Medicinal Chemistry and Pharmacology of Erythropoisis-Stimulating Agents, Phosphate Binders, Vitamin D Analogs, Calcimimetics

What is Erythropoisis?

the production of red blood cells (RBCs)

What is Hematopoiesis?

The continuous process of replacing mature blood cells.

What is the ability of hematopoietic stem cells?

They can develop into many different types of blood cells

Hematopoietic stem cells are located in the marrow cavities of:

Skull

Vertebral bodies

Pelvis

Proximal long bones

What stimulates the stem cells?

• SCF = stem cell factor

• FL

• IL-3

• GM-CSF

Growth factors that help stem cells develop work with _ to stimulate stem cells to form BFUs and CFUs

cell-cell in the bone marrow

For the erythroid lineage, the important progression includes:

BFU-E → CFU-E → mature RBCs

What is Erythropoietin (EPO)?

the hormone that stimulates red blood cell production

What is EPO produced by?

peritubular interstitial cells of the kidney

a 193 amino acid, ~30-kDa protein

What does EPO bind to?

receptors on committed progenitor cells in the bone marrow

EPO secretion is a

feedback mechanism regulated by oxygen sensing

What is the feedback mechanism of feedback secretion?

Low oxygen/anemia → kidney responds → EPO production → bone marrow RBC production increases

Why can patients with chronic kidney failure develop anemia, and how is epoetin alfa used?

Failing kidneys produce too little endogenous EPO, so epoetin alfa replaces the inadequate EPO production

What is the mechanism of action of epoetin alfa?

It replaces deficient EPO and stimulates committed RBC progenitor cells in bone marrow to increase RBC production

Why must hematocrit/hemoglobin be monitored with epoetin alfa?

To prevent levels from rising too quickly or becoming too high, which increases cardiovascular/thrombotic risk

What hematocrit target is recommended for CKD patients receiving epoetin?

Gradually increase to 33–36%; >36% is not recommended

What is the most common adverse effect of epoetin alfa?

Hypertension

What hemoglobin increase is generally considered safe with darbepoetin?

Less than 1 g/dL every 2 weeks

The goal is not to normalize the hematocrit as quickly as possible, but a gradual rise and monitoring because

rapid increases can cause cardiovascular/thrombotic problems

What are the major functions of calcium?

Muscle contraction, intracellular signaling, blood coagulation, and bone formation/remodeling

Where is most of the body's calcium located?

About 99% is in bone and teeth

What are the major roles of phosphate?

Bone, phospholipids, energy metabolism, enzyme regulation, intracellular functions, and urine buffering

Where is most of the body's phosphorus located?

>80% is in bone

Which hormones regulate calcium and phosphate homeostasis?

PTH, vitamin D, calcitonin, and FGF23

When is PTH primarily secreted?

In response to hypocalcemia (low blood calcium)

How is PTH biosynthesized?

A 115-aa pre-prohormone is processed into an 84-aa hormone and stored in secretory granules

What commercial form of PTH is mentioned in the lecture?

Teriparatide (Forteo), a recombinant 34-aa form of PTH

What is the first step in vitamin D biosynthesis?

UV irradiation of 7-dehydrocholesterol in skin produces cholecalciferol (D3)

What is the major circulating/storage form of vitamin D?

25-hydroxyvitamin D3

[25(OH)D3]

What is the active form of vitamin D?

1,25-dihydroxyvitamin D3

(calcitriol)

What is the mechanism of action of calcitonin?

It inhibits osteoclast-mediated bone resorption, lowering blood calcium

Where is calcitonin produced?

Thyroid parafollicular C cells

What is calcium gluconate used for in hypocalcemia?

IV calcium gluconate treats moderate-severe hypocalcemia and severe hypocalcemic tetany

Why must IV calcium be given slowly?

To avoid cardiac arrhythmias

What is the mechanism of IV bisphosphonates?

They inhibit osteoclast-mediated bone resorption, decreasing calcium release from bone

What is the mechanism of nitrogen-containing bisphosphonates?

They inhibit FPPS, disrupting protein prenylation and osteoclast function

What structural feature identifies a bisphosphonate?

A nonhydrolyzable P–C–P backbone instead of pyrophosphate's P–O–P

What does the R1 hydroxyl group of bisphosphonates do?

Maximizes hydroxyapatite affinity and contributes to antiresorptive activity

What does the R2 group of bisphosphonates affect?

Potency and interactions at the active site

What are the two IV Bisphosphanates drugs?

Pamidronate

Zolexranate

Pamidronate disodium

Alendronate sodium

Etidronate disodium

Zoledronic acid (Zolexranate)

What is the mechanism of action of phosphate binders?

They bind dietary phosphate in the GI tract, preventing its absorption and lowering serum phosphate

What is Renagel?

Sevelamer HCl, a nonabsorbable polymeric phosphate binder

What is the mechanism of action of sevelamer HCl?

It acts as a nonselective anion exchanger that binds intestinal phosphate and decreases absorption

Why is sevelamer taken with meals?

To bind dietary phosphate in the intestine before it can be absorbed

What structural feature should you recognize for sevelamer?

A nonabsorbable polymer with amine groups that acts as an anion exchanger.

What are the novel iron-based phosphate binders in the lecture?

Sucroferric oxyhydroxide and ferric citrate

What is the mechanism of sucroferric oxyhydroxide?

Iron(III)-oxyhydroxide binds phosphate through ligand exchange, preventing phosphate absorption

What is important about sucroferric oxyhydroxide compared with sevelamer?

Similar phosphate control with a lower daily pill burden

What is important about ferric citrate?

It binds phosphate and also delivers significant iron, but chronic use can cause iron overload

What adverse effect is common to the iron-based phosphate binders?

Diarrhea

Sucroferric oxyhydroxide

Ferric citrate

What are vitamin D analogs?

Modified forms of vitamin D/calcitriol that can affect calcium/phosphate balance and PTH

What is an important advantage of some calcitriol analogs?

They suppress PTH with less hypercalcemic activity than calcitriol

What is rickets?

A disease involving poor mineralization of developing bone

What is used to treat established rickets?

Vitamin D plus oral calcium

What is calcipotriene?

A synthetic calcitriol derivative with a modified side chain

What is important about calcipotriene's activity in calcium metabolism?

It has less than 1% of calcitriol's activity

What is calcipotriene primarily used for?

Topical treatment/study for psoriasis

What structural feature should you recognize for calcipotriene?

Its cyclopropyl side chain

Calcipotriene

What is a calcimimetic?

A drug that mimics calcium's effect on the calcium-sensing receptor

What is the mechanism of action of cinacalcet?

It increases CaSR sensitivity to extracellular Ca²⁺, decreasing PTH secretion

What type of calcimimetic is cinacalcet?

Type II calcimimetic

What receptor does cinacalcet act on?

The calcium-sensing receptor (CaSR)

How does cinacalcet affect CaSR?

It positively allosterically modulates CaSR, increasing its sensitivity to calcium

What is the ultimate effect of cinacalcet on PTH?

Decreased PTH secretion

Cincalcet →

increase in CaSR sensitivity → decrease PTH