RENAL CLEARENCE
OF DRUGS
Introduction
• Excretion is the process by which the drugs and
their metabolites are irreversible transferred from
internal to external environment .
• The principle organ of excretion are kidneys
• Excretion by organs other than kidney is know
as non renal excretion
• Agents that are water soluble ,non volatile
small in molecular size and which are
metabolized slowly are excreted in the urine
The principle process that determine
urinary excretion of drugs are
1)glomerular filtration
2)Active tubular secretion
3)Active tubular reabsorption
Rate of excretion =rate of filtration + rate
of secretion-rate of reabsorption
•In the new born the effective renal blood
flow effects the rate.
•When the drugs subjected to renal
excretion will be eliminated more slowly.
•The renal elimination is the primary route
for anti bacterials in new born and children's.
•The neonatal renal plasma flow and the
glomerular filtration rates are only 30-40%.
•The different process of renal excretion in
new born and children mature at different
rates
•The pre mature and term infants require
dose administration based on measurement
or estimation of GFR for drugs that are
eliminated by GFR
•The estimation of dose for new born and
children are based on the surface area
SA(m sq)=weight(kg)0.5378x0.024265
SA(m sq)=weight(kg)0.78
DRUG CLEARENCE
• It determines the maintainance Dose-rate.
• Physiological Relevance of Drug Clearence:-
CL (total) = CL (renal) + CL (liver) + CL (other)
• Kinetics
• CL doesn’t apply to drugs with ZERO-ORDER Kinetics.
Rate of elimination ∞ Cp
∴ R.E (mg) = Constant (L/h) * Cp (mg/L)
this constant is the CL.
i.e. R.E = CL × Cp
CL = R.E / Cp
First order Elimination
Css
admn
Cp
Cp
elimn
T Half lives
• Achievement of constant Css of Drug.
– To maintain a target Cpss.
– Drug must be administered at a rate equal to the rate of
Elimination at that concn.
R.A = R.E
R.E = CL × Cp
R.A = CL × Cpss
– Maintainance Dose rate = CL × Cpss.
• Determination of CL .
– By AUC (Trapezoidal Rule).
– AUC is bigger smaller the CL.
– For Oral admn
CL = F × Dose
AUC
– Longer the CL Lower the t1/2 .
t1/2 ∞ Vd/CL t1/2 = 0.693Vd
CL
RENAL DRUG ELIMINATION
For Drugs that are not metabolized & are Cleared renally
unchanged.
Dg CL ∞ Cr CL
Drug By Metabolism By Renal CL
Digoxin Unchanged
Phenytoin Metabolized
Enalapril Active Unchanged
DRUG CL & RENAL FUNCTION
• Fu (fraction excreted unchanged).
Fu is an index describing the fraction excreted unchanged
through the kidneys.
An fu = 1. it describes a Drug totally Cleared renally
unchanged.
An fu = 0. means without Renal Elimination.
An fu = 0.5 mixed Elimination.( B/n 1-0 )
DOSING IN RENAL IMPAIRMENT
fu =1 fu =0
Drug CL
Cr CL Cr CL
Dose should be reduced in
direct proportion to the degree No Dose reduction
of impairement in CrCL.
If CrCL is half normal
Dose should be half normal.
fu = 0.5
• if CrCL is half normal that fraction of
the dose should be halved. The meta
Drug CL
-bolized fraction should be unchanged
so the total dose – 75% of normal.
Cr CL
FACTORS AFFECTING RENAL CLEARENCE
• Physico-chemical properties of the Drugs
• Plasma concentration of the Drug
• Distribution & Binding characteristics of the Drug
• Urine pH
• Blood flow to the kidney
• Drug interactions
• Disease states
DOSING IN RENAL IMPAIRMENT
Def Drug excreted unchanged trough the kidney may need dose
adjustment.
• When ever any active Drug moiety is excreted renally unchanged,
dose adjustment in relation to renal function may be necessary,
especially if the Drug has low Therapeutic index.
CrCL of patient
Renal function (RF) =
CrCL of normal person
The required dose in patients with renal impairment can be calculated
by the simple formula:
Normal dose × RF
Dosing interval in hours can be computed from the following formula:
Normal interval (in hours)
RF
• By COCK CROFT & GAULT Equation:
CrCL (ML/Sec) = (140-age) × wt (kg)
50000 × (CL)(m mol/L)
• For females ( becoz of less muscle mass)
CrCL (ML/Sec) = (140-age) × wt (kg)
× 0.85
50000 × (CL)(m mol/L)
• For Obese patients
use ideal body wt. An approximation of this
replace 50000 by 815 for CrCL in ml/min.
CrCL (ml/min)= (140-age) × ideal body wt
815 × (CL)(m mol/L)
Equations are not valid for < 12 yrs children.
(Note: if CrCL is < 0.06mmol/L, use 0.6 in the eq.)
For Drugs 100% excreted unchanged by Kidney.
DR(Patient) Calculated CrCL
DR(normal) 1.5
In this Dose Rate (DR) is decreased in direct proportion to the
impairment in renal function.
E.g.: Gentamycin.
For Drugs < 100% excreted unchanged by Kidney.
DR(Patient) 1.5 CrCL
(1-fu) + fu ×(calculated )
DR(normal)
where,
1-fu = metabolized,
fu = fractional renal function.
The final decision is whether dose adjustment should be by
reducing the dose itself / by prolonging the dose intervel.
