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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
Absorption of Ca++ from intestine
-Ca2+ enters cell via TrpV6 on brush border -exists in cell bound to calbindin-D9k -released from cell by Ca2+ ATP-ase (requires ATP)
26
Vit D3 upregulates
-TrpV6 -calbindin -Ca2+ATPase -also NPt2b which enhances PO4 absorption
27
Fibroblast Growth Factor 23 (FGF23)
-32kDa protein -STIMULATES PO4 excretion (supress Npt2a and c) -INHIBITS PTH secretion -INHIBITS 1,25(OH)2D3 synthesis (=less P absorption by intestine)
28
FGF23 secreted by
-osteocytes and osteoBLAsts -in response to elevated serum PHOSPHATE
29
FGF23 Auto/paracrine effect on osteoctyes
-inhibits bone mineralization
30
High levels of FGF23 correlate w
-poor prognosis in pts w CKD on dialysis
31
Protease-resistant mutant of FGF23
-causes autosomal dominant hypophosphatemic rickets -excreting too much phosphate
32
Inhibitors of PTH secretion
-1,25-(OH)2 Vit D3 -FGF23 -High Ca2+
33
Calcitonin
-negative regulator of serum Ca++ -secreted by C-cells in thyroid gland -32aa peptide
34
Calcitonin actions
-INHIBIT osteoCLASTs -INCREASE Ca++ and PO4 excretion in urine
35
Calcitonin stimulated by
high serum Ca++
36
Paget's Disease
-uncontrolled osteoCLASTIC bone resorption and secondary bone formation that is poorly organized
37
Paget's Disease characteristics
-bone pain -bone deformities -loss of hearing, HYPERcalcemia -may be caused by slowly acting virus
38
Osteoporosis
-shift in bone balance toward resorption -more osteoCLASTs -spontaneous or minimal trauma fractures -hip, vertebrae ribs
39
causes of osteoporosis
-postmenopause: dec in estrogen levels dec bone mass -age related dec in osteoBLAST activity
40
Vertebral complications of osteoporosis
-fragility fracture -pain -height loss -kyphosis -activity limitations -restrictive lung disease -psychological symptoms
41
Risk factors for osteoporosis
-physical INactivity -age -low Ca++ intake in early years -long term glucocorticoid therapy
42
Hypercalcemia symptoms
-CNS -depression -coma
43
Hypercalcemia causes
-Hyperparathyroidism (more PTH) -malignant tumors (some produce peptide w PTH activity)
44
HYPOcalcemia symptoms
-neuromuscular disturbances -paresthesias -tetany -muscle cramps
45
HYPOcalcemia causes
-HYPOparathyroidism -vit D deficiency
46
Vit D deficiency in children
-can cause weight bearing bone deformities
47
Vitamin D preparations
-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
Vitamin D preparations mech of action
-inc Ca++ and PO4 absorption from gut -inc Ca++ and PO4 reabsorption in renal tubules
49
Drugs to treat osteoporosis
-Vit D supplement first 1. Bisphosphonates/Denosumab 2. Ibandronate 3. Raloxifene 4. Calcitonin
50
Drugs to treat osteoporosis in HIGH fracture risk | 3
-teriparatide/abaloparatide -romosozumab
51
Vitamin D for osteoporosis treatment
-vitamin D (800-1000 IU) -Ca++ (>1200mg) -daily -slight reduction in fracture risk -supplement w osteoporosis therapy
52
Vitamin D use in Hypocalcemia/Hypoparathyroidism
-Vit D and Ca++ -with rPTH
53
Vitamin D treatment in hyperparathyroidism 2' to CKD
-analogs suppress PTH
54
Vitamin D overdose
-Ca++ deposits in kidney and soft tissues -Hypercalcemia = coma and death
55
Bisphosphonates
-first line therapy for osteoporosis -inorganic pyrophosphoric acid -nitrogen side chain -inhibits bone resorption
56
Bisphosphonates action
-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
Bisphosphonate dosing precautions
-10% absorbed orally -take w water 30 min before breakfast
58
Bisphosphonate problems
-may lead to HYPOcalcemia (supplement w Ca++ and vit D) -esophagitis, nausea, heart burn -necrosis of the jaw -atypical femur fractures
59
Bisphosphonates approved for Paget's and cancer (not osteoporosis)
-Pamidronate -Etindronate
60
Bisphosphonates approved for osteoporosis
-Zoledronate (IV/year) -Alendronate (oral) -Risendronate (oral) -Ibandronate (IV or oral) (doesn't prevent hip fractures)
61
importance of N-side chain in bisphosphonates
-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
Farnesyl
-allows proteins to be held at membrane -allows Ras and Rac to signal to osteoCLAST
63
Teriparatide (Froteo)
-aa 1-34 of PTH produced in E. coli -treat osteoporosis in patients with HIGH RISK of fracture
64
Abaloparatide (Tymlos)
-aa 1-34 of PTHeP produced syntheticallly -treat osteoporosis in HIGH risk patients
65
TeriPARAtide and AbaloPARAtide dosing
-inject SQ qd (20/80ug) w oral Ca++ and Vit D -better stimulation of osteoBLASTs this way
66
TeriPARAtide and AbaloPARAtide problems
-potential for HYPERcalcemia -but rare -only drug w this side effect
67
Teriparatide (Forteo) mech of action
-interacts with PTH1 receptor -dosing can affect stimulation of osteoclasts or blasts
68
PTH1 recptor
-GPCR -Gs and adenylyl cyclase -Gq/PLC -expressed on osteoblasts and kidney cells
69
Differentiation of Osteoclasts
-Osteoblast secretes RANKL -RANKL binds to receptors on osteoclast precursor -regulated by OPG (osteoprotegerin) binding excess
70
Intermittent teriparatide dosing
-dec osteoblast apoptosis =more osteoblasts -inc BMD
71
continuous teriparatide dosing
-inc RANKL -dec OPG =inc osteoCLASTs -inc serum Ca++ =HYPERcalcemia
72
Pros of Teriparatide over Bisphosphates
-may be more effective at PREVENTING fractures -builds bone mass at higher rate -may allow better bone healing after fracture
73
Cons of teriparatide
-must be injected daily -not recommended beyond 2 years -black box warning for bone cancer
74
Teriparatide black box warning
-bone cancer -dont use more than 2 years
75
Denosumab (Prolia)
-mAb against RANKL =prevents osteoCLAST differentiation
76
Denosumab (Prolia) dosing
-inject SC every 6 months -must take 1000mg Ca++ and 400 IU vit D daily
77
Denosumab (prolia) risks
-Hypocalcemia (must treat underlying hypocalcemia first) -inc risk of fracture upon discontinuation
78
Romosozumab (Evenity)
-treat HIGH RISK pts -mAB aginst sclerostin
79
Romosozumab (Evenity) dosing
-inject SC monthly for 12 months -w Ca/VitD supplementation
80
Sclerostin
-dec osteoBLASTS -inc osteoCLASTS
81
Sclerostin secretion increases with
-unloading -after menopause
82
Romosozumab (evenity) problems
-MACE (not used in pts w MI or stroke in last year) -hypersensitivity -hypocalcemia -osteonecrosis -atypical fractures
83
Sclerostin mech
-binds LRP 5/6 =inhibits Wnt signaling -GSK3 complex displaced from Wnt =phosphorylates B-cantenin -B-cantenin (required for osteoblast diff) degraded
84
Estrogens and SERMs
-prevention of postmenopausal bone resorption -inc activity of osteoblasts -maybe dec activity of osteoclasts
85
SERM drugs
-Raloxifene (evista) -Bazedoxifene + conjugated estrgogens (Duavee)
86
Raloxifene and Bazedoxifene action
-ANTAgonists in breast, uterus, brain (hot flashes) -AGONISTs in bone and liver
87
Raloxifene and Bazedoxifene risk
-blood clots
88
Salmon Calcitonin (Miacalcin)
-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
salmon calcitonin clinical use
-Paget's disease -hypercalcemia 2' to malignancy -postmenopausal osteoporosis (alt to ERT)
90
salmon calcitonin side effects
-uticaria -hand swelling -nausea -hypersensitivity reactions -risk of malignancies w long-term use -hypocalcemia
91
Cinacalcet (Sensipar)
-treat 2' HYPERparathyroidism -dec serum levels of PTH and Ca++
92
Cinacalcet (sensipar) dose
-oral -30mg BID initial
92
Common causes of hyperparathyroidism
-CKD with dialysis (loss of 1,25OHVitD3 production) -parathyroid carcinoma
93
Cinacalcet (Sensipar) mech
-binds to calcium-sensing receptor (CSR) (GPCR) to inc sensitivity to Ca++ =inhibits release of PTH -dec PTH and Ca++
94
Cinacalcet (Sensipar) risk
-HYPOcalcemia -seizures -adynamic bone disease
95
CSR in CKD w dialysis
-less responsive to Ca++ -also elevated PO4 can lock CSR in inactive state
96
Etelcalcetide (Parsabiv)
-treat 2' hyperparathyroidism -PAM of CSR to inhibit PTH release -dec PTH and Ca++ -big ass molecule
97
Etelcalcetide (parsabiv)
-hypocalcemia -adynamic bone disease -worsening HF -upper GI bleeding
98
Etelcalcetide (parsabiv) dose
-IV 5mg 3x/week initial
99
Vit D analog drugs
-Zemplar -HectorolV
100
Vit D analogs
-IV or oral -inhibit secretion of PTH w less effect on serum Ca++ than vit D3
101
Zemplar
-Vit D analog -2' hyperparathyroidism in CKD stage 3-4 -CKd w dialysis -1-4mcg 3x/week IV or oral
102
Hectorol
-Vit D analog -2' hyperparathyroidism in CKD w dialysis -prodrug 25 hydroxylation by CYP27 in liver -4mcg/week. IV or oral
103
CKD often results in
-loss of phosphate excretion in response to PTH and FGF23 -Hyperphosphatemia -Calcific Uremic Arteriolopathy risk
104
Calcific Uremic Arteriolopathy
-Ca++ combine w PO4 and precipitate in tissues -calification
105
Phosphate binder
-complex w dietary PO4 -prevent absorption from GI -treat hyperphosphatemia in CKD w dialysis
106
Phosphate binder drugs
-Lanthanum Carbonate (Fosrenol) -Sevelamer (Renagel, Renvela)
107
Lanthum Carbonate (Fosrenol)
-phosphate binder -treat hyperphosphatemia in CKD w dialysis -forms insoluble LaPO4 salts in GI tract -dec serum PO4 AND Ca!!
108
Sevelamer (Renagel, Renvela)
-phosphate binder -treat hyperphosphatemia in CKD w dialysis -contains amine -binds PO4 in GI tract -dec ONLY PO4
109
Which phosphate binder only decreases PO4
Sevelamer
110
Which phosphate binders dec PO4 AND Ca++
Lanthum Carbonate

Therapeutics (78 decks)

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