renal failure pharmacology Flashcards
Which stages of chronic kidney disease require adjustment of drug doses for renally eliminated drugs
Stage 3-5
How does CKD affect absorption/bioavailability of drugs
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
How does CKD affect distribution of drugs
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.
How does CKD affect distribution of digoxin
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
How does CKD affect distribution of phenytoin
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
How does CKD affect elimination of drugs
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)
How to calculate GFR based on creatinine clearance
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)
Do patients with stage 1 or 2 CKD require changes in maintenance dosing?
no- Dosing reductions are generally not recommended until GFR falls below 50 ml/min/1.73 m2 (stage 3 to stage 5)
List drugs that : dilate afferent, constrict afferent, dilate efferent, constrict efferent
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
Diuretics for HTN in CKD patient
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
Angiotensin II action at glomerulus
slightly constricts afferent arteriole, really constricts efferent arteriole. This increases wall pressure in glomerulus leading to destruction and end stage renal failure
In general, what therapies can be used to slow progression of CKD?
treat diabetes, HTN and hyperlipidemia (in stage 3-4 CKD)
Drugs used to treat diabetes in CKD
oral hypoglycemics: Glyburide (half life prolonged) and Metformin (not recommended if serum Creatinine >1.5). Insulin (half life prolonged in CKD)
Drugs used to treat HTN in CKD
Diuretics (avoid K sparing diuretics), ACEI (monitor for hyperkalemia), ARBs, Beta blockers (atenolol has prolonged half life, metoprolol is preferred)
Drugs used to treat hyperlipidemia in CKD
Fibrates (Gemfibrozil is recommended fibrate in CKD stage 5)
Pathophys of anemia in CKD
reduced synthesis of EPO by kidney during CKD
Epoetin and darbepoetin MOA, pharmacokinetics and side effects
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
Iron salts and IV iron sucrose 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
Iron salts and IV iron sucrose pharmacokinetics, side effects, drug-drug interaction
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
Pathophys of renal osteodystrophy
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
Drugs used to treat renal osteodystrophy
phosphate binding agents, Vitamin D compounds, and calcimimetics
Phosphate binding agents list
Calcium acetate and sevelamer
Phosphate binding agents MOA, pharmacokinetics and side effects
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.
List Vitamin D compounds
Calcitriol (1,25 dihydroxy vitamin D)- does not require renal conversion
Calcitrol MOA, pharmacokinetics, side effects, drug-drug interactions
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.
Calcimimetics MOA, pharmacokinetics, side effects, drug-drug interactions
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.
Pathophys of hyperkalemia in CKD plus drugs that can cause hyperkalemia
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
List drugs used for hyperkalemia in CKD
Hemodialysis is definitive treatment; temporizing therapies include IV calcium gluconate, insulin and glucose, sodium bicarbonate, and nebulized albuterol, sodium polystyrene sulfonate
Hyperkalemia drugs MOA
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)
K wasting drugs
angiotensin II, aldosterone, loop diuretics, thiazide diuretics
