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Home >> Flashcards >> Pharmacology >> Drugs affecting bone and mineral metabolism

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Details Title: Drugs affecting bone and mineral metabolism Description: PHS 204 Lecture 27 K.L. Houseknecht 10 November 2010 Total Flash Cards: 55 Created: 12/15/2010 05:47:53

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Term Definition

Functions that drive physiological processes that depend on the ionized form of calcium (Ca2+):

essential for the Ca2+ component of current flow across excitable membranes, fusion and release of storage vesicles and muscle contraction Ca2+ is a pivotal 2nd messenger molecule for myriad signaling pathways Ca2+ concentrations in extracellular fluid stimulate blood coagulation and support bone remodeling
Definition

Term

Most Ca2+ in the body found in?

bone and teeth (crystalline form; 99%)

Term

Definition

Ca2+ homeostasis is mainly regulated by:

endocrine systems

Term

Definition

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Serum calcium levels tightly controlled by hormones

Vitamin D & PTH

Term

Definition

Organs involved in the absorption/retention of Ca2+: Daily whole-body calcium turnover

Term

Definition

Calcium absorption

enters the body from dietary sources not generated in the body absorbed exclusively from the intestine

Term

Definition

Mechanism of absorption:

Active vitamin D-dependent transport occurs in the proximal duodenum and facilitated diffusion throughout the small intestine Bulk of Ca2+ uptake is via facilitated diffusion UptakecounterbalancedbydailyCa2+loss( 150 mg) via secretion and sloughed intestinal cells Efficiency of intestinal Ca2+ absorption inversely related to Ca2+ intake In part due to activation of Vitamin D Response less robust in elderly patients
Definition

Term

Calcium excretion:

Excretion by the kidney Urinary Ca2+ excretion is the net difference between the quantity filtered in the glomerulus and the amount reabsorbed in the tubules. Approx. 9 grams of Ca2+ is filtered each day >98% of filtered Ca2+ reabsorbed to the circulation reabsorption highly regulated by parathyroid hormone (PTH)
Definition

Term

Calcium in bone

is crystalline form, similar to hydroxyapatite Levels in skeleton are determined by bone remodeling Bone formation

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Bone Ca2+ resorption

Term

Definition

Two main subdivisions of bone:

Peripheral (appendicular) 80% of bone mass (compact bone) Axial (centr

Term

Definition

Alterations in bone turnover are seen first in;

axial bone

Term

Definition

When bone is constantly undergoing breakdown and renewal it is called?

bone remodeling

Term

Definition

Remodeling is carried out by bone remodeling unitscalled?

Osteoclastsresorption Osteoblastsbonebuilding

Term

Definition

Bone remodeling cycle (Figure 61-8)

Term

Definition

RANK is receptor required for cytokine-induced

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RANK ligand and osteoclast formation (Figure 61-9)

osteoclastic bone resorption RANKL (ligand) is membrane-spanning osteoblastic protein RANKL binding induces osteoclast formation OPG, produced by osteoblasts, inhibits RANKL binding to RANK OPGsuppressedinconditionsfavoringbone resorption (e.g. E2 deprivation) OPG suppression is reversible. OPG is more efficacious than bisphosphonates in suppressing bone resorption and hypercalcemia in some test systems
Definition

Term

Phosphate(Pi) exists in the body in both

organic and inorganic forms

Term

Definition

Phosphate is absorbed in:

the GI tract

Term

Definition

GI phosphate absorption is via:

energy-dependent transport Regulated by several factors including Vitamin D (stimulatory)

Term

Definition

Phosphate reabsorption is regulated by:

PTH and levels of dietary P P deficiency up-regulatesPtransportersand excretion; P excess has opposite effect Phosphate in bone is complexed with Ca2+

Term

Definition

Calcium and phosphate ion levels in the body are regulated?

hormonally

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Term

Definition

The most important calcium and phosphate regulatory hormones are:

Parathyroid hormone (PTH) 1,25-dihydroxyvitamin D (calcitriol)

Term

Definition

________ and ______regulate mineral homeostasis.

PTH and calcitriol

Term

Definition

PTH and calcitriol regulate mineral homeostasis via their effects on:

the kidney bone the intestine

Term

Definition

Regulation of Ca2+ homeostasis: PTH and Calcitrol (Figure 61-3)

Term

Definition

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The four parathyroid glands are located on the __________.

posterior surface of the thyroid gland

Term

Definition

The four parathyroid glands are derived from the:

3rd and 4th pharyngeal pouches

Term

Definition

Cells of the parathyroid glands make and secrete:

parathyroid hormone (PTH)

Term

Definition

PTH is what type of hormone?

PTH is a polypeptide hormone

Term

Definition

PTH regulates plasma Ca2+ by affecting:

Bone resorption/formation Renal Ca2+ excretion/reabsorption

Term

Definition

Parathyroid cells synthesize

preproparathyroid hormone (PPTH)

Term

Definition

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PPPTH is a:

115 amino acid translation product PPPTH is cleaved in the endoplasmic reticulum to proparathyroid hormone Proparathyroid hormone is converted to PTH in the golgi apparatus Freshly synthesized PTH is stored in secretory granules of parathyroid cells

Term

Definition

Regulation of PTH Secretion

Ca2+ in the plasma is the main factor in regulating PTH release Low Ca2+ levels stimulate the secretion of PTH High levels of Ca2+ decrease PTH secretion Ca2+ influences nearly all phases of PTH synthesis and secretion Calcium-sensitive receptor (CaSR) on parathyroid cell membranes detect levels of Ca2+ in the blood CaSR is a G protein-coupled receptor that is coupled to Gi CaSR activation by Ca2+ results in decreased PTH secretion
Definition

Term

PTH: Physiological Effects and Receptors

PTH acts to maintain appropriate concentrations of Ca2+ in the extracellular fluid of the body MOA: PTH regulates Ca2+ absorption by the kidney and Mobilization of Ca2+ from bone(resorption) This can come at the price of skeleton instability! PTH Receptors At least 2 types of PTH receptors GPCRs that couple to Gq or Gs PTH-1R binds both PTH and PTH-related protein PTH-related protein may inhibit PTH-1R by internalization Expressed in kidney and bone PTH-2R binds only PTH Expressed in brain, pancreas, vascular tissue
Definition

Term

PTH effects on Bone

PTHboneresorptionCa2+deliverytothe extracellular fluid 1skeletaltargetappearstobetheosteoblast with indirect effect on osteoclasts PTH recruits osteoclast precursor cell to form new bone remodeling units Binds to osteoblasts and stimulates production of RANKL which acts on osteoclasts SustainedincirculatingPTHresultsin characteristic histological changes in bone: prevalenceofosteoclasticresorptionsites inproportionofbonesurfacethatiscovered w/unmineralized matrix.
Definition

Term

PTH effects on osteoblasts

PTH stimulates cAMP production in osteoblasts Some PTH effects appear to be mediated by intracellular Ca2+ Increases the total number of osteoblasts However, at the cellular level, the direct effects of PTH on osteoblasts is generally inhibitory. Specifically, PTH reduces the formation of: Type I collagen

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Alkaline phosphatase Osteocalcin (aka bone glial protein) Biomarker of bone turnover
Term Definition

PTH Effects on Kidney

Overall: Ca2+ is retained PTH increases the efficiency of Ca2+ reabsorption Overall: Phosphate is excreted PTH inhibits tubular reabsorption of phosphate Stimulates the conversion of Vit D to its active form: calcitriol Overalleffect:[Ca2+]plasmais

Term

Definition

Vitamin D

Vitamin D is a hormone! Plays an active role in Ca2+ homeostasis Vitamin D is synthesized in mammals; may/may not be required in the diet (RDA under scrutiny) Our understanding of the role of Vitamin D in physiology/pathophysiology is broadening Receptors for the activated form of Vitamin D are expressed in many cells not involved in Ca2+ homeostasis including: Hematopoietic cells Lymphocytes Epidermal cells Pancreatic islets Muscle cells Neurons
Definition

Term

Vitamin D

Vit D3 = cholecalciferol Vit D2 = ergocalciferol Vitamin D requires modification to become active The primary active metabolite of Vit D is calcitriol

Term

Definition

Vitamin D Synthesis

Exposure to the sun converts the provitamin 7dehydrocholesterol in the skin to cholecalciferol (Vit D3) Exposure to the sun converts Provitamin D2 (ergosterol) to ergocalciferol (Vit D2) Ergosterol is only present in plants Vitamins D3 and D2 are hyroxylated in the liver to 25-OH-D2 and 25-OH-D3, respectively These are then hyroxylated again in the kidney to by the mitochondrial enzyme CYP1a, aka 1ahydroxylase Levels of the enzyme 1a-hydroxylase are tightly regulated in order to keep Ca2+ levels in homeostasis DecreaseddietaryVitD,CA2+orphosphate= 1a hydroxylase activity IncreaseddietaryVitD,Ca2+orphosphate=1a hydroxylase activity
Definition

Term

Calcitriol aids in the absorption and retention of Ca2+ and phosphate in the small intestine Calcitriol interacts with PTH to enhance Ca2+

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Pharmacology of Vitamin D

mobilization in the bone It also has direct physiological effects on bone mineralization The formation of calcitriol is tightly regulated This regulation can be both acute and chronic Chronic regulation via changes in protein synthesis Low Ca2+ increased 1a-hydroxylase synthesis/activity High Ca2+ decreased 1a-hydroxylase synthesis/activity Calcitriol controls 1a hydroxylase synthesis and PTH secretion via negative feedback loops Both calcitriol and 1a hydroxylase can be hydroxylated to inactive metabolites in the liver by 24-hydroxylase 24-hydroxylase activity is stimulated by calcitriol 24-hyrdroxylase activity is inhibited by factors that stimulate 1a hydroxylase
Definition

Term

MOA of Vitamin D

Calcitriol has its actions via binding the Vit D receptor (VDR) Nuclear receptor Calcitriol binds to cystolic VDRs in target cells The calcitriol-VDR complex translocates to the nucleus and interacts with DNA to modify gene transcription Vitamin D increases the transcellular movement of Ca2+ in the intestine via three steps: Increased Ca2+ movement across the mucosal membrane Increased Ca2+ diffusion through the cell Increased energy-dependent extrusion of Ca2+ across the serosal membrane Calbindin is a Ca2+ binding protein whose activity is stimulated by Vit D Calbindin aids in the diffusion of the ion through small intestine cells
Definition

Term

Other effects of Vitamin D/Calcitrol

Calcitriol affects the maturation and differentiation of cells May prove to have anti-cancer use Calcitriol inhibits epidermal proliferation May have use as dermatological treatment

Term

Definition

Calcitonin

32 amino acid peptide made in thyroid (C cells) Calcitonin is a hormone that has actions that oppose those of PTH Hypocalcemic and hypophosphatemic effects Calcitonin directly inhibits osteoclastic bone resorption Interacts directly w/receptors on osteoclasts to producerapidandprofoundresorptiveactivity Calcitonin synthesis and secretion are regulated by plasma [Ca2+] When Ca2+ levels are high, calcitonin levels are high When Ca2+ levels are low, calcitonin levels are low
Definition

Term

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Disorders of Mineral Homeostasis

Hypercalcemia in acute cases, can cause neuromuscular problems Hypocalcemia in acute cases, can cause tetany, muscle cramps Disturbed phosphate metabolism can result in an under-mineralized bone structure Vitamin D too much can cause problems with Ca2+ metabolism, hypercalcemia-like symptoms Vitamin D deficiency causes over-secretion of PTH, bone loss
Definition

Term

Osteoporosis: a specific bone disorder

Condition of low bone mass and microarchitectural disruption that results in fractures with minimal trauma Major and growing public health problem in developed nations Effects both women and men, but most pronounced in post-menopausal women Typical fracture sites: vertebral bodies, distal radius, proximal femur, ribs, long bones. Fractureriskexponentiallyw/agewith survival following fracture
Definition

Term

Osteoporosis

Term

Definition

Rx for treatment of mineral homeostasis disorders

Hypercalcemia: first line Rx is hydration + diuretics Hypocalcemia: acute Rx is Ca2+ gluconate or CaCl- (severe cases). Chronic Rx depends upon underlying cause Drug Rx: Calcitonin Bisphosphonates Calcimimetics Sodium phosphate Vitamin D PTH
Definition

Term

Osteoporosis Rx

Non-drug Rx DietCaandVitaminD(prevention) Weight bearing exercise (prevention) Stop smoking (prevention) At risk patients avoid drugs which cause bone loss e.g. glucocorticoids Pharmaceutical Rx Bisphosphonates SERMs Calcitonin Teriparatide Prolia
Definition

Term

Calcitriol can be used to treat Vitamin D

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Vitamin D Therapies

disorders Analogs of calcitriol suppress PTH secretion but have little hypercalcemic activity Doxercalciferol (hectorol) is synthetic Vitamin D that must be activated by liver hydroxylation Dihydrotachysterol(DHT) is a reduced form of Vit D2; activated in the liver (does not require renal hydroxylation) Rapid onset of action (2 hours), a shorter halflife, and a greater effect on mineralization of bone salts than does vitamin D. Alphacaldidol (1-hydroxycholecalciferol) is a Vit D3 derivative that is hydroxylated to its active form Less effect on calcium metabolism than calcitriol but more potent effects on PTH concentrations Ergocalciferol (calciferol) is pure vitamin D2
Definition

Term

Calcitonin

Salmon calcitonin (more active than human calcitonin) is effective and well tolerated for treatment of postmenopausal osteoporosis. Inhibits bone resorption Less effective than bisphosphonates serumCa2+andphosphatelevels Effects are greater when bone turnover rates area high Unique property: relief of pain associated w/osteoporotic fracture. Beneficial for patients who have recently suffered vertebral fracture Resistance to efficacy can occur w/chronic Rx
Definition

Term

Bisphosphonates

Analogs of pyrophosphate Capable of chelating Ca2+ Have a strong efficacy for remodeling bone First line Rx for prevention and treatment of postmenopausal osteoporosis. Rx for Pagets disease (excessive breakdown and formation of bone tissue), bone metastases and hypercalcemia of malignancy. Directly inhibit bone resorption by osteoclasts Inhibition of osteoclastic proton pump necessary for dissolution of hydroxyapaptite inosteoclasticformation/activation osteoclasticapoptosis Inhibition of the cholesterol biosynthetic pathway (needed for osteoclast function)
Definition

Term

Calcimimetics: MOA

Calcimimetics (e.g. cinacalet) mimic the stimulatory effects of Ca2+ on PTH secretion Allosteric activator of calcium sensitive receptor Enhances the sensitivity of the calcium sensitivereceptor(CaSR)toCa2+lowerthe concentration of Ca2+ in the serum that is required to suppress PTH secretion Absorbed in the gut Mainly (85%) secreted unchanged in the urine; some metabolized by hepatic CYPs Metabolized by: CYP 1A2, CYP 2D6, and CYP 3A4 Inhibitor of CYP 2D6 Potential drug interactions: Agents that interfere with Ca2+ homeostasis Other agents that are metabolized by hepatic CYPs

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Term

Definition

Parathyroid hormone Rx: Teriparatide

Recombinant human PTH peptide, administered s.c. for treatment of osteoporosis Continuous administration: bone demineralization Intermittent administration (q.d. sc) leads to bone growth spinalbonedensityriskofvertebralfracture First approved Rx for osteoporosis that stimulates bone formation. Other Rx inhibit bone resorption. riskofosteosarcomainrats.Safetyand efficacy in humans not evaluated >24 mo. Rx For patients at high risk of fractures or who cannot tolerate other Rx.
Definition

Term

Selective estradiol receptor modulators: SERMs

Estrogen replacement is an effective Rx for the prevention of post-menopausal bone loss. EstrogenRxisassociatedw/riskcancerand cardiovascular disease. SERMs can enhance the actions of estrogen on bone, i.e., reduce osteoclast-mediated resorption of bone SERMS have different effects on various tissues selective Agonist, agonist/antagonist, antagonist Raloxifene (evista) is a SERM that is a selective estrogen agonist Alters ER activity in bone and liver bonedensityw/oriskofendometrialcancer Mayriskofinvasivebreastcancer First-line alternative in patients who are intolerant to bisphosphanates totalandLDLcholesterolinserum Risk of venous thromboembolism similar to estrogen Hot flashes and leg cramps
Definition

Term

Prolia: First biologic bone loss Rx

FDA approved June 2010 Fully humanized monoclonal Antibody Rx Approved for: Postmenopausal women with osteoporosis and high risk of fracture Previous fracture due to osteoporosis or multiple risk factors Patients with osteoporosis for whom other osteoporosis treatments have failed Patients who cannot tolerate other osteoporosis Rx MOA:targetsRANKligandslowsthebone break-down process as well as the entire boneremodeling process. Long term consequences? Possible adverse events: Muscle and joint pain, elevated cholesterol, delayed fracture healing, osteonecrosis of the jaw, atypical fractures, increased rate of infections (RANK ligand is involved in normal immune system function), lowered Ca2+ concentration

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