Describe the role of the kidney in drug excretion and the factors  affecting this (80% marks). Briefly outline how you would alter the  dosing of a drug with high renal excretion in a patient with renal impairment (20% marks).

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College Answer

The preponderance of marks was allocated to a discussion of renal drug excretion and factors altering this function. Detail was expected including a definition of clearance, and the balance between filtration / secretion / reabsorption in the tubules. Specific mention of GFR, molecular weight of filterable compounds, protein binding, and charge effects determining filtration at the glomerular level was 
anticipated. Tubular transport mechanisms for secretion and reabsorption in the proximal and distal tubule should have been included in the discussion.Candidates needed to cover factors which alter GFR, competition for transport proteins, changes in pH on drug elimination, and disease states in answering the question.

An understanding that drug dosing should be based on estimating creatinine clearance and plasma concentration monitoring was essential. Loading dose is usually unaltered. However, maintenance dose and dosing interval need to be adjusted owing to an increased half-life. Many candidates did not emphasise the need to increase dosing interval as well as reduce maintenance dose in renal 
impairment.


Syllabus: II2d, D12h
References: Goodman and Gilman's the Pharmacological Basis of Therapeutics 
p10-14. Foundations of Anaesthesia Basic and Clinical Science, Hemmings p107.
Basic and Clinical Pharmacology, Katzung p35, 48-49.

Discussion

As far as college commentary goes, this one is particularly good. Much of the renal clearance chapter has been constructed using this as a framework. The next time this question showed up ( ), the pass rate went from 0% to 52%.

In short:

  • 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 for renal impairement requires the assessment of the degree of impairment, the alteration of the regular dose and dosing frequency, and the monitoring of plasma drug levels for drugs with a narrow therapeutic index.
    • Renal impairement is quantified by measurement or estimation of the creatinine clearance
    • 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 decreasing the regular dose, increasing the dosing interval, or both
    • Plasma drug levels are measured for drugs which have a narrow therapeutic index

References

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.

Miner, Jeffrey H. "The glomerular basement membrane." Experimental cell research 318.9 (2012): 973-978.

Elwi, Adam N., et al. "Renal nucleoside transporters: physiological and clinical implications This paper is one of a selection of papers published in this Special Issue, entitled CSBMCB—Membrane Proteins in Health and Disease." Biochemistry and cell biology 84.6 (2006): 844-858.

Nigam, Sanjay K., et al. "Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters." Clinical journal of the American Society of Nephrology 10.11 (2015): 2039-2049.

Bendayan, Reina. "Renal drug transport: a review." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 16.6 (1996): 971-985.

Birnbaum, Jerome, et al. "Carbapenems, a new class of beta-lactam antibiotics: Discovery and development of imipenem/cilastatin." The American journal of medicine 78.6 (1985): 3-21.

Lohr, James W., Gail R. Willsky, and Margaret A. Acara. "Renal drug metabolism." Pharmacological Reviews 50.1 (1998): 107-142.

Bott, Phyllis A., and A. N. Richards. "The passage of protein molecules through the glomerular membranes." Journal of Biological Chemistry 141.1 (1941): 291-310.