altered pharmaco kinetics in renal disease

7/28/2019 Altered Pharmaco kinetics in Renal Disease

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ALTERED PHARMACOKINETICS

IN RENAL DISEASE

BY- VJ

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Contents Introduction

Renal clearance

Creatinine clearance

Renal impairment

Effect of renal impairment on pharmacokinetics Dose adjustment in renal disease

References

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A Functional unit of Kidneys: Nephron Kidney has 1 to 1.5 million

functional nephron

Receives 25% of thecardiac output out-of-which10% is filtered (ultrafiltrateis devoid of Grossparticulate matter &globular proteins)

Physiological functions ofkidneys are

Maintains extra-

cellular fluid volume&osmolality Conserves importantsolutes Regulates acid-basebalance

Excretion ofexogenous substance 3


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Three Major Process of Elimination in

Kidney

1.

Glomerular filtration

2. Active tubular secretion

3. Active (or)passive tubular reabsorption

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Glomerular Filtration

Glomerular filtration occurs in the Bowmans Capsule.

1100 ml/min blood flow in the renal artery out-of-which 125 ml/min of

ultra-filtrate is formed; it is called the glomerular filtration rate (GFR).

Most of this ultrafiltrate is re-absorbed: final urine volume formed is at 1-2

ml/min.

Glomerular filtration depends on Molecular weight.

Inulin (a fructose polymer of MW- 5,200), Physiologically inert, non-toxic,

neither destroyed or synthesized nor stored within the kidney easily

measured in plasma & urine. Only filtered, no secretion or re-absorptionhence a measure of GFR.

Creatinine,inulin,mannitol,sodium thio sulphate are used to estimate GFR

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Active tubular secretion

It is a carrier mediated process which requires energy for

transportation of compounds against the concentration

gradient. The system is capacity-limited and saturable.

Active tubular secretion occurs in the proximal tubule

region of the nephron.

Para amino hippuric acid and iodopyracet are used to

determine active secretion.

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Tubular reabsorption

Tubular reabsorption is the process by which the solutes

and water removed from the tubular fluid andtransported in to blood.

Tubular reabsorption occurs in two processes.

1. Active process

2. passive process

Tubular reabsorption results in an increase in the half-

life of a drug.

Active tubular reabsorption is conducted by carriers and

pumps..

Passive tubular reabsorption is influenced by the pH of

the urine ,the pka of drug molecule.

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Renal clearance

Renal clearance is the volume of blood or plasma which iscompletely cleared of the unchanged drug by the kidney per unittime.

CLR= Rate of urinary excretion

Plasma drug concentration

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

CLR= Rate of filtration+ Rate of secretion Rate of reabsorptionplasma drug concentration

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Estimation of creatinine clearance

The method recommended by the Food and drug Administration to

estimate renal function for the purposes of drug dosing is tomeasure creatinine clearance(crcl).

Creatinine is a by-product of muscle metabolism that is primarily

eliminated by glomerular filtration rate .Because of this property ,it

is used to measure glomerular filtration rate..

Creatinine clearance rates can be measured by collecting urine for

a specified period and collecting a blood sample for

determination of serum creatinine at the mid point of the

concurrent urine collection time

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Clcr= Rate of urinary excretion of creatinine

Average serum creatinine concentration

Normal value: 100-125ml/min for 1.73m2 body surface area

Moderate renal failure: 20-50ml/min

Severe renal failure : less than 10ml/min

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Eliminated only by the kidney

Freely filtered Good approximation

Neither secreted nor reabsorbed.

Easily and accurately measured

Why do we use creatinine for estimating glomerular filtration rate ?

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Formula for estimating creatinine clearance

as per FDA

Crcl = Creatinine clearanceUcr = urine creatinine concentration(mg/dl)

Vurine= volume of urine collected in mlScr = serum creatinineT =time in min. of urine collection

Crcl(ml/min)=(Ucr . Vurine)/(Scr.T)

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Comparison of creatinine clearance values

Creatinine clerance values condition

100-125 ml/min

20- 50 ml/min 10>ml/min

Normal

moderate renal failure severe renal failure

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Limitations of serum creatinine measurement

(a) The relationship between the serum creatinine level and ClCr

(GFR) also depends on the endogenous production of creatinine by

muscle metabolism, which in turn depends largely on muscle bulk.

Eg. The elderly have less skeletal muscle than do younger persons, as

so an elderly person with the same serum creatinine level as a

young person can still have a low Clcr (GFR). Ie. an elderly person can

have renal impairment, despite a normal serum creatinine level.

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Cockcroft and Gault method: According to this method creatinine clearance can be

calculated by fallowing formulas.

For males: Crclest={(140-age)BW}/(72.Scr)

For females: Crclest={0.85(140-age)BW}/(72.Scr)Crcl = ml/min

Body weight = kg

serum creatinine= mg/dl

Limitations: Should be used in adults aged 18years and older.

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Renal impairment

The 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.

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GFR


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Common Causes of Kidney Failure

Hypertension

Chronic overloading of the kidney with f luid and electrolytes maylead to kidney insufficiency.

Diabetes mellitus

The disturbance of sugar metabolism and acid-base balance may lead

to or predispose a patient to degenerative renal disease.

Nephrotoxic drugs/metals

Certain drugs taken chronically may cause irreversible kidneydamageeg, the aminoglycosides, phenacetin, and heavy metals, suchas mercury and lead.

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Hypovolemia

Any condition that causes a reduction in renal blood flow will eventually

lead to renal ischemia and damage.

Neophroallergens

Certain compounds may produce an immune type of sensitivity reaction

with nephritic syndromeeg, quartan malaria nephrotoxic serum.

Uremia generally reduces glomerular filtration and secretion, which lead to

decrease in renal drug excretion resulting in a longer elimination half-life the

administred drug.

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Drug excretion Many studies shown that there is a linear relationship

between the renal clearance of a drug and creatinine

clearance in patients with varying degrees of renalfunction.

A=Drug specific constant

patients with renal disease also excrete lessunchanged drug in the urine than patients withnormal renal function.

Renal clearance=A* Creatinine clearance

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Effect of renal disease on pharmacokinetics

Pharmacokinetic processes such as drug distribution(including volume

of distribution and renal excretion),and elimination ( biotransformation

and renal excretion) altered by renal impairment.

Therapeutic and toxic responses 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, metbolism, elimination is as fallows. Acute diseases or trauma to the kidney can cause uremia, in which

glomerular filtration is impaired or reduced, leading to accumulation of

excessive fluid and blood nitrogenous products in the body.

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Effect of renal disease on drug elimination

The effect of renal disease on the elimination of a drug

depends on the renal status of the patient and theelimination characteristics of the drug.

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

CLE = CLR+ CLNR

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

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Mechanisms of renal excretion of drugs

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Effect of renal disease on drug metabolism

Most 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 clearance of the drug.

The impact of impaired renal function on drug metabolism is

dependent on the metabolic pathway.

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Effect of renal disease on drug distribution

Impaired renal function is associated with important changes inthe 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 forthe fallowing reasons.

a) Reduction in serum albumin concentration.

b) Structural changes in binding sites.

c) Displacement of drug from albumin binding sites by organic

molecules that accumulate in uremia.

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For example phenytoin is an acidic drug showing changes in kinetics in

impaired renl function.

Due to the reduced protein binding volume of distribution is increased. 27


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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.

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Effect of renal disease on drug absorption

Impaired renal function will result in increasedbioavailability of drugs exhibiting first-passmetabolism when the function of drug metabolizingenzymes is compromised.

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Dose adjustment in renal disease

In the renal disease, the renal clearance and elimination rate arereduced, the elimination half-life is increased and the volume ofdistribution is altered.

The half- lives of some drugs are changed sufficiently in patients

with impaired renal function to warrant change in the usualdosage regimen to prevent accumulation of the drug in the bodyto toxic levels.

Generally, one should consider a possible, modest decrease in drugdoses when creatinine clearance is


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Approaches for dose adjustment

Decrease the drug dose and retain the usual dosageinterval.

Retain the usual dose and increase the dosage

interval. Decrease the dosage and prolong the dosage interval.

The dosage change is usually proportional to therelative difference in half-life between the patients

with renal disease and the person with normal renalfunction.

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Patients with renal failure sometimes need loading doses

because the time required to reach steady state with a particulardrug may be much longer than in patients with normal function.

This is particularly important when planning antibiotic or cardiac

glycoside therapy.

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.

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References

Applied biopharmaceutics and pharmacokinetics Leon shargel.

Gibaldi Milo.Pharmacokinetic Variability-Disease.In:Biopharmaceutics

and ClinicalPharmacokinetics.

Applied clinical pharmacokinetics LARRY A.BAUER.

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altered pharmaco kinetics in renal disease

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