H1v: The role of the kidney in drug excretion

Clearance

Renal clearance = the volume of plasma completely cleared of a substance per unit of time
- Units = mL/min
Clearance is based on the FICK PRINCIPLE, which is the conservation of mass

DELIVERY (renal a.) = RETURNS (renal v, reabsorption) x EXCRETION (urine, secretion)

Clearance is one of the kidneys’ 1° function & the most important route of drug elimination (others: bowel, bile, lungs, lactation)

RENAL DRUG CLEARANCE = DRUG FILTERED (GFR) + DRUG SECRETED – DRUG REABSORBED

Glomerular filtration of drugs
- GF = volume of plasma filtered by the kidneys per minute
- Normal GFR = 125mL/min
- GFR = Kf (permeability x SA) x NFP
Permeability depends on the integrity of 3 layers of filtration barriers
Cap Endothelium – fenestrated, particles <7000Da (easily pass), negatively charged
BM – negatively charged, filters based on charge
Bowman’s Capsule Endothelium – podocytes + slit diaphragms, filter on size, <30 Angstroms (= 22,446 Da)
Surface Area depends on no. of functioning nephrons

∴↑age/renal failure = ↓functioning nephrons → ↓SA → ↓Kf → ↓GFR → ↓Renal Drug Elimination

NFP = (P_GC – π_GC) – (P_BC – π_BC)
- These are Starling’s Forces
- NFP depends on BP which is autoregulated to maintain constant GFR
- Also controlled by Aff. & Eff. Arterial Tone
- ↑ R = ↑P_GC = ↑GFR = ↑renal drug clearance
- ↓BP/↑ R = ↓P_GC = ↓GFR = ↓renal drug clearance
For a drug to be cleared it must end up in the ULTRAFILTRATE (i.e. more from glom caps → Bowman’s capsule)

Clearance by glomerular filtration = Fraction of unbound drug in plasma x GFR

Determined by:
- PROTEIN BINDING → only free drug is filtered
- LIPID SOLUBILITY → easily reabsorbed but not well filtered
- CHARGE → negatively charged BM ∴less likely to filter negatively charged drugs
- SIZE → freely filters <7000 Da

Occurs in PCT
By ACTIVE TRANSPORT & exchange pumps
Influenced by:
- PROTEIN BINDING
- RBF
- SUBSTRATE COMPETITION FOR TRANSPORTER
- DRUG CONCENTRATION (transporters are saturable)
Transport systems are:
- WEAK ACID (frusemide, β-lactams)
- WEAK BASE (ranitidine, trimethoprim)
- NUCLEOSIDE (ribavirin)
- P-GLYCOPROTEIN (digoxin, verapamil)
∴saturable
Multiple substrates will compete with each other
Molecules that are too big to be cleared can be excreted this way
Protein bound drugs are not cleared this way
The rate of clearance depends on RBF

Depends on the amount of H₂O reabsorbed
↑urine [ ] = drug becomes v. concentrated in urine → creates a great [ ] grad for drug reabsorption
∴factors influencing passive reabsorption
- Drug [ ]
- Urinary flow rate
- Urine pH
- Drug ionisation

Mainly in PCT
Drugs resembling glucose/amino acids/vits will compete with their binding sites to get reabsorbed

DCT has peptides which can metabolise protein i.e. INSULIN → 30% eliminated this way!
Imipenem to Tx UTI is metabolised by PCT peptidases → ∴needs co-admin with CILASTATIN to inhibit peptidase digestion of drug

Required if drug is 50% renally cleared + renal function <50% normal
First → establish DEGREE OF RENAL DYSFUNCTION
- Crt Cl
- As a marker of GFR
- Renal drug clearance ∝ Crt cl.

EXCEPT → DIGOXIN → ↓V_D in renal impairment ∴need ↓loading dose 50%

NB: ↓ V_Dwith digoxin through to be due to ↓ tissue levels of Na/K/ATPase which is the major tissue-binding site for digoxin

↓dose interval or ↓regular dose or both
e. Vancomycin → no metabolism → cleared by RENAL ELIMINATION
10mg/kg Q12h → based on body weight & renal function
- Requires monitoring
- Trough levels every 4d for courses > 5 days
- Therapeutic index 15 – 20mg/L

Essential for drugs with narrow therapeutic index, esp. critically ill whose volumes & renal function fluctuate daily