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Dosing of Drugs in Renal Failure

Dosing of Drugs in Renal Failure. John Noviasky, PharmD. Background. Without careful dosing and therapeutic drug monitoring in patients with renal dysfunction, accumulation of drugs/toxic metabolites can occur Renal disease affects the pharmacokinetic as well as pharmacodynamic effect of drugs

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Dosing of Drugs in Renal Failure

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  1. Dosing of Drugs in Renal Failure John Noviasky, PharmD

  2. Background • Without careful dosing and therapeutic drug monitoring in patients with renal dysfunction, accumulation of drugs/toxic metabolites can occur • Renal disease affects the pharmacokinetic as well as pharmacodynamic effect of drugs • Uremia can alter drug disposition, protein binding, distribution and elimination (PK), and can also increase sensitivity to drugs (PD)

  3. Effect of Renal Failure on Bioavailability • Absorption of drugs in patients with renal disorders could be inhibited by GI disturbances seen in uremia (nausea, vomiting, diarrhea), uremic gastritis, and pancreatitis • Edema of GI tract can occur with nephrotic syndrome and impair absorption • Gastric motility can be impaired by uremia

  4. Effect of Renal Failure on Bioavailability • Uremia can also increase gastric ammonia and lead to increased gastric pH->drugs that require acidic pH (ferrous sulfate) • First-pass effect is reduced in patients with renal disease (therefore, absorption is increased in drugs with high first pass effect, e.g. propranolol) • Other drugs whose absorption is increased include: cloxacillin, propoxyphene, dihydrocodeine, zidovudine

  5. Effect of Renal Failure on Protein Binding (PB) and Volume of Distribution (VD) • The effect of a drug is related to the amount of free or unbound drug available to target tissues • Acidic drugs have decreased PB whereas basic drugs are usually unchanged or decreased • This is most important for highly PB drugs (>80%)

  6. Effect of Renal Failure on Protein Binding (PB) and Volume of Distribution (VD) • Uremic toxins may alter protein binding • Free fraction of highly PB drug increases so that total concentration may not reflect actual PD effect • Also, hypoalbuminemia is common to patients with renal failure. Therefore, highly PB drug has less albumin to cling to. • The above is especially important with Phenytoin

  7. Elimination • Drugs are eliminated through renal excretion or hepatic metabolism • As kidney disease progresses, the kidney’s ability to excrete uremic toxins decreases as does its ability to eliminate certain drugs • Kidney eliminates primarily through filtration or active secretion

  8. Elimination • Drugs with low protein binding are filtered more readily • Large Molecules (Molecular weight >20000) daltons are not readily filtered due to size • Some metabolites may accumulate and lead to adverse event when not eliminated by renal filtration (e.g. meperidine, morphine, procainamide)

  9. Elimination • Itraconazole and Voriconazole contain B-cyclodextrin which can accumulate in renal dysfunction causing GI disturbance

  10. Drug Removed by Dialysis • Removal by dialysis is specific to each drug • Factors affecting removal • type of machine, membrane surface area, pore size, flow rates • Dialysis is sometimes used to remove excess drug in overdose situation

  11. Section 1 • What is a “therapeutic window (TW)”? • If a drug has a large “TW”, will it need aggressive dose modification in cases where elimination is reduced? • What is an example of drug with wide “TW”, narrow “TW” • What may occur if beta-lactam such as ceftazidime is not dose-adjusted for renal dysfunction?

  12. Section 2 • Name 3 aminoglycosides (AG) • Do these AG have wide or narrow therapeutic window (TW)? • What important Gram- organism is covered by AG? • What are peak serum conc. for AG, serum trough conc? • What does peak of AG correlate with, trough of AG correlate with?

  13. Section 2 • If AG are not adjusted, what adverse events can result? • What is the Cockroft Gault equation for men and women? 34-2, 34-3

  14. Section 3 • What are limitations in calculating creatinine clearance?

  15. Section 11 • What can occur with acyclovir in renal tubules? • What can be done to minimize nephrotoxicity with acyclovir? • How does t1/2 of acyclovir differ in pts with ESRD compared to normal kidney function?

  16. Section 16 • What penicillin toxic symptoms are shown by TH? • What are several possible reasons that TH became toxic with use of penicillin?

  17. Section 18 • How well is vancomycin absorbed through GI tract? • What is usual peak for vancomycin? Usual trough? • Above what level can auditory dysfunction occur?

  18. Section 21 • How is phenytoin concentration calculated in patient with altered protein binding? 34-27 • For RS, what is total serum concentration of 5 microgram/ml comparable to in patient without hypoalbuminemia?

  19. Section 22 • What is normeperidine? • Table 34-4

  20. Section 23 • What is morphine-6-glucoronide? And what does it do? • How is it’s halflife change with renal dysfunction? • How is codeine halflife change with renal dysfunction? • Should propoxyphene be avoided in renal failure?

  21. Section 26 • How is enoxaparin eliminated?

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