Pharmacokinetics and Renal Function

Question 1

Creatinine

Answer 1

• by-product of muscle metabolism as a result of creatine phosphate dephosphorylation
• ## removed by kidney through glomerular filtration (85-90%) and active tubular secretion (10-15%)

Question 2

Describe what happens to SCr and CrCl levels if the kidneys are not functioning normally. Which one is most imp to estimate renal function?

Answer 2

• SCr levels begin to rise
• CrCl is reduced

Creatinine can’t pass through the glomerulus properly = reduced kidney function
*CrCl is the best estimate of renal function

Question 3

eGFR

Answer 3

estimated Glomerular Filtration Rate
- only valid up to 60mL/min because eGFR usefulness hasn’t been validated over this, plus a GFR over 60 is usually doesn’t require a drug dose adjustment

Question 4

Cockroft and Gault equation

Answer 4

CrCl (mL/min/72kg) = (140-age)(80*)(0.85 for females)/SCr

*80 is the updated way! Can be 88.4

Question 5

Describe 4 limitations to using equations to estimate renal function

Answer 5

1. Use only in adults (>18)
2. They are only valid if renal function is stable
3. The equations are not validated in patients with “markedly abnormal body composition” (ie amputation, pregnancy, extreme obesity, paralysis)
4. Estimations may also be inaccurate in patients following vegetarian diets, taking creatine supplements, or taking meds that inhibit tubular secretion of creatinine

Question 6

Name 2 drugs that inhibit the tubular secretion of creatinine

Answer 6

trimethoprim, fenofibrate

Question 7

A 24 hr urine collection may be required to estimate GFR in what conditions?

Answer 7

• extremes of age and body size
• severe malnutrition or obesity
• disease of skeletal muscle
• paraplegia or quadriplegia
• vegetarian diet
• rapidly changing renal function
• pregnancy

Question 8

eGFR may overestimate GFR in what populations? What can be done?

Answer 8

May overestimate GFR in Asians, and has not been validated in Canadian Indigenous patients. Therefore, in these situations, the eGFR when reported should be interpreted cautiously and could be supplemented with a 24hr collection.

Question 9

What formulas or methods could help to estimate GFR in pediatric patients?

Answer 9

the Schwartz or the Counahan-Barratt methods

Question 10

In general, most renally eliminated drugs will not need major dosage adjustments until the patient’s GFR falls below what? What do we do?

Answer 10

50-60mL/min

• If CrCl below this threshold, renally eliminated drugs may require dosage decreases or dosage interval increases

Question 11

Even drugs initially metabolized by the liver may need dosage adjustments in renal failure. Why?

Answer 11

Take for example meperidine and morphine. The liver metabolizes them to active water-soluble metabolites that will be renally eliminated. With decreased renal function, the active metabolite accumulates, causing toxicity (severe AEs)

Question 12

What 3 factors help to determine if a medication will be removed during hemodialysis?

Answer 12

• Molecular weight (MW)
• Protein Binding of the drug
• Volume of distribution

Question 13

MW: when will a drug be removed by hemodialysis?

Answer 13

• small MW molecules (less than 5000Da) will generally have a much larger clearance and be removed by dialysis
• Large MW proteins over 5000Da will generally not be removed

Question 14

protein binding: when will a drug be removed by hemodialysis

Answer 14

• Highly protein-bound drugs (>90-95%) are NOT typically removed

Question 15

Vd: when will a drug be removed by hemodialysis

Answer 15

• Drugs with a large Vd (>1L/kg) are typically widely distributed in the body (less in plasma) and therefore will have less removal
• Drugs with a small Vd (<1L/kg) will have greater removal

Question 16

How many factors would have to apply to a drug to determine if it will be removed by dialysis?

Answer 16

Only one! Ex: even if a drug has a very small MW, if it has a very large Vd it will be poorly removed

Question 17

Dialysis factors: a drug will also be removed more extensively if what parameters exist?

Answer 17

• by “high flux” hemodialysis
• if the dialysis session is 4hrs
• if blood flow rates are >300mL/min

Question 18

fistula

Answer 18

Used to describe an artery and vein sewn together in the forearm to create a high pressure area for dialysis
=> Can also be done using a central line into the right jugular vein into the right atria

Question 19

Linagliptin

Answer 19

• Not extensively metabolized by kidney
• 5% excreted in urine and 80% excreted in feces unchanged
• don’t typically need dose adj in low kidney function

Question 20

Metformin

Answer 20

• excreted in urine 90% unchanged
• not metabolized by liver
• Metformin not recommended if CrCl <30mL/min so consider stopping/dose adj if this applies to a patient on this therapy

Question 21

Candesartan

Answer 21

• hepatic metabolism, but 33% excreted in urine
• 26% removed by kidneys as unchanged drug
• Exercise clinical judgement when deciding to adj dose or remove drug in decreased kidney function => would however want to know pts BP before adjusting the dose

Question 22

ASA

Answer 22

• hydrolyzed to salicylate in GI, further metabolized to an active metabolite (salicyluric acid)
• removed by the kidney (75% as salicyluric acid; 10% as salicylic acid)
• benefit of low-dose ASA outweighs risks EVEN in severe renal impairment. If patient’s ASA range is within 81-162mg daily, we leave the dose alone in decreased kidney function
• if they’re on high dose ASA for pain, would stop it then or decrease.

Question 23

Naproxen

Answer 23

• Significant problems associated with Naproxen in cases of decreased kidney function. These patients are more dependent on renal prostaglandins to keep blood flowing in the glomerulus.
• Keeping a kidney failure patient on an NSAID for pain will decrease blood flow through the kidney, which compromises the ability to make urine and throw them into acute renal failure.
• TLDR: don’t bother even lowering dose, just don’t use it if CrCl <30mL/min

Question 24

Colchicine

Answer 24

• Renal excretion data varies for this drub depending on the source (some say 10-20% renal excretion, another says 40-65% ; just know there is some renal elimination)
• In CrCl <30: dose reduction not required, but should not repeat the “stat” starting dose of this drug more frequently than every 2 weeks

Question 25

Allopurinol

Answer 25

• 75% metabolized to active metabolite (oxypurinol)
• excretion 76% in urine for active metabolite
• Can still use max dose of 300mg daily in low CrCl

Question 26

When does a patient usually start dialysis?

Answer 26

CrCl <10mL/min ; usually around 5-8mL/min