E3: Drugs and Minerals for CKD Flashcards
Chronic Kidney Disease Overview (5)
- Loss of nephron mass
- Compensatory renin release –> angiotensin
- Vasoconstriction (temporary improvement)
- Glomerular capillary hypertension
- Albuminuria (local toxicity, inflammation, scarring)
Which portions of the CKD overview does treatment with ACEi/ARB address
- Compensatory renin release –> angiotensin
- Vasoconstriction
Why are ACEi and ARBs used in CKD? (3)
Examples (3 ACEi and 2 ARB)
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)
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
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»_space; other antihypertensives because they inhibit angiotensin II
Monitoring for ACEi/ARB
Co-administration of ACEi/ARB with these agents could cause _______
Hyperkalemia
Especially with coadministration of K+ salts and K-sparing diuretics
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
- non-anion gap: accumulation of Cl– decreased available HCO3–
- high-anion gap acidosis: accumulation of titratable acid, in late-stages CKD
<22 mmol/L
What agent is used to treat metabolic acidosis?
What are some of its side effects and administration considerations in regards to a specific mineral
Agent: NaHCO3tablets
Side effects: Na+ absorption -> edema, HTN, etc
Administration: Reduced absorption of Fe, 2 hour spacing for drugs that need acidic environment
Describe CKD-Related Mineral and Bone Disorder (5)
What portions do phosphate-binding agents target
- Loss of nephron mass
- Decreased phosphate elimination (↑serum phosphate)
- Hyperphospatemia + low serum Ca2+
PTH synthesis, secretion by parathyroid) - Calcium reabsorption in distal tubules + mobilization from bone
- Bone disease -Loss of bone structural integrity & abnormal turnover
P-agents target parts 2 and 3
Describe the general MOA of phosphate binders
When should they be administered?
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!)
MOA of calcium-containing phosphate binders
2 examples
Brand name
% elemental Ca
Dosage form
- 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
Non-calcium binders (4 + 1 given by Shiltz)
What patient population are these preferred in
Sevelamer (Renvela; Renagel)
Lanthanum carbonate (Fosrenol)
Sucroferric oxyhydroxide (Velphoro)
Ferric citrate (Auruxyia)
Preferred in patients at risk for extraskeletal calcification
Aluminum hydroxide
When should we use them/why and how long
Aluminum hydroxide
last line due to neurotoxicity, encephalopathy, bone disease, & anemia
short course ≤7 days for refractory hyperphosphatemia
Name (brand and generic) of resin based phosphate binders
Administration (Chew or not)
MOA (5)
Side effects (5)
DI (1)
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
Elemental phosphate binder (brand and generic name)
Administration (Chew or don’t chew)
Why is that element useful
MOA
SE
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
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
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
Vitamin D: Name and VDR preference
Nutritional forms (2)
Active forms (1)
Vitamin D analogs (2)
Nutritional forms
Ergocalciferol: VDR1 = VDR2
Cholecalciferol: VDR1 = VDR2
Active form
Calcitriol (Rocaltrol): VDR1 = VDR2
Vitamin D analogs
Doxercalciferol (Hectorol): VDR1 >VDR2
Paricalcitol (Zemplar): VDR1»_space; VDR2
MOA of Vitamin D (3)
ADME (2)
ADR (3)
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.
Differentiate between calcitriol (1) and paricalcitol (3)
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
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)
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.
Cinacalcet (Sensipar)
ADME
Clinical indication
ADR (5)
DI (2 classes)
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).
Etelcalcitide (Parsabiv)
SAR
Clinical indication
Pharmacokinetics (3)
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
Why is Fe deficiency common in advanced CKD
What is the purpose of Fe supplements
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
Name the 5 iron salt supplements available PO
Roughly how much oral iron is absorbed
- Ferrous gluconate
- Ferrous sulfate
- Ferrous fumarate
- Iron polysaccharide
- Carbonyl iron
25%
Name the 5 iron compounds available IV
What is the dosing for IV iron
Toxicity and antidote
- Ferric carboxymaltose - Injectafer
- Ferumoxytol - Feraheme
- Iron dextran - INFeD
- Iron sucros - Venofer
- 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)
Name the 3 erythropoiesis stimulating agents (brand/generic) and differentiate between their structures
MOA (5)
ADR (9)
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
