ALTERED PHARMACOKINETICS IN RENAL INSUFFICIENCY

BY SAMUDRALA VIJAY KUMAR M.PHARM(1st SEM )

DEPARTMENT OF PHARMACEUTICS BALAJI INSTITUTE OF PHARMACEUTICAL SCIENCES NARSAMPAET, WARANGAL.

Contents
y Introduction y Renal clearance y Creatinine clearance y Renal impairment y Effect of renal impairment on pharmacokinetics y Dose adjustment in renal disease y References

A Functional unit of Kidneys: Nephron

Kidney has 1 to 1.5 million functional nephron Receives 25% of the cardiac output out-of-which 10% is filtered (ultrafiltrate is devoid of Gross particulate matter & globular proteins) Physiological functions of kidneys are Maintains extracellular fluid volume &osmolality Conserves important solutes Regulates acid-base balance Excretion of exogenous substance

Three Major Process of Elimination in Kidney

1. Glomerular filtration 2. Active tubular secretion 3. Active (or)passive tubular reabsorption

Glomerular Filtration
y Glomerular filtration occurs in the Bowmans Capsule. y 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.
y Glomerular filtration depends on Molecular weight. y 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-absorption hence a measure of GFR.
y Creatinine,inulin,mannitol,sodium thio sulphate are used to estimate GFR

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.

Tubular reabsorption
y Tubular reabsorption is the process by which the solutes

and water removed from the tubular fluid and transported 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.

Renal clearance
y Renal clearance is the volume of blood or plasma which is
completely cleared of the unchanged drug by the kidney per unit time. y CLR = Rate of urinary excretion
Plasma drug concentration

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

CLR = Rate of filtration+ Rate of secretion Rate of reabsorption plasma drug concentration

Estimation of creatinine clearance

 The method recommended by the Food and drug Administration to

estimate renal function for the purposes of drug dosing is to measure 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

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

Why do we use creatinine for estimating glomerular filtration rate ?

Eliminated only by the kidney Freely filtered Good approximation Neither secreted nor reabsorbed. Easily and accurately measured

Formula for estimating creatinine clearance as per FDA

Crcl(ml/min)=(Ucr . V urine)/(Scr.T)

Crcl = Creatinine clearance Ucr = urine creatinine concentration(mg/dl) Vurine= volume of urine collected in ml Scr = serum creatinine T =time in min. of urine collection

Comparison of creatinine clearance values

Creatinine clerance values

y 100-125 ml/min y 20- 50 ml/min y 10>ml/min

condition y Normal y moderate renal failure y severe renal failure

Limitations of serum creatinine measurement

y (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.

Cockcroft and Gault method:

y According to this method creatinine clearance can be

calculated by fallowing formulas. y For males: Crclest={(140-age)BW}/(72.Scr)

y

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 18 years and older.

Renal impairment
y The kidney is an important organ in regulating body fluids,

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

y Impairment (or) degeneration of kidney function affects the

pharmacokinetics of the drugs.

y some of the common causes for kidney failure include disease,

injury,and drug intoxication.

GFR <60 mL/min/1.73 m2 for 3 months classified having chronic kidney disease, irrespective of the presence or absence of kidney damage.

GFR <90 mL/min/1.73 m2 would be abnormal in a young adult. GFR of 60 89 mL/min/1.73 m2 could be normal from approximately 8 weeks to 1 year of age and in older individuals.

Common Causes of Kidney Failure

y Hypertension

Chronic overloading of the kidney with fluid and electrolytes may lead to kidney insufficiency.
y Diabetes mellitus

The disturbance of sugar metabolism and acid-base balance may lead to or predispose a patient to degenerative renal disease. y Nephrotoxic drugs/metals Certain drugs taken chronically may cause irreversible kidney damage eg, the aminoglycosides, phenacetin, and heavy metals, such as mercury and lead.

 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 syndrome eg, 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.

Drug excretion
y 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 renal function.
enal clearance=A* reatinine clearance

A=Drug specific constant patients with renal disease also excrete less unchanged drug in the urine than patients with normal renal function.

Effect of renal disease on pharmacokinetics

y Pharmacokinetic processes such as drug distribution(including volume

of distribution and renal excretion),and elimination ( biotransformation and renal excretion) altered by renal impairment.
y Therapeutic and toxic responses may altered as a result of changes in

drug sensitivity at the receptor site.

y The effect of renal disease on pharmacokinetic processes such as

absorption, distribution, metbolism, elimination is as fallows.

y 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.

Effect of renal disease on drug elimination

y The 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.

CLE = CLR + CLNR

 Non renal excretion incl excretion etc..

es

iliary excretion,

l onary excretion, salivery

Mechanisms of renal excretion of drugs

Effect of renal disease on drug metabolism

y Most drugs are not excreted by the kidneys unchanged but are
biotransformed to metabolites that are then excreted.
y Renal failure retard the excretion of metabolites. y Renal failure alteres the metabolic clearance of the drug. y The impact of impaired renal function on drug metabolism is

dependent on the metabolic pathway.

Effect of renal disease on drug distribution

y Impaired renal function is associated with important changes in

the binding of drugs to plasma proteins.



Protein binding in serum from uremic patients is decreased.

y Most acidic drugs bind to the bilirubin site on albumin. y The reduced binding occurs when renal function is impaired for

the fallowing reasons.

a) b) c)

Reduction in serum albumin concentration. Structural changes in binding sites. Displacement of drug from albumin binding sites by organic molecules that accumulate in uremia.

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.

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.

Eff ct of r
y I

al dis as on drug absor tion

aire renal f nction ill res lt in increase ioavaila ility of r s ex i iting first- ass eta olis en t e f nction of r g eta olizing enzy es is compromise .

Dose adjustment in renal disease

y In the renal disease, the renal clearance and elimination rate are

y y y

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 clearance is <50-60mL/min. A moderate decrease in drug doses when creatinine clearance is <2530 mL/min. A substantial decrease in drug doses when creatinine clearance is <15mL/min.

Approaches for dose adjustment

y Decrease the drug dose and retain the usual dosage

interval. y Retain the usual dose and increase the dosage interval. y Decrease the dosage and prolong the dosage interval. y 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 to 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 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.

References
y Applied biopharmaceutics and pharmacokinetics Leon shargel.

y Gibaldi Milo.Pharmacokinetic Variability-Disease.In:Biopharmaceutics

and

ClinicalPharmacokinetics.

y Applied clinical pharmacokinetics LARRY A.BAUER.

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