Canonical Question
Glomerulus & Tubule
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 ∝ (PG – PBC) – ( πG – πBC)
Where- PG = Glomerular hydrostatic pressure (60mmHg)
- PBC = Bowman’s Capsule hydrostatic pressure (18mmHg)
- πG = Glomerular oncotic pressure (32mmHg)
- πBC = 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
- Size (Due to filtration slits and podocyte foot processes)
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
- pH of urine may lead to drug “trapping”
- 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 Vd
- 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
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 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. | historical_member | — |
| 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) | historical_member | — |
| 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). | historical_member | — |