Drug Dosing in Renal Impairment

Question 1

who do we assess

Answer 1

By medical history:
◦ Diabetes
◦ Hypertension
◦ Age
◦ Vascular Disease
By Drug:
◦ Drugs that can be nephrotoxic
◦ Drugs that have significant renal excretion and require dose adjustments

Question 2

Why do we assess drug dosages in renal

impairment?

Answer 2

Prevent adverse effects
◦ Toxicity
◦ Further kidney injury

Question 3

CKD and ADME

Answer 3

Absorption • Reduced due to edematous GI tract

Distribution • Reduced protein binding
• E.g. phenytoin
• Increases Vd
• Altered tissue binding
• Decreased affinity for binding sites (e.g. digoxin)
• Decreased Vd

Metabolism • Reduced metabolism due to uremic toxins and chronic oxidative stress
on the liver
• Difficult to predict effect on individual drugs

Excretion • Reduced excretion of drugs that are renally eliminated

Question 4

Assessing Kidney Function

Answer 4

Creatinine
◦ Metabolic by-product of muscle
◦ Serum concentration primarily determined by patient’s muscle mass
◦ Almost exclusively eliminated by glomerular filtration
◦ ~15% eliminated by tubular secretion

Question 5

Serum Creatinine

Answer 5

Affected by: • Age • Gender • Weight • Malnutrition • Muscle Wasting • Amputation/Paralysis • Hydration

Question 6

Which Weight Do I Use?

Answer 6

C-G equation becomes less accurate in weight extremes (underweight and obesity).
◦ Underweight (BMI < 18.5): Use actual/total body weight (TBW)
◦ Normal Weight (BMI 18.5- 24.9): Use Ideal Body Weight (IBW)
◦ Overweight/Obese (BMI ≥ 25): Use Adjusted Body Weight (ABW)
IBW(females) = 45.5kg + 2.3 x (# inches above 5 ft.)
IBW (males) = 50kg + 2.3 x (# inches above 5 ft)
Adjusted (dosing) Weight = IBW + 0.4 (TBW-IBW)

Question 7

Obesity

Answer 7

In CG equation:
◦ IBW may underestimate CrCl
◦ TBW may overestimate CrCl
◦ ABW may slightly improve accuracy

Question 8

eGFR (MDRD, CKD-EPI equation)

Answer 8

● Standard measure of kidney function
● Initial method of identifying patients with kidney dysfunction
● inter-patient variability
● Adjusted to standard body size: 1.73 m2
● Population normal: 120-140 ml/min
● Generally will decrease by 1ml/min/1.73m2
/year after 30-35 years of age

Question 9

CG vs. reported eGFR

Answer 9

Significant variability can occur when using MDRD/CKD-EPI vs. CG in estimating
kidney function
Using MDRD can result in a different dosing recommendation
◦ Up to 40% of recommendations can be discordant
◦ Vast majority of recommendations when using MDRD result in a higher dose being used

CG has been used to validate drug dosing, MDRD/CKD-EPI has not**

Question 10

How Are You Going To Assess GFR?

All of this applies to CHRONIC kidney disease, NOT:
◦ Acute Kidney Injury
◦ Dialysis

Answer 10

Which formula?
◦ Cockcroft-Gault has been the gold standard for drug adjustment
◦ Majority of drug-dosing studies use Cockcroft-Gault, and the majority of monographs will recommend Cockcroft-Gault
◦ But –What about reported eGFR ?
◦ All methods are only ESTIMATES of renal function.
◦ Need to consider other information as well
Bottom Line
◦ Lab reported eGFR provides initial information about kidney function
◦ Calculate CrCl using weight based or non-weight based formula
◦ Does the estimate make sense with the clinical picture of the patient?

Question 11

1. Obtain patient history- relevant demographic and clinical history, obtain eGFR from
   lab measured with serum creatinine
2. Calculate Creatinine Clearance (use appropriate weight, or no weight),
3. Review current medications – determine which drugs MAY require dosage adjustment
4. Consult one or more drug dosing references to determine an appropriate dosage
   ◦ Empirically adjust the dose and/or interval
5. Monitor for response to drug as well as for adverse effects
6. Revise regimen if required based on response and clinical status.

Answer 11

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Question 12

Questions to ask yourself about the drug:

Answer 12

Is an immediate effect required? Can the dose be titrated up?
Is the drug effective/safe in patients with renal failure?
Is the drug nephrotoxic?
Is the drug >50% renally eliminated?
Does the drug have toxic metabolites?
Are there other options available that don’t require dosage adjustment?

Question 13

Drug Classes Requiring Dosage Adjustment in CKD

Answer 13

● Anticoagulants
● Anti-diabetic agents
● Antimicrobials and related drugs
● Centrally acting drugs
● Cardiac drugs
● GI drugs
● Other

Question 14

Other situations: Dialysis

Answer 14

Creatinine clearance cannot be calculated
Need to answer the same questions but add:
◦ Can the drug be dialyzed?
Many drug dosing references will have specific recommendations for dosing in various types of dialysis:
• Hemodialysis (Intermittent Hemodialysis – IHD)
• Continuous Renal Replacement Therapy (CRRT)
• Peritoneal Dialysis

Question 15

Can the drug be dialyzed?

Answer 15

Molecular Weight Consider type of membrane and pore size. Large MW have reduced clearance

Protein Binding Amount of free drug available
May be altered in CKD
High PB has reduced drug available to be eliminated
In Peritoneal Dialysis (PD) some proteins are able to pass through the membrane

Volume of Distribution: Large VD reduces clearance

Water solubility: High water solubility increases clearance
Plasma Clearance Degree of renal vs. non-renal clearance. Dialysis considered significant if renal clearance increases clearance by >30%

Dialysis Membrane Pore size, surface area, geometry can alter clearance rates.

Blood/Dialysate flow rate
Increases with blood flow rates; greater dialysis rates can increase clearance. In PD more
frequent exchanges increase clearance.

Question 16

Consult references:

Answer 16

• References:
– Bennett’s Drug Prescribing in Renal Failure
– Dialyize IHD (dializeihd.com)
– Sandford/Bugs & Drugs
– Micromedex
– Lexi-Drugs or Dynamed
• Most references will divide CrCl into categories:
• > 50, 10 – 50 and < 10 mL/min
• >60, 30-60, 15-30 and < 15 ml/min
• Most also provide suggestions for adjustment in terms of dose or interval
• Dialysis dosing often provided too