Calcium Metabolism Drugs Flashcards
What are the segments of the bone?
Spongy trabecular bone
Compact bone => bone mineralization process
What is the osteoblast differentiation factor?
RANK-L
What are the diff factors that affect bone turnover?
Humoral factors: PTH, VIt D, Calcitonin
Others: Glucocorticoids, TH, Gonadal steroids
What are the local factors that help fine tune bone remodeling?
IGF-1 = INC osteoblast proliferation
TGF-B & IL-6 = INC osteoClast activity
PGs = INC bone turnover
Bone morphogenetic proteins = bone formation
WHat are other factors affected by bone remodeling?
Local stresses: exercise
Electrical stimulation
Environmental: temp, O2 levels, ABB
What are the 3 hormones that regulat Ca?
PTH
Calcitonin
Vitamin D
What is the most important endocrine regulator of Ca homeostasis? What cell secretes it?
Parathyroid gland
Cell: Chief cells
How does plama Ca level stimulate PTH secretion?
Low plasma Ca levels => stimulates PTH secretion
High plama Ca levels => suppresses PTH secretion
What are the 3 organs acted on by PTH indirectly & directly?
Indirectly = GI tract
Directly = Kidneys & bone
From what cells is Calcitonin produced & released? IN response to what?
Parafollicular cells
In response to HYPERCALCEMIA —> inhibits resoprive activity of osteoclasts => DEC bone resorption & plasma Ca levels
In what organ is Vit D activated? What is Vit D’s purpose?
Kidneys
Regulator of PTH => Inhibits PTH synthesis & release => INC osteoClast activity
INC Ca uptake, binding protein (Calbindin), Ca to capillaries
What is the effect of Intermittend PTH signal?
INC bone formation & bone mass
What is the often cause of bone mineral disorders?
Disruption of bone turnover
WHat are the three factors that cannot be imbalanced for they can lead to poor mineralization of the bone?
- Abnormal levels of Vit D, PTH
- INC rate of bone remodeling
- Failure of organs that maintain mineral homeostasis
What are the 3 pharmacologic agents for Osteoporosis? WHat are its MOA?
Antiresorptive agents => inhibits bone resoprtion
Bone anabolic agents => stimulates bone formation
Supplements = given depending on stage of osteoporosis (oral Ca & Vit D)
What are the diff Bone anabolic agents?
Teriparataide, Abaloparatide, Stronitum ranelate, Fluoride
What is the effect of antiresopritve agents & what are the diff drugs under it?
INC osteoclast acitivity (rate of turnver)
Bisphosphonates
Calcitonin homrone replacement therapy
Selective estrogen receptor modulators
Denosumab
What pharmacological agents are given to px w/ CKD? What are its purpose?
Oral PO4 binders = DEC plasma PO4 levels
Vit D & Calcimimetic = DEC PTH synthesis & secretion
What drugs are given for px w/ Rickets, Osteomalacia, & HYPOthyroidism?
Oral Ca & Vit D = prevention & tx
WHat are the 3 drug clases for hormonal/mineral imbalance?
Vit D analogues
Vitamin D (Calcitriol)
Ca Analogues
What are the diff Vit D analgoues?
Calcitriol
Doxercalciferol
Paricalcitol
Doxercacliferol & Paricalcitol
CHolecalciferol, Ergocalciferol, Calcifediol
Calcipotriene
What Vit D analgue is given w/in 24-48 hrs for Vit D-dependent rickets?
Calcitriol
What vitamin D analogues are used for tx of Secondary hyperthyroidism of CKDs?
Doxercaliferol & Paricalcitol
What vit D analogues are used in tx of HYPOthyroidism, rickets, Osteomalacia, Osteoporosis, & CKD?
Cholecalciferol, Ergocalciferol, Calcifediol
What Vit D analogue is used as an adjuvant tx of psoriasis due to its immunomodulatory effects?
Calcipotriene
Of all the Vit D analogues, what are the only 2 drugs that are in activated form already?
Calcitriol & Paricalcitol
What is the stimulus & inhibition of Vit D/Calcitriol?
Stimulus: LOW Ca, LOW Phosphorus
Inhibition: HIGH Ca, HIGH P
WHat are the 3 actions of Vit D?
Activates Ca pump in the lumen
INC ATP w/ diverts Ca into the blood
INC Ca binding protein
Explain the photosynthesis & activation of Vit D/Calcitriol?
Endogenous vit D (synthesized on the skin)
=> 7-dehydrocholesterol —(sunlight) —> CHolecaliferol. (Vit D3)
Exogenous VIt D
CHolecalciferol (Vit D3) —> animal source OR
Ergocalciferol (Vit D2) —> plant source
Cholecaliferol —(25-hydroxylase: liver)—> 25 (OH) Cholecalciferol (calcifediol) —(1a-hyoxylase: kidneys)—> 1,25(OH)2 cholecalciferol (Calcitriol) —> active form
For what conditions are Ca analogues used?
Therapeutic & prophylactic use of:
- THerapy for HYPOcalcemia
- Prevention against Osteoporosis
What Ca analogue is given for mild hypocalcemia?
Ca acetate => most accessible & readily absorbable
Ca citrate
Ca carbonate => most widely used due to low cost
What Ca analogue is used for severe hypocalcemia?
Ca gluconate = less venous irritation
Ca Cl
What are the different antiresorptive agents?
Seletive estrogen receptor modulators
Bisphosphonates (-dronates)
Monoclonal Ab
Mineral
Calcitonin analogs
Hormone replacement therapy
What is the goal of Selective estrogen receptor modulators?
To retain the beneficial effects of estrogen in 1 or more tissues while eliminating theundesirable effects of estrogen in other tissues
WHat is the only selective estrogen receptor modulator & its MOA?
Raloxifene
MOA: agonist in bone, Antagonist in Estrogen (endometrium & breast)
What are the Indications, Effects, & AE of Raloxifene?
Indication:
- prevention & tx of Osteoporosis
- DEC risk for endometrial & breast cancer
SE:
- INC vertebral & non-vertebral bone mineral density
- DEC LDL-C levels
AEs: INC risk of venous thromboemboilsm, hot flashes, leg cramps
What is the mOA of Bisphosphonates (SERMs)
MOA: inhibits bone resorption & osteoClast activity
DEC solubility of hydroxyapatite —> more resistant to osteoClastic bone resorption
What are the 1st, 2nd & 3rd gen of Bisphosphonates?
1st gen = Etidronate
2nd gen = Alendronate, Ibandronate, Pamidronate
3rd gen = Risedronate, Zoledronate
What are indications, AE, CI, & clinical trials of Bisphosphonates?
Indications:
- Postmenopausal, osteoporosis, Paget’s disease, & hypercalcemia of malignancy
AE:
- Esophageal erosion of ulcer
- Esophagitis, diarrhea
- Osteonecrosis of jaw
CI:
- tendencies to develop bone malignancies
CTs:
- INC spine & hip bone mass density
- DEC risk of vertebral & non vertebral fractures
What is the only monoclonal Ab of Antiresoprtive agents? MOA? Indication?
MOA: binds to RANKL => prevent sstimulation of osteoClast differentiation & function —> prevents further bone loss
Indication: Postmenopausal osteoporosis
Breast & prostate CAs
What is a mineral anti-resorptive agent? MOA, Indication, AE?
Strontium Ranelate
MOA: blocks differentiation & activation of osteoClasts while promoting their apoptosis, inhibits bone resorption
Indication: Osteoporosis
AEs: Skin rashes, venous thromboembolism
What are the diff Calcitonin analogs & its MOA?
Fortical, Miacalcin, Calcimar, Salmonine
MOA: activates GPCR on osteoclats —> DEC resorptive acctivity of osteoclasts
What are the indications, AEs, CI of Calcitonin analogs?
Indications: Paget’s disease, osteoporosis, Primary hyperparathyroidism, Hypercalcemic emergency, Vit D intoxication
AEs: Hypersensitivity rash, rhinitis, epistaxis, tachyphylaxis
CI: hypersensitivty
What is an alternative to bisphosphonates in px who are unable or unwilling to take them?
Calcitonin analogs
What hormone is used in hormone replacement therapy? Indication, MOA, AEs?
Estrogen
MOA: reduce bone resorption
Indication: Postmenopausal osteoporosis
AEs: vaginal bleeding, breast tenderness, venou thromboembolism, INC long term risk of breast cancer
Postmenopasual women => given w/ Progesterone to DEC risk of endometrial cancer
What are the diff drugs that stimulate bone formation?
Recombinant human PTH analogs: Teriparatide, Abaloparatide, Natpara
Fluoride
What are the MOA, Indications, AEs, C/I & Caution for Recombinant human PTH analogs?
MOA: INC osteoblast differentiation & activity
Indications: Postmenopausal osteoporosis & HYPOthyroidism
AEs: HYPERcalcemia, HYPERcalciuria, muscle weakness
Caution: Osteosarcoma development
C/I: bone malignancy, Piagets disease
What is the diff betw recombinant human PTH analogs vs PTH?
PTH: continuous exposure => bone catabolism
PTH analog: bone anabolism
What are the MOA, indications, & AE of Fluoride for bone formation?
MOA: stabilize hydroxyapatite crystal -> INC mineralization of trabecular bone (Hydroxyapatite-> Fluorapatite)
Indication: Tx of osteoporosis
AE: Osteomalacia
What drug class is used for CKD?
Oral PO4 binders
What is the MOA of Oral PO4 binders?
Lowers plasma PO4 levels by preventing dietary PO4 absorption
Produce non-absorbable form of PO4
WHat are the diff oral PO4 binders?
Aluminum hydroxide
Ca Carbonate/ACetate
Sevelamer
What are the MOA, indication, CI, AE & THerapeutic considerations of Aluminum hydroxide?
MOA: Al ppt with PO4 in GIT —> non-absorbable complexes
Indication: HYPERPO4emia
CI: HSN to aluminum hydroxide
AE: aluminum toxicity (anemia, osteomalacia, & neurotoxicity)!!!!!!!
What are the MOA, Indication, CI, AE, & therapeutic considerations for Ca Carbonate/Acetate?
MOA: binds to dietary PO4 inhibitng its absorption
Indication: CKD, Osteoporosis, Hypocalcemia
CI: Hypercalcemia, Vit D toxicity
AE: Iatrogenic hypercalcemia, INC risk of vascular calcification, Milk-alkali syndrome, constipation
TCs: acidic environment for effective action, has antacid properties
What are the MOA, indication, CI, AE, TC of Sevelamar?
MOA: Non-absorbable cationic ion-exchange resin that binds intestinal PO4 decreasing absorption of dietary PO4
Indication: CKD
CI: DEC plasma PO4, Bowel osbtruction
AE: binds bile acids interrupting enterophetatic circulation, DEC CHOLESTEORL ABSORPTION, thrombosis, HTN, constipation
TC: lowers serum cholesterol by binding bile acids
What is the only Calcimimetic drug? Its MOA, Indi, CI, effect, & AE?
Clinacalcet
MOA: INC sensitivity of Ca-sensing receptors —> DEC PTH synthesis & secretion
Indication: 2ndary HYPERparathyroidism, HYPERcalcemia assoc w/ Parathyroid CA, CKD
AE: HYPOcalcemia, HTN, dizziness
What are the most important modulators of bone remodeling and mineral homeostatsis?
PTH & VIt D
What pharamcologic class is given if there is an INC in osteoClast activity?
Antiresorptive agents: SERMs, bisphosphonates, Denosumab, Strontium ranelate
What pharmacologic agents are used in conditions where there is DEC in osteoBlast activity?
Bone anabolic agents: Teriparatide, Abaloparatide, Natpara
What pharmacologic agents are given in CKD?
Vit D, PO4 binders, & Calcimimetics
What drugs are given to INC bone anabolism?
Teriparatide, Abaloparatide
What drugs are given to INC bone formation ?
HRT, SERM
What drugs are given to DEC osteoclastic activity ?
Bisphosphonates, Calcitonin, HRT, SERM, Strontium ranelate
What drugs are given to inhibit binding of RANKL to its receptor ?
Denosumab
What causes primary hypoparathyroidism?
Post-thyroidectomy => DEC osteoclastic activity -> DEC Ca & PO4 resorption
What are the effects & tx of primary hypoparathyroidism?
Effects:
Paresthesia, Neuromuscular excitability (CHOVESTEK’s sign), Hypocalcemia tetany
Tx: Ca & VIt D
What are the causes of 2ndary hypoaprathyroidism? Effect, tx?
Causes: INC Vit D
Effect: Nephrocalcinosis!!!
Tx: Corticosteroids, Bisphosphonates
What are the causes of primary HYPERparathyroidism? Effects, tx?
Tumor in PTG
INC osteoClastic activity
Effects:
Osteoporosis, Nephrolithiasis, Osteitis fibrosa cystica!!!
Tx: surgical removal of tumor, IV bisphosphonates
What are the causes fo 2ndary HYPERparathyroidism? Effects, Tx?
DEC Vit D
Chronic renal failure
Effects: Osteomalacia, Osteitis fibrosa cystica!!
Tx: Cinacalcet, PO4 binders, Calcitriol, Paracalcitriol, Doxercalciferol
What ar the effects of HYPERcalcemia? Tx used?
INC GI absorption, osteoClastic activity
DEC bone mineralization, urinary excretion
Tx:
- Thiaxide diuretics
- Oral PO4
- Bisphosphonate
- Calcitonin
- Prednisone
- Saline diuresis + loop diuretics
What is plasma Ca level of mild & severe hYPERcalcemia?
Mild hypercalcemia = <12mg/dL
Severe hypercalcemia = >13-14mg/dL
What are the effects of HYPOcalcemia? Tx?
DEC GI absorption
DEC bone resorption/INC mineralization
INC urinary excretion
Tx:
- loop diuretics
- Ca
- VIt D
- thiazide diuretics
What is the normal plasma level of Ca?
8-10mg/dL
