Chronic Kidney Disease/Pharmacology of CKD

Question 1

What is the definition of Chronic Kidney Disease?

Answer 1

A permanent reduction in GFR (at least 3 months).

Question 2

What are the 6 most common causes of CKD?

Answer 2

1) Diabetic nephropathy- most common
2) Hypertensive nephrosclerosis; Renal vascular disease
3) Glomerulonephritis
4) Polycystic kidney disease
5) Interstitial nephritis
6) Obstruction

Question 3

What are the 5 stages of renal degeneration?

Answer 3

1 - GFR>90
2 - GFR 60-90
3 - GFR 30-60
4 - GFR 15-30
5 - GFR less than 15

**Drug dosage must be adjusted in stage 3-5

Question 4

Nitric oxide, PGE2, PGI1 have this effect on the GFR and arterioles

Answer 4

Dilate the afferent arteriole, increase the GFR

Question 5

Caffeine and dopamine do what to the GFR

Answer 5

Increase the GFR, dilate the afferent arteriole

** Caffeine is an adenosine agonist

Question 6

Angiotensin II, Norepinephrine, and Adenosine have what effect on the arteriole and the GFR?

Answer 6

All three constrict the afferent arteriole, decrease in the GFR.

Ang II and NE also constrict the efferent which increases the GFR.

Question 7

NSAIDS have what effect on the GFR and the afferent arteriole?

Answer 7

Decrease the GFR and constrict the afferent arteriole.

Question 8

ACE inhibitors and ARBs have what effect on the GFR?

Answer 8

Decrease AngII levels which preferentially dilates the efferent arteriole and decreases the GFR.

Question 9

If hypovolemic, which three drug classes can cause AKI?

Answer 9

NSAID
ARB
Ace inhibitors

Question 10

Recommendations for diuretics in people with Stage 3+ CKD:

Answer 10

Thiazides may lose effectiveness as renal function declines; more potent loop diuretics (e.g., furosemide) are recommended

Avoid potassium-sparing diuretics

Question 11

Recommendations for ACE inhibitors/ARBs in people with Stage 3+ CKD:

Answer 11

Used through all CKD stages; monitor for hyperkalemia and elevations in serum creatinine; may cause ARF in hypovolemic patients

Question 12

Recommendations for Beta-blockers in people with Stage 3+ CKD:

Answer 12

Atenolol: Half-life prolonged

Metoprolol, Carvedilol: No adjustments necessary

Question 13

Recommendations for Ca channel blockers in people with Stage 3+ CKD:

Answer 13

No adjustment necessary.

Question 14

Recommendations for clonidine in people with Stage 3+ CKD:

Answer 14

No adjustment necessary.

Question 15

Recommendations for alpha blockers in people with Stage 3+ CKD:

Answer 15

No adjustment necessary.

Question 16

Recommendations for vasodilators in people with Stage 3+ CKD:

Answer 16

No adjustment necessary.

Question 17

Describe the relationship between Calcium, Phosphorus, and Parathyroid Hormone (PTH) in chronic kidney disease. Include Active Vitamin D and FGF-23.

Answer 17

Serum Ca is tightly regulated, as is phosphorus. The maintenance of levels is dependent on the GFR. When the GFR falls, Ca levels drop and PO4 levels rise. To re-establish normal, the body increases secretion of PTH (PTH secretes PO4 and preserves Ca), this is called secondary parathyroidism. Active Vitamin D (1,25dihydroxyvitamin D) is produced by the kidney, and also regulates PTH. When GFR falls, so does production of Active vitamin D.

Fibroblast Growth Factor 23 (FGF-23) has a primary function of secreting PO4 (is a regulator of phosphate balance). However, it suppresses 1,25 Vitamin D production, which decreases Ca absorption from the gut.

So decreased renal functhion decreases 1,25 VD, which leads to decreased Ca, which leads to increased PTH.

Decreased renal function also causes a rise in PO4, which triggers increased levels of FGF-23, which suppresses 1,25 VD, which decreases Ca levels, which raises PTH.

**Starts at GFR below 60, but don’t really see this until the GFR is below 25%.

Question 18

What is the negative clinical effect of high PTH (secondary parathyroidism).

Answer 18

Bone disease (osteitis fibrosa, demineralization, bone pain, fractures)

Systemic toxicity (nervous system, endocrine, immunologic, cutaneous, cardiac)

Question 19

What is uremia?

Answer 19

Urea and other solutes accumulate in the blood (Urea is the marker). Also see overproduction of counter-regulatory hormones (PTH, for example). Underproduction of EPO and 1,25 Vitamin D also a result of kidney atrophy.

Clinical features: All organ systems. Patients always have anemia.

Question 20

When GFR is low, what hematologic issue can arise?

Answer 20

Anemia. EPO markedly decreased, and marrow space fibrosis occurs due to secondary hyperparathyroidism.

Question 21

Why is CKD progressive?

Answer 21

The intact nephron hypothesis. Compensatory changes actually damage the functioning nephrons.
-Glomerular hypertrophy, blood flow per nephron increases, intra-glomerular pressure increases, solute flow per tubule increases.

Question 22

True/False: more patients die than make it to dialysis.

Answer 22

True. Only 20% of people in stage 4 CKD make it to dialysis, whereas 47% die (primarily of Cardiovascular disease). This is independent of all the traditional risk factors, so there is something unique.

**IF a patient has CKD, they are automatically in the highest risk category for cardiovascular disease. (Even higher than a previous MI).

Question 23

What is the most important factor in slowing progression of CKD?

Answer 23

Controlling blood pressure. (Combine 3 or more drugs).

In addition to a diuretic, all CKD patients should be on an ACEi or ARB. There is a clear renal-protective benefit. Unknown why, but several studies show this.

Can also give bicarbonate and vitamin D (less well proven).

Question 24

What happens to the distribution of drug (Vd) in CKD?

Answer 24

Decreases and increases in Vd have been observed but in each case it resulted in an increase in levels of free unbound drug and Cp

In CKD patients, the Vd has been shown to decrease by as much as 50% in stage 5 as a result of decreased tissue binding (mechanism uncertain). Thus, any given dose of digoxin will result in a higher Cp due to the smaller Vd and as CKD progresses it will be necessary to gradually reduce the daily dose of digoxin to prevent toxic accumulations.

The anticonvulsant phenytoin (Dilantin) is highly protein bound in patients with normal kidney function. In CKD, organic acids are excreted less efficiently and accumulate in plasma competing with phenytoin for albumin binding sites (analogous to protein-binding displacement drug-drug interaction). Hypoalbuminemia may also occur in CKD and these changes result in less phenytoin binding to proteins, greater levels of free phenytoin and greater ability to distribute outside of the plasma and greater potential for toxicity. Generally, these effects would be of potential clinical significance only in the acute initialization of dose phase.

Question 25

In general, what happens to the

1) distribution
2) metabolism
3) excretion
4) absorption

of drugs in CKD patients?

Answer 25

1) distribution - Vd may go up or down, but availability of drug increases
2) metabolism - as GFR declines, renally metabolized drugs will persist longer
3) excretion - excretion will decrease and half life will increase
4) absorption - most likely changes, but little data available

**Drug-drug interactions are possible and even likely given the large number of drugs a typical CKD patient is taking, especially with cation-containing phosphate binders (for hyperphosphatemia) and bile acid sequestrants (for hyperlipidemia) that can bind concomitantly administered drugs and reduce their bioavailability.

Question 26

What two EPO drugs are used to treat anemia in CKD? Describe their MOA,

Answer 26

Epoetin, Darbepoetin

Mimic EPO.
Given parenterally.
Side effects: HTN. Generally well-tolerated.

Question 27

Iron. MOA, side effects, drug drug ix.

Answer 27

MOA: Iron deficiency is most common cause of resistance to erythropoietic therapy. Supplements provide iron for production of hemoglobin and incorporation into red blood cells

Pharmacokinetics: Oral route commonly used, but absorption is generally poor (bid-tid). IV administration often required, especially in Stage 5 CKD

Side effects: Oral – constipation, nausea, abdominal cramping, often leading to reduced compliance. IV – allergic reactions, hypotension, headaches, anaphylactoid reactions

Drug-drug interactions: Absorption decreased by calcium and by drugs that increase gastric pH (antacids, proton pump inhibitors, H2 antagonists)
B. Renal Osteodystrophy

Question 28

What is renal osteodystrophy?

Answer 28

Declining kidney function results in decreased phosphate elimination and elevated serum phosphate levels –> lowers serum calcium –> stimulates release of PTH
–> PTH initially normalizes serum calcium and phosphate concentrations by increasing renal calcium reabsorption and decreasing renal phosphate reabsorption BUT long term elevation of PTH leads to osteodystrophy due to RESORPTION from bone.

Problem is compounded by the failing kidney’s decreased ability to convert 25-hydroxy vitamin D to the most active 1,25-dihydroxy vitamin D resulting in a vitamin D deficiency and a further reduction in serum calcium levels and increased release of PTH

Question 29

What are treatments for renal osteodystrophy? (3 classes)

Answer 29

1) Phosphate binding agents: calcium compounds (calcium acetate) or non-elemental agents (sevelamer HCl, sevelamer bicarbonate) which have a reduced incidence of metabolic acidosis.
2) Vitamin D compounds: Best choice is agent that does not require renal conversion to the most biologically active form, i.e., 1, 25-dihydroxy vitamin D (calcitriol)
3) Calcimimetics: Cinacalcet is an alternative to Vitamin D in patients who are developing hypercalcemia

Question 30

What are the side effects, MOA, and administration of the phosphate binding agents?

Answer 30

MOA: Bind dietary phosphate in GI tract to form insoluble magnesium, calcium, or aluminum phosphate, which is excreted in the feces, thus decreasing phosphate absorption and serum levels.

Pharmacokinetics: Given orally, best taken with meals.

Side effects: Primarily GI side effects – constipation (Al+++ or Ca++), diarrhea (Mg++), nausea, vomiting, abdominal pain. Hypercalcemia possible with Ca++ salts; CNS toxicity with Al+++ salts limits use.

Question 31

What is the MOA, side effects, pharmacokinetics and drug-drug ix of Calcitriol (Vitamin D compound)?

Answer 31

MOA: SUPPRESSES PTH SECRETION indirectly by stimulating intestinal calcium absorption and directly by decreasing PTH synthesis in parathyroid gland.

Pharmacokinetics: Available in oral (Stage 1-4) and intravenous (Stage 5) dosage forms

Side effects: Hypercalcemia and hyperphosphatemia possible.

Drug-drug interactions: Absorption reduced by concomitant administration of cholestyramine.

Question 32

What is the MOA, side effects, administration, and drug-drug ix of Cinacalcet?

Answer 32

MOA: Binds to calcium-sensing receptors on parathyroid cells, increasing sensitivity to plasma Ca++ levels, resulting in reduced release of PTH directly.

Pharmacokinetics: Available orally, metabolized by CYP450

Side effects: Hypocalcemia (monitor plasma Ca++); GI side effects.

Drug-drug interactions: Potent inhibitor of CYP2D6

Question 33

RECALL: Drugs that can cause hyperkalemia (4 big categories, try to name specific drugs):

Answer 33

Potassium sparing diuretics: aldosterone antagonists (spironolactone, eplerenone) - collecting duct Na+ channel blockers (triamterene, amiloride)

ACE inhibitors: lisinopril, enalapril, captopril, and more

Angiotensin receptor blockers: losartan, valsartan, candesartan, and more

Digoxin (toxic doses)

Question 34

How is hyperkalemia treated in CKD patients?

Answer 34

Acute (symptomatic): Hemodialysis is definitive treatment; temporizing therapies include IV calcium gluconate, insulin and glucose, sodium bicarbonate, and nebulized albuterol

**[Shift of K+ into intracellular fluid compartment (insulin / glucose, albuterol, sodium bicarbonate), antagonism of cardiac conduction abnormalities (calcium)]

Chronic (asymptomatic): Sodium polystyrene sulfonate (Kayexalate)

MOA: Cation exchange resin that binds (exchanges) potassium for sodium in intestine. Pharmacokinetics: Oral (more effective) and rectal.

Side effects: Constipation, fecal compaction, nausea, vomiting.

** can also use insulin, NaHCO3, albuterol