renal failure pharmacology

Question 1

Which stages of chronic kidney disease require adjustment of drug doses for renally eliminated drugs

Answer 1

Stage 3-5

Question 2

How does CKD affect absorption/bioavailability of drugs

Answer 2

Altered gastrointestinal motility, Changes in gastric pH, Nausea and vomiting, Diarrhea all can affect absorption. Also, patients on lots of drugs may have drug-drug interactions that occur in GI tract preventing absorption. This is especially common with phosphate binders and Bile acid sequestrants that bind other drugs and reduce bioavailability

Question 3

How does CKD affect distribution of drugs

Answer 3

CKD can decrease or increase the volume of distribution of drugs, resulting in an increase in levels of free unbound drug and plasma concentration of that drug.

Question 4

How does CKD affect distribution of digoxin

Answer 4

CHF drug digoxin has large volume of distribution (Vd) due to extensive tissue binding. In CKD, Vd is decreased due to decreased tissue binding, this results in higher plasma concentration of free drug. It is necessary to reduce dose of digoxin in stage 5 CKD

Question 5

How does CKD affect distribution of phenytoin

Answer 5

Phenytoin in an anticonvulsant that is highly bound to proteins when kidney function is normal. In CKD, organic acids are excreted less efficiently and accumulate in plasma competing with phenytoin for albumin binding sites. This results in an increased Vd but increased levels of free phenytoin in plasma

Question 6

How does CKD affect elimination of drugs

Answer 6

in CKD, renal excretion (clearance) decreases and drugs will accumulate leading to increased plasma concentration. Also, metabolism via kidneys decreases (ie. CYP450 metabolism and phase II conjugations) so drug doses must be decreased. Also, active metabolites from hepatic metabolism may accumulate in CKD such as Meperidine (excitotoxic metabolite) and acetaminophen (hepatotoxic)

Question 7

How to calculate GFR based on creatinine clearance

Answer 7

CLcr (ml/min) = [(140 - Age) (ABW)] / Scr X 72 Where For females result is multiplied by 0.85,Age (in years), ABW (actual body weight in kg; use ideal body weight (IBW) in obese patients), Scr (serum creatinine, mg/dL)

Question 8

Do patients with stage 1 or 2 CKD require changes in maintenance dosing?

Answer 8

no- Dosing reductions are generally not recommended until GFR falls below 50 ml/min/1.73 m2 (stage 3 to stage 5)

Question 9

List drugs that : dilate afferent, constrict afferent, dilate efferent, constrict efferent

Answer 9

Dilate afferent (increase GFR): dopamine and caffeine. Constrict afferent (decrease GFR): NSAIDs (decrease PGs), angiotensin II, NE. Constrict efferent (increase GFR): Angiotnsin II, NE. Dilate efferent (decrease GFR): ACEI (decrease AngII), ARB

Question 10

Diuretics for HTN in CKD patient

Answer 10

Thiazide are first line for HTN, but as GFR falls (<30m/min) in CKD, less drug reaches target so a more potent loop diuretic is necessary. Diuretic resistance occurs at later stages of CKD and can be overcome with synergistic combo of loop and thiazide

Question 11

Angiotensin II action at glomerulus

Answer 11

slightly constricts afferent arteriole, really constricts efferent arteriole. This increases wall pressure in glomerulus leading to destruction and end stage renal failure

Question 12

In general, what therapies can be used to slow progression of CKD?

Answer 12

treat diabetes, HTN and hyperlipidemia (in stage 3-4 CKD)

Question 13

Drugs used to treat diabetes in CKD

Answer 13

oral hypoglycemics: Glyburide (half life prolonged) and Metformin (not recommended if serum Creatinine >1.5). Insulin (half life prolonged in CKD)

Question 14

Drugs used to treat HTN in CKD

Answer 14

Diuretics (avoid K sparing diuretics), ACEI (monitor for hyperkalemia), ARBs, Beta blockers (atenolol has prolonged half life, metoprolol is preferred)

Question 15

Drugs used to treat hyperlipidemia in CKD

Answer 15

Fibrates (Gemfibrozil is recommended fibrate in CKD stage 5)

Question 16

Pathophys of anemia in CKD

Answer 16

reduced synthesis of EPO by kidney during CKD

Question 17

Epoetin and darbepoetin MOA, pharmacokinetics and side effects

Answer 17

MOA: Glycoproteins prepared with recombinant DNA technology with biologic activity identical to erythropoietin
Pharmacokinetics: subcutaneous every week (epo) or every 1-2 weeks (darbepoetin). Side effects: hypertension, if HgB >12g/dL increased risk of CV events

Question 18

Iron salts and IV iron sucrose MOA

Answer 18

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

Question 19

Iron salts and IV iron sucrose pharmacokinetics, side effects, drug-drug interaction

Answer 19

Poor absorption, IV often required. Oral ferrous sulfate has GI effects and IV iron dextran, etc can cause hypotension or allergic events. DDI: absorption decreased by calcium and proton pump inhibitors

Question 20

Pathophys of renal osteodystrophy

Answer 20

Declining kidney function results in decreased phosphate elimination and elevated serum phosphate levels plus less D3 is synthesized> lowers serum calcium > stimulates release of PTH > normalized PO4 and Ca levels but osteodystrophy occurs

Question 21

Drugs used to treat renal osteodystrophy

Answer 21

phosphate binding agents, Vitamin D compounds, and calcimimetics

Question 22

Phosphate binding agents list

Answer 22

Calcium acetate and sevelamer

Question 23

Phosphate binding agents MOA, pharmacokinetics and side effects

Answer 23

MOA: Bind dietary phosphate in GI tract to form insoluble salt which is excreted in the feces, thus decreasing phosphate absorption and serum levels.. Pharmacokinetics: Given orally.
Side effects: Primarily GI – constipation (Al+++ or Ca++), diarrhea (Mg++), nausea, vomiting, abdominal pain. Hypercalcemia possible with Ca++ salts; CNS toxicity with Al+++ salts limits use.

Question 24

List Vitamin D compounds

Answer 24

Calcitriol (1,25 dihydroxy vitamin D)- does not require renal conversion

Question 25

Calcitrol MOA, pharmacokinetics, side effects, drug-drug interactions

Answer 25

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

Question 26

Calcimimetics MOA, pharmacokinetics, side effects, drug-drug interactions

Answer 26

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 27

Pathophys of hyperkalemia in CKD plus drugs that can cause hyperkalemia

Answer 27

Failing kidney cannot excrete sufficient potassium to maintain homeostasis. Hyperkalemia is most common in stage 5 CKD. Drugs that cause hyperkalemia: K sparing diuretics (Aldosterone antagonists and Na channel blockers), ACEI, ARBs, digoxin

Question 28

List drugs used for hyperkalemia in CKD

Answer 28

Hemodialysis is definitive treatment; temporizing therapies include IV calcium gluconate, insulin and glucose, sodium bicarbonate, and nebulized albuterol, sodium polystyrene sulfonate

Question 29

Hyperkalemia drugs MOA

Answer 29

Shift of K+ into intracellular fluid compartment (insulin / glucose, albuterol, sodium bicarbonate), antagonism of cardiac conduction abnormalities (calcium), or cation exchange resin that exchanges K for Na in intestine (sodium polystyrene sulfonate)

Question 30

K wasting drugs

Answer 30

angiotensin II, aldosterone, loop diuretics, thiazide diuretics