Question 5(p.2)

College Answer

The main points candidates were expected to cover included a brief definition of renal
clearance followed by a description of the drug factors that affect this (filtration, secretion
and reabsorption), recognition that GFR and protein binding was important in the answer. A
brief description of gentamicin kinetics that affect dosing regimens and a statement that
dosing would be guided by calculated GFR and measured drug levels would round out a good
answer. Correct elaboration of the above factors was rewarded with additional marks.
Candidates failing this question submitted answers where concepts were randomly mentioned
with no attempt to integrate these into a cohesive answer that demonstrated an understanding
of the topic. Writing random words without examples or explanations did not demonstrate
sufficient understanding to be rewarded with marks. Again, many answers lacked sufficient
detail in the answer.

Discussion

• The magnitude of renal drug clearance is the sum of glomerular filtration and active excretion, minus renal drug reabsorption
• Glomerular filtration (GFR) is influenced by the following factors, in the following ways:
  • Molecule size (anything larger than 30 Angstrom is not filtered)
  • Molecule charge (negatively charged molecules are repelled)
  • Protein binding (only the free fraction is filtered)
  • Renal blood flow
  • Age and renal disease
• Drug secretion occurs in the proximal tubule and is mediated by active transporters and exchange pumps. It is influenced by the following factors
  • Protein binding (only the free fraction is available for uptake from the blood)
  • Renal blood flow
  • Competition between substrates eligible for the same transporter
  • Concentration of the drug (these transporters are saturable)
• Drug reabsorption can be active or passive, and occurs in the distal tubule and collecting duct. Most drugs are reabsorped passively by diffusion.
  • Passive diffusion occurs along a the concentration gradient which develops because of the removal of water from the tubular lumen, and is therefore strongly influenced by the urine flow rate. 
  • It is affected by the fraction of non-ionised drug (only non-ionised drug can be reabsored passively), which is in turn influenced by the pH of the urine. Ionised drugs are "trapped" in the urine and are excreted.
  • Only drugs which chemically resemble naturally available substrates are reabsorbed by active transport (eg. glucose, vitamins, amino acids).
• Dose adjustment of gentamicin for renal impairement 
  • Dose is adjusted according to the degree of impairement and the proportion of the drug excreted unchanged in the kidney
  • Loading dose does not need to be adjusted
  • Maintenance dose is adjusted by increasing the dosing interval
  • Plasma drug levels are measured, as gentamicin has a narrow therapeutic index

Miners, J. O., et al. "The Role of the Kidney in Drug Elimination: Transport, Metabolism and the Impact of Kidney Disease on Drug Clearance." Clinical Pharmacology & Therapeutics (2017).

Mahasen, Laila M. Aboul. "Evolution of the Kidney." Anatomy Physiol Biochem Int J 1(1) : APBIJ.MS.ID.555554 (2016)

Brater, D. Craig. "Measurement of renal function during drug development." British journal of clinical pharmacology 54.1 (2002): 87-95.

Levy, Gerhard. "Effect of plasma protein binding on renal clearance of drugs." Journal of pharmaceutical sciences 69.4 (1980): 482-483.

Regårdh, Carl G. "Factors contributing to variability in drug pharmacokinetics. IV. Renal excretion." Journal of Clinical Pharmacy and Therapeutics 10.4 (1985): 337-349.