symptoms

A

-CNS
-depression
-coma

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43
Q

Hypercalcemia causes

A

-Hyperparathyroidism (more PTH)
-malignant tumors (some produce peptide w PTH activity)

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44
Q

HYPOcalcemia symptoms

A

-neuromuscular disturbances
-paresthesias
-tetany
-muscle cramps

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45
Q

HYPOcalcemia causes

A

-HYPOparathyroidism
-vit D deficiency

46
Q

Vit D deficiency in children

A

-can cause weight bearing bone deformities

47
Q

Vitamin D preparations

A

-Cholecalciferol Vit D3 (OTC)
-Calcifediol 25 OH Vit D3 (Calderol) (liver disease)
-Calcitriol 1,25OH2 Vit D3 (Rocaltrol) (kidney disease)
-Ergocalciferol (Vit D2) from UV radiated yeast

48
Q

Vitamin D preparations mech of action

A

-inc Ca++ and PO4 absorption from gut
-inc Ca++ and PO4 reabsorption in renal tubules

49
Q

Drugs to treat osteoporosis

A

-Vit D supplement first
1. Bisphosphonates/Denosumab
2. Ibandronate
3. Raloxifene
4. Calcitonin

50
Q

Drugs to treat osteoporosis in HIGH fracture risk

3

A

-teriparatide/abaloparatide
-romosozumab

51
Q

Vitamin D for osteoporosis treatment

A

-vitamin D (800-1000 IU)
-Ca++ (>1200mg)
-daily
-slight reduction in fracture risk
-supplement w osteoporosis therapy

52
Q

Vitamin D use in Hypocalcemia/Hypoparathyroidism

A

-Vit D and Ca++
-with rPTH

53
Q

Vitamin D treatment in hyperparathyroidism 2’ to CKD

A

-analogs suppress PTH

54
Q

Vitamin D overdose

A

-Ca++ deposits in kidney and soft tissues
-Hypercalcemia = coma and death

55
Q

Bisphosphonates

A

-first line therapy for osteoporosis
-inorganic pyrophosphoric acid
-nitrogen side chain
-inhibits bone resorption

56
Q

Bisphosphonates action

A

-reduce formation and dissolution of hydroxyapatit crystals
-accumulates in bone as part of matrix (50% of dose)
-disrupt cytoskeleton
-induce apoptosis
-inhibit farnesyl-PP synthesis of osteoCLASTS

57
Q

Bisphosphonate dosing precautions

A

-10% absorbed orally
-take w water 30 min before breakfast

58
Q

Bisphosphonate problems

A

-may lead to HYPOcalcemia (supplement w Ca++ and vit D)
-esophagitis, nausea, heart burn
-necrosis of the jaw
-atypical femur fractures

59
Q

Bisphosphonates approved for Paget’s and cancer (not osteoporosis)

A

-Pamidronate
-Etindronate

60
Q

Bisphosphonates approved for osteoporosis

A

-Zoledronate (IV/year)
-Alendronate (oral)
-Risendronate (oral)
-Ibandronate (IV or oral) (doesn’t prevent hip fractures)

61
Q

importance of N-side chain in bisphosphonates

A

-inhibts farnesyl pyrophosphate synthase
-disrupts prenylation of proteins in osteoCLASTS
=Rac and Ras cannot get to membrane to start signal
-apoptosis of osteoclast
-Lys and Thy

62
Q

Farnesyl

A

-allows proteins to be held at membrane
-allows Ras and Rac to signal to osteoCLAST

63
Q

Teriparatide (Froteo)

A

-aa 1-34 of PTH produced in E. coli
-treat osteoporosis in patients with HIGH RISK of fracture

64
Q

Abaloparatide (Tymlos)

A

-aa 1-34 of PTHeP produced syntheticallly
-treat osteoporosis in HIGH risk patients

65
Q

TeriPARAtide and AbaloPARAtide dosing

A

-inject SQ qd (20/80ug) w oral Ca++ and Vit D
-better stimulation of osteoBLASTs this way

66
Q

TeriPARAtide and AbaloPARAtide problems

A

-potential for HYPERcalcemia
-but rare
-only drug w this side effect

67
Q

Teriparatide (Forteo) mech of action

A

-interacts with PTH1 receptor
-dosing can affect stimulation of osteoclasts or blasts

68
Q

PTH1 recptor

A

-GPCR
-Gs and adenylyl cyclase
-Gq/PLC
-expressed on osteoblasts and kidney cells

69
Q

Differentiation of Osteoclasts

A

-Osteoblast secretes RANKL
-RANKL binds to receptors on osteoclast precursor
-regulated by OPG (osteoprotegerin) binding excess

70
Q

Intermittent teriparatide dosing

A

-dec osteoblast apoptosis
=more osteoblasts
-inc BMD

71
Q

continuous teriparatide dosing

A

-inc RANKL
-dec OPG
=inc osteoCLASTs
-inc serum Ca++
=HYPERcalcemia

72
Q

Pros of Teriparatide over Bisphosphates

A

-may be more effective at PREVENTING fractures
-builds bone mass at higher rate
-may allow better bone healing after fracture

73
Q

Cons of teriparatide

A

-must be injected daily
-not recommended beyond 2 years
-black box warning for bone cancer

74
Q

Teriparatide black box warning

A

-bone cancer
-dont use more than 2 years

75
Q

Denosumab (Prolia)

A

-mAb against RANKL
=prevents osteoCLAST differentiation

76
Q

Denosumab (Prolia) dosing

A

-inject SC every 6 months
-must take 1000mg Ca++ and 400 IU vit D daily

77
Q

Denosumab (prolia) risks

A

-Hypocalcemia (must treat underlying hypocalcemia first)
-inc risk of fracture upon discontinuation

78
Q

Romosozumab (Evenity)

A

-treat HIGH RISK pts
-mAB aginst sclerostin

79
Q

Romosozumab (Evenity) dosing

A

-inject SC monthly for 12 months
-w Ca/VitD supplementation

80
Q

Sclerostin

A

-dec osteoBLASTS
-inc osteoCLASTS

81
Q

Sclerostin secretion increases with

A

-unloading
-after menopause

82
Q

Romosozumab (evenity) problems

A

-MACE (not used in pts w MI or stroke in last year)
-hypersensitivity
-hypocalcemia
-osteonecrosis
-atypical fractures

83
Q

Sclerostin mech

A

-binds LRP 5/6
=inhibits Wnt signaling
-GSK3 complex displaced from Wnt
=phosphorylates B-cantenin
-B-cantenin (required for osteoblast diff) degraded

84
Q

Estrogens and SERMs

A

-prevention of postmenopausal bone resorption
-inc activity of osteoblasts
-maybe dec activity of osteoclasts

85
Q

SERM drugs

A

-Raloxifene (evista)
-Bazedoxifene + conjugated estrgogens (Duavee)

86
Q

Raloxifene and Bazedoxifene action

A

-ANTAgonists in breast, uterus, brain (hot flashes)
-AGONISTs in bone and liver

87
Q

Raloxifene and Bazedoxifene risk

A

-blood clots

88
Q

Salmon Calcitonin (Miacalcin)

A

-nasal spray/inj
-dec osteoclast activity
-blocks renal reabsorption of PO4 and Ca++
-not drug of choice
-not great to treat hypercalcemia (loses efficacy quickly)

89
Q

salmon calcitonin clinical use

A

-Paget’s disease
-hypercalcemia 2’ to malignancy
-postmenopausal osteoporosis (alt to ERT)

90
Q

salmon calcitonin side effects

A

-uticaria
-hand swelling
-nausea
-hypersensitivity reactions
-risk of malignancies w long-term use
-hypocalcemia

91
Q

Cinacalcet (Sensipar)

A

-treat 2’ HYPERparathyroidism
-dec serum levels of PTH and Ca++

92
Q

Cinacalcet (sensipar) dose

A

-oral
-30mg BID initial

92
Q

Common causes of hyperparathyroidism

A

-CKD with dialysis (loss of 1,25OHVitD3 production)
-parathyroid carcinoma

93
Q

Cinacalcet (Sensipar) mech

A

-binds to calcium-sensing receptor (CSR) (GPCR) to inc sensitivity to Ca++
=inhibits release of PTH
-dec PTH and Ca++

94
Q

Cinacalcet (Sensipar) risk

A

-HYPOcalcemia
-seizures
-adynamic bone disease

95
Q

CSR in CKD w dialysis

A

-less responsive to Ca++
-also elevated PO4 can lock CSR in inactive state

96
Q

Etelcalcetide (Parsabiv)

A

-treat 2’ hyperparathyroidism
-PAM of CSR to inhibit PTH release
-dec PTH and Ca++

-big ass molecule

97
Q

Etelcalcetide (parsabiv)

A

-hypocalcemia
-adynamic bone disease
-worsening HF
-upper GI bleeding

98
Q

Etelcalcetide (parsabiv) dose

A

-IV 5mg 3x/week initial

99
Q

Vit D analog drugs

A

-Zemplar
-HectorolV

100
Q

Vit D analogs

A

-IV or oral
-inhibit secretion of PTH w less effect on serum Ca++ than vit D3

101
Q

Zemplar

A

-Vit D analog
-2’ hyperparathyroidism in CKD stage 3-4
-CKd w dialysis
-1-4mcg 3x/week IV or oral

102
Q

Hectorol

A

-Vit D analog
-2’ hyperparathyroidism in CKD w dialysis
-prodrug 25 hydroxylation by CYP27 in liver
-4mcg/week. IV or oral

103
Q

CKD often results in

A

-loss of phosphate excretion in response to PTH and FGF23
-Hyperphosphatemia
-Calcific Uremic Arteriolopathy risk

104
Q

Calcific Uremic Arteriolopathy

A

-Ca++ combine w PO4 and precipitate in tissues
-calification

105
Q

Phosphate binder

A

-complex w dietary PO4
-prevent absorption from GI
-treat hyperphosphatemia in CKD w dialysis

106
Q

Phosphate binder drugs

A

-Lanthanum Carbonate (Fosrenol)
-Sevelamer (Renagel, Renvela)

107
Q

Lanthum Carbonate (Fosrenol)

A

-phosphate binder
-treat hyperphosphatemia in CKD w dialysis
-forms insoluble LaPO4 salts in GI tract
-dec serum PO4 AND Ca!!

108
Q

Sevelamer (Renagel, Renvela)

A

-phosphate binder
-treat hyperphosphatemia in CKD w dialysis
-contains amine
-binds PO4 in GI tract
-dec ONLY PO4

109
Q

Which phosphate binder only decreases PO4

A

Sevelamer

110
Q

Which phosphate binders dec PO4 AND Ca++

A

Lanthum Carbonate

therapeutics (78 decks)

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