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Chlinical Pharmacokinetics on Renal Failure Patients

IntroductionChronic kidney disease is a common,

progressive illness that is becoming a global public health problem.

In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination.

(Roger K. Verbeeck, 2009: 2)

Three major process of Elimination in Kidney1. Glomerulus filtration2. Active tubulus

secretion3. Active tubulus

reabsorption

Renal clearanceRenal clearance is the volume of blood or

plasma which is completely of the unchanged drug by the kidney per unit time.

CLR =

Renal clearance is the ratio of “sum of glomerular filtration and secretion minus rate of reabsorption” to “plasma drug concentration (c)”.

CLR =

(Samudrala Vijay, 2011:8)

If renal clearance exceeds drug filtration rate, there is net renal tubular secretion of the drug.

If renal clearance is less than drug filtration rate, there is net renal tubular reabsorption of the drug.

(Atkinson, 1999: 5)

Creatinine clearanceClCl =

Normal value: 100-125 ml/min for 1.73m2 body surface areaModerate renal failure: 20-50 ml/minSevere renal failure: less than 10 ml/min

(Samudrala Vijay, 2011:10)

Renal impairmentThe kidney is an important organ in

regulating body fluids, removal of metabolic waste, electrolyte balance and drug excretion from the body.

Impairment or degeneration of kidney function affects the pharmacokinetics of the drugs.

Some of the common causes for kidney failure include disease, injury, and drug intoxication.

Effect of Renal Disease on PharmacokineticsPharmacokinetic processes such as drug

distribution (including volume of distribution and renal excretion) altered by renal impairment.

Therapeutic and toxic respones may altered as a result of changes in drug sensitivity at the receptor site.

The effect of renal disease on pharmacokinetic processes such as absorption, distribution, metabolism, elimination is as follows.

Acute diseases or trauma to the kidney can cause uremia, in which glomerular filtration is impaired ore reduced, leading to accumulation of excessive fluid and blood nitrogenous products in the body.

(Samudrala Vijay, 2011:21)

Effect of renal disease on drug absorption

Impaired renal function will result in increased bioavailability of drugs exhibiting first-pass metabolism when the function of drug metabolizing enzymes is compromised.

(Roger K.Verbeeck, 2009:5)

Effect of renal disease on drug distributionImpaired renal function is associated with

important changes in the binding of drugs to plasma proteins.

Protein binding in serum from uremic patients is decreased.

Most acidic drugs bind to the bilirubin site on albumin.

The reduced binding occurs when renal function is impaired for the following reasons.

a. Reduction in serum albumin concentrationb. Structural changes in binding sitesc. Displacement of drug from albumin binding sites

by organic molecules that accumulate in uremia.

The volume of distribution of a drug can decrease if compounds normally excreted by the kidney accumulate to the extent that displacement of drug from tissue binding sites occurs.

The decrease of albumin will increase the volume of distribution.

(Samudrala Vijay, 2011:26)

Effect of renal disease on drug eliminationThe effect of renal disease on the elimination

of a drug depends on the renal status of the patient and the elimination characteristics of the drug.

For many drugs CLE consists of renal (CLR) and non renal (CLNR) components.

Non renal excretion includes Biliary excretion, Pulmonary excretion, salivery excretion, etc.

CLE = CLR + CLNR

The total clearance (CLE) and the dose of drug can influence the consentration of steady-state (Css) in the blood.

The decrease of total clearance value will increase the concentration of steady-state (Css) in the blood.

Dose adjustments may be done by:Reducing the drug doseLengthening the dosing interval

(Atkinson, 1999:4)

Effect of renal disease on drug metabolismMost drugs are not excreted by the kidneys

unchanged but are biotransformed to metabolites that are then excreted.

Renal failure retard the excretion of metabolites.

Renal failure alteres the metabolic of clearance of the drug.

The impact of impaired renal function on drug metabolism is dependent on the metabolic pathway.

(Atkinson, 1999:5)

Monitoring Patients Renal Function

1. Patient’s clinical condition2. Biochemical data3. Other biochemical abnormalities

Classification of Renal Failure

Classification GFR (ml/min/1.73m2) Serum Creatinine (μmol/L)

Mild 20 to 50 150 to 300

Moderate 10 to 20 300 to 700

Severe < 10 > 700

Dosing in renal impairmentPredicting GFR using serum and urine

creatinine concentrationsCockroft and Gault Equation

GFR =

F = 1.23 for males ans 1.04 for females

Examples – estimating renal function using serum creatinine

Patient detailsMr JB 75 years old gentleman admitted to the renal

unit.Ideal body weight = 80 kg, serum creatinine = 400

μmol/LUrine creatinine = 3.7 mmol/L, 24 hr urine volume

= 2400mlsClassification GFR (mls/min/1.73m2)

Serum creatinine (μmol/L)

Mild 20 to 50 150 to 300

Moderate 10 to 20 300 to 700

Severe < 10 > 700

Moderate

10 to 20

300 to 700

GFR =

=

= 16 ml/min = Moderate renal impairment

Dose adjustment in renal diseaseIn the renal disease, the renal clearance and

elimination rate are reduced, the elimination half-life is increased and the volume of distribution is altered.

The half-lives of some drugs are changed sufficiently in patients with impaired renal function to warrant change in the usual dosage regimen to prevent accumulation of the drug in the body to toxic levels.

Generally, one should consider a possible, modest decrease in drug doses when creatinine is < 50-60mL/min

A moderate decrease in drug dose when creatinine clearance is < 25-30 mL/min.

A substantial decrease in drug doses when creatinine clearance is < 15 mL/min.

Approaches for dose adjustmentDecrease the drug dose and retain the usual

dosage interval.Retain the usual dose and increase the

dosage interval.Decrease the dosage and prolong the dosage

interval.The dosage change is usually proportional to

the relative difference in half-life between the patients with renal disease and the person with normal renal function.

Patients with renal failure sometimes need loading doses because the time required reach steady state with a particular drug may be much longer than in patients with normal function. This is particularly important when planning antibiotic or cardiac glycoside theraphy.

When dosing interval extension is applied in severe renal disease to drugs with short half-lives, like the aminoglycoside antibiotics, prolonged the periods of serum concentrations below the therapeutic range may result.

(Samudrala Vijay, 2011:30-33)

ReferencesVerbeeck, R.K. 2009. Pharmacokinetics and

Dosage Adjustment in Patients with Renal Dysfunction. Springer: Verlag

Vijay, Samudrala. 2011. Altered Pharmacokinetics In Renal Insuffiency. Warangal: Departement of Pharmaceutics Balaji Institute of Pharmaceutical Sciences

Atkinson. 1999. Effect of Renal Disease on Pharmacokinetics

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