E3: Drugs and Minerals for CKD

Question 1

Chronic Kidney Disease Overview (5)

Answer 1

1. Loss of nephron mass
2. Compensatory renin release –> angiotensin
3. Vasoconstriction (temporary improvement)
4. Glomerular capillary hypertension
5. Albuminuria (local toxicity, inflammation, scarring)

Question 2

Which portions of the CKD overview does treatment with ACEi/ARB address

Answer 2

2. Compensatory renin release –> angiotensin
3. Vasoconstriction

Question 3

Why are ACEi and ARBs used in CKD? (3)
Examples (3 ACEi and 2 ARB)

Answer 3

ACEI & ARBs are the antihypertensive agents of choice in CKD
–delay progression of CKD
–help preserve renal function
↓ proteinuria

ACEi
1. Enalapril (Vasotec®)
2. Lisinopril (Prinivil®, Zestril®)
3. Fosinopril (Monopril®)

ARB
1. Valsartan (Diovan)
2. Losartan (Cozaar)

Question 4

Mechanism of proteinuria
Starting with angiotensin acting on _____ causing 4 things

How do ACEi/ARB treat proteinuria
Why do we use ACEi/ARB instead of other agents

Answer 4

Angiotensin II preferentially constricts efferent arteriole causing:
1. ↑ pressure in glomerular capillaries
2. expands the pores in the glomerular basement membrane
3. alter the size-selective barrier
4. allow proteins to be filtered through the glomerulus

Treatment: ACEIs & ARBs ↓ glomerular capillary pressure & volume due to their effects on Ang II causing:
1. dilatation of renal efferent arterioles
2. ↓ amount of protein filtered through the glomerulus, independent of the ↓ BP
3. ↓ progression of CKD

ACEIs & ARBs ↓ proteinuria&raquo_space; other antihypertensives because they inhibit angiotensin II

Question 5

Monitoring for ACEi/ARB
Co-administration of ACEi/ARB with these agents could cause _______

Answer 5

Hyperkalemia
Especially with coadministration of K+ salts and K-sparing diuretics

Question 6

Metabolic acidosis is commonly caused in CKD by one of these two mechanisms, define each
1. non-anion gap
2. high-anion gap

What serum HCO3- level and below is considered metabolic acidosis

Answer 6

1. non-anion gap: accumulation of Cl– decreased available HCO3–
2. high-anion gap acidosis: accumulation of titratable acid, in late-stages CKD

<22 mmol/L

Question 7

What agent is used to treat metabolic acidosis?
What are some of its side effects and administration considerations in regards to a specific mineral

Answer 7

Agent: NaHCO3tablets
Side effects: Na+ absorption -> edema, HTN, etc
Administration: Reduced absorption of Fe, 2 hour spacing for drugs that need acidic environment

Question 8

Describe CKD-Related Mineral and Bone Disorder (5)
What portions do phosphate-binding agents target

Answer 8

1. Loss of nephron mass
2. Decreased phosphate elimination (↑serum phosphate)
3. Hyperphospatemia + low serum Ca2+
   PTH synthesis, secretion by parathyroid)
4. Calcium reabsorption in distal tubules + mobilization from bone
5. Bone disease -Loss of bone structural integrity & abnormal turnover

P-agents target parts 2 and 3

Question 9

Describe the general MOA of phosphate binders
When should they be administered?

Answer 9

Normal serum phosphorus 2.7-4.6mg/dL

Binders- bind dietary phosphate in the GIT to form an insoluble complex that is excreted in the feces.
-↓ serum phosphorus levels.
-Take with each meal/snacks (dietary!)

Question 10

MOA of calcium-containing phosphate binders
2 examples
Brand name
% elemental Ca
Dosage form

Answer 10

• effective in ↓serum [PO4] as well as in ↑ serum [Ca]
  **Ca acetate is preferred - potent > carbonate in phosphorus binding
  **Ca carbonate can aid in correction of metabolic acidosis in CKD

Calcium carbonate - Tums
—40% elemental Ca
—Chewable tablets

Calcium acetate - PhosLo
—25% elemental Ca
—capsule/tablet

Question 11

Non-calcium binders (4 + 1 given by Shiltz)
What patient population are these preferred in

Answer 11

Sevelamer (Renvela; Renagel)
Lanthanum carbonate (Fosrenol)
Sucroferric oxyhydroxide (Velphoro)
Ferric citrate (Auruxyia)

Preferred in patients at risk for extraskeletal calcification

Question 12

Aluminum hydroxide
When should we use them/why and how long

Answer 12

Aluminum hydroxide
last line due to neurotoxicity, encephalopathy, bone disease, & anemia
short course ≤7 days for refractory hyperphosphatemia

Question 13

Name (brand and generic) of resin based phosphate binders
Administration (Chew or not)
MOA (5)
Side effects (5)
DI (1)

Answer 13

Sevelamer hydrochloride (Renagel)
Sevelamer carbonate (Renvela) - 1st-line agent
Do NOT Chew/crush tablets

MOA:
1. Sevelamer is a nonabsorbable cationic polymer that acts as a nonselective anion exchanger
2. binds to PO4 in GIT, prevents absorption & promotes excretion via feces
3. ↓ serum [PO4] in hemodialysis patients
4. binds bile acids & ↓ LDL-C & ↑ HDL-C levels
5. useful in patients with ↑[PO4] & ↑[Ca] or who have vascular or soft tissue calcifications

SE:
Sevelamer hydrochloride – N,V,D, dyspepsia, & metabolic acidosis
Sevelamer carbonatewillnot worsen metabolic acidosis

DI: ↓Fat soluble vitamins

Question 14

Elemental phosphate binder (brand and generic name)
Administration (Chew or don’t chew)
Why is that element useful
MOA
SE

Answer 14

Lanthanum carbonate (Fosrenol); Chewable tablets

Lanthanummay improve bone turnover > Ca-containing products

MOA:
1. La2(CO3)3 quickly dissociates in the acidic stomach
2. La3+ binds to dietary phosphorus → insoluble compound excreted in the feces

Side effects: N,V,D, abdominal pain

Question 15

Iron-based phosphate binders (2)
Brand and generic name
Which one(s) are useful for Fe deficiency
MOA of both
Administration
DI of just one agent
SE of both

Answer 15

Sucroferric oxyhydroxide (Velphoro): CHEW
- P binding only
- not useful for Fe deficiency due to poor absorption
DI

Ferric citrate (Auryxia): DO NOT CHEW
- low dose vs high dose
P binding & iron replacement
- iron is systemically absorbed →
↑erythropoietic parameters
- ↑ serum ferritin & transferrin saturation
- ↑ overload with chronic dosing

SE
Diarrhea, constipation, discolored (black) feces

Question 16

Vitamin D: Name and VDR preference
Nutritional forms (2)
Active forms (1)
Vitamin D analogs (2)

Answer 16

Nutritional forms
Ergocalciferol: VDR1 = VDR2
Cholecalciferol: VDR1 = VDR2

Active form
Calcitriol (Rocaltrol): VDR1 = VDR2

Vitamin D analogs
Doxercalciferol (Hectorol): VDR1 >VDR2
Paricalcitol (Zemplar): VDR1&raquo_space; VDR2

Question 17

MOA of Vitamin D (3)
ADME (2)
ADR (3)

Answer 17

MOA:
1. bind to intracellular vitamin D receptors (VDRs) to promote/inhibit gene transcription
inhibits or suppresses PTH synthesis
2. promotes intestinal PO4 & Ca absorption & utilization → ↑ serum [Ca]
3. ↑ serum [Ca] → ↓ PTH secretion by the parathyroid glands

ADME
1. Fat soluble vitamin
2. Absorption can be impaired hepatic or biliary dysfunction

Adverse Effects:
1. Can cause hypercalcemia leading tohypoparathyroidism
2. Hyperphosphatemia + hypercalcemia -lead to soft tissue calcification (calciphylaxis)
3. Hypervitaminosis D - cheilitis, conjunctivitis, photophobia, pruritus.

Question 18

Differentiate between calcitriol (1) and paricalcitol (3)

Answer 18

Calcitriol (Rocaltrol®)​
Typical 1st-line fullyactive form of Vit D supplement used if indicated in late-stage CKD(stages 4-5)​

Paricalcitol (Zemplar®) - 1,25-dihydroxy-19-norvitamin D2
PO or IV
1. Synthetic calcitriol derivative with vit D2rather than vit D3side chain.
2. Suppress PTH secretion with less or negligible hypercalcemic activity
3. Offer a safer & more effective means of controlling secondary hyperparathyroidism

Question 19

Calcimimetic agents
When are they used?
What are the 2nd gen type II calimimetics called?
What are the two agents names (brand/generic)
MOA (3)

Answer 19

Calcimimetic are often added onto Vitamin D preparations
2nd gen type II calcimimetic - positive allosteric modulators at CaSRs
-Cinacalcet (Sensipar®)
-Etelcalcitide (Parsabiv®)

MOA:
1. Ca-sensing receptors (CaSRs) on the chief cells of parathyroid gland - regulate PTH secretion
2. Calcimimetics - mimic stimulatory effect of Ca2+ on CaSR to inhibit PTH secretion
3. ↑ the sensitivity of the CaSR → ↓ PTH secretion → ↓ serum Ca2+ levels.

Question 20

Cinacalcet (Sensipar)
ADME
Clinical indication
ADR (5)
DI (2 classes)

Answer 20

ADME:
CYP3A4 (mostly); N-dealkylation, oxidation, & conjugation; Strong inhibitor of CYP2D6
Excretion - biliary (15%); renal (85%)
PO route only – taken with food  up to 81% increase in oral absorption!

Clinical Indication: - hyperparathyroidism resulting from parathyroid tumors & CKD.

Adverse effect: -
1. hypocalcemia
2. muscle spasms
3. diarrhea
4. nausea
5. ↓ seizure threshold

Drug Interactions:
1. Drugs that interfere with Ca2+homeostasis or cinacalcet absorption – Vit. D analogues, PO4 binders, bisphosphonates, calcitonin
2. Strong inhibitors of CYP2D6; dose adjustment for CYP2D6 substrates (e.g., β-blockers,TCAs).

Question 21

Etelcalcitide (Parsabiv)
SAR
Clinical indication
Pharmacokinetics (3)

Answer 21

Long-acting 8–amino acid peptide CaSR agonist
act as both a direct agonist & allosteric modulator of CaSR (major mech.)

Clinical Indication:
1. secondary hyperparathyroidism in CKD patient on dialysis - 3x weekly via venous line of hemodialysis

Pharmacokinetics:
1. Binds serum albumin
2. no hepatic metabolism
3. Renal elimination is significant -t1/2 ∼ 18.4h

Question 22

Why is Fe deficiency common in advanced CKD
What is the purpose of Fe supplements

Answer 22

Fe deficiency anemia is common in advanced CKD due to ↓GI absorption of Fe , inflammation, ESA therapy etc.

Fe supplements provide elemental Fe required for production of Hb

Question 23

Name the 5 iron salt supplements available PO
Roughly how much oral iron is absorbed

Answer 23

1. Ferrous gluconate
2. Ferrous sulfate
3. Ferrous fumarate
4. Iron polysaccharide
5. Carbonyl iron

25%

Question 24

Name the 5 iron compounds available IV
What is the dosing for IV iron
Toxicity and antidote

Answer 24

1. Ferric carboxymaltose - Injectafer
2. Ferumoxytol - Feraheme
3. Iron dextran - INFeD
4. Iron sucros - Venofer
5. Sodium ferric gluconate - Ferrlecit

∼ 1 gram elemental Fe is rec. but it varies based on the salt formulation.
Recommendation: ∼ 1 gram cumulative Fe salt (not elemental Fe)

Toxicity -Fatal iron overdose (1–10 g) esp. parenteral

Antidote - Deferoxamine (Desferal)

Question 25

Name the 3 erythropoiesis stimulating agents (brand/generic) and differentiate between their structures
MOA (5)
ADR (9)

Answer 25

Epoetin alfa (Procrit®, Epogen®) - Glycoprotein - same aa sequence as endogenous erythropoietin - recombinant DNA tech.

Darbepoetin alfa (Aranesp®) - has 2 additionalN-linked carbohydrate chains → a longer DOA > epoetin

Methoxy PEG-epoetin beta (Mircera)- has amide bond between the N-terminal group of epoetin beta & methoxy polyethylene glycol butanoic acid → a longer t1/2 > the other ESAs

MOA: EPO bind & activate erythropoietin receptor to stimulate erythropoiesis
1. ↑ rate of proliferation & differentiation of erythroid precursor cells in the bone marrow.
2. induces transformation of erythroid colony-forming unit to a proerythroblast
3. ↑ release of reticulocytes from marrow
4. ↑ hemoglobin synthesis

Adverse effect :
1. aggravation of htn (20%–30%);
2. HTN encephalopathy & seizures in CKD
3. Headache
4. tachycardia
5. edema
6. shortness of breath
7. NVD
8. injection site stinging
9. flu-like symptoms