Renal Tubular Physiology — Drug Excretion/Dosing

Current · V5 (2025) → B1.iv Historical · V4 (2023) → B.iv, H1.iii 3 exam appearances

2011B Q03

Exam question

Describe the role of the kidney in drug excretion and the factors affecting this (60% marks). Briefly outline how you would alter the dosing of a drug with high renal excretion in a patient with renal impairment (40% marks).

CICMWrecks answer

Master answer

Renal Drug Excretion

{Renal\;Drug\;Clearance} = { {Urine\; [Drug] \times V} \over {Plasma\; [Drug]} }

Due to glomerular filtration and balance of secretion and reabsorption

Glomerular Filtration

Physiological factors
- Starling forces
- Filtration pressure ∝ (P_G – P_BC) – ( π_G – π_BC)
  Where
  - P_G = Glomerular hydrostatic pressure (60mmHg)
  - P_BC = Bowman’s Capsule hydrostatic pressure (18mmHg)
  - π_G = Glomerular oncotic pressure (32mmHg)
  - π_BC = Bowman’s Capsule oncotic pressure (Negligible)
- Filtration decreases
  - Shock → decreased glomerular pressure
  - Obstruction → increased bowman’s capsule hydrostatic pressure
  - Hypoproteinaemia → hepatic failure, nephrotic syndrome
- Fick’s Law (see eqn)
  - Filtration increases with decreased MW, increased concentration gradient
  - Filtration decreases with increased GBM thickness (glomerulosclerosis, deposition) and loss of glomerular surface area (usually 0.8m². may be lost with renal failure)

Fick’s Law:

Diffusion\;\propto{{1\over\sqrt{Molecular Weight}} \times {Surface\;Area \over Thickness} \times \Delta conc}

Drug factors
- Size (Due to filtration slits and podocyte foot processes)
  - Particles <4nm freely filtered
  - Particles >8nm excluded
- Charge
  - GBM has negative charge, therefore negatively charged molecules repulsed → decreased filtration
- Protein binding
  - Highly protein bound drugs inhibited from filtration due to large size and charge of proteins

Secretion

Due to specific transporters
- P-glycoprotein (Amphipathic anions)
- MPR-2 (Conjugated metabolites)
- ATP-Binding Cassette Transporters (Organic cations)

Reabsorption

Passive reabsorption occurs in PCT and DCT
Membrane transporters for facilitated transport are present in DCT
Ionization
- pH of urine may lead to drug “trapping”
  - Acids ionized with pH > pKa
  - Bases ionized when pH < pKa
Lipophilicity
- Allows permeation through phospholipid bilayers of cell membrane → reabsorption

Dose adjustment of renally excreted drugs

According to clearance and GFR
Loading dose = Target concentration x V_d
- Usually no alteration of loading dose required
- In ESRF, volume of distribution may be increased → loading dose may need to be increased
Dosing rate = Target concentration x Cl
- As clearance is reduced in renal failure dosing rate requires reduction
- Maintenance dose = Dosing rate x Dosing interval
- Maintenance dose and/or the dosing interval may need to be reduced (depending on whether AUC or peak concentration of drug is required for drug effect)
Plasma monitoring of [drug] concentration required for drugs with low therapeutic index

Dose adjustment of Gentamicin

MoA: Inhibition of bacterial protein synthesis through irreversible binding to the 30s bacterial ribosome

Has a narrow therapeutic window, hence dose optimization and therapeutic drug monitoring are crucial.

Concentration dependant killing	Active concentration needs to be acheived (~8-10 times Minimim Inhibitory Concentration/MIC) Time above MIC does not need to be maintained	Loading dose should not be altered even in renal failure (5-7mg/kg)
Significant postantibiotic effect Distribution: Hydrophilic, so Distribute mainly to extra-cellular fluid. Redistribution can occurs upto 16-24 hours.		Once daily dosing sufficient without renal failure
	ESRF – Volume of distribution theoretically larger (but in case of Aminoglycosides, might be lower – suspected due to tissue displacement by other molecules like urea)	Loading dose adjustment in ESRF 4mg/kg

Metabolism: Nil Excretion: Rapidly excreted by glomerular filtration. Hence accumulate in renal failure (t1/2 upto 30-60hrs)	Subsequent Dosing interval based on renal clearance (GFR / CrCl) Frequent dosing only increases toxicity with no improvement in efficacy.	Maintenance dosing less frequent in renal failure Dose interval based on pre-existing guidelines, and with monitoring of pre-administration levels CrCl 40 to 59 mL/minute: Administer every 36 hours CrCl 20 to 39 mL/minute: Administer every 48 hours CrCl <20 mL/minute: Monitor serum levels and redose when gentamicin level is less than 1 mg/L
End stage renal disease / Dialysis (t1/2 upto 100hrs)		Check level prior to dialysis, and only administer dose after dialysis (based on expert advice)
Low Therapeutic index		Frequent monitoring of levels required

Sakurai / JC 2019

Reusable content

Formulae used in this answer

Absorption

CWF-0012

Diffusion\;\propto{{1\over\sqrt{Molecular Weight}} \times {Surface\;Area \over Thickness} \times \Delta concentration}

Renal Drug Excretion

CWF-0025

{Renal\;Drug\;Clearance} = { {Urine\; [Drug] \times V} \over {Plasma\; [Drug]} }

Answer by JC, Sakurai

Past papers

Exam appearances

3 appearances

Exam	Exact exam wording	Candidate success
2011B Q03	Describe the role of the kidney in drug excretion and the factors affecting this (60% marks). Briefly outline how you would alter the dosing of a drug with high renal excretion in a patient with renal impairment (40% marks).	52%
2010A Q08	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)	0%
2008A Q17	Describe the role of the kidney in drug excretion, and the factors affecting this. Briefly outline how you would alter the dosing of gentamicin in a patient with H impairment.	—