Transcript Slide 1

A seminar on
ALTERED KINETICS IN RENAL DISEASES
BY
A.SRILATHA
(M.Pharm I sem )
Department of Pharmaceutics
BLUE BIRDS COLLEGE OF PHARMACY
(Affiliated to Kakatiya University)
Bheemaram, Warangal.
CONTENTS
 Introduction
 Glomerular Filtration Rate
 Creatinine Clearance
 Pharmacokinetic Parameters
 Dosage Regimen
 Drugs effect on Binding
 Conclusion
 References
Introduction
Pharmacokinetics involves the kinetics of drug absorption, distribution &
elimination(excretion & metabolism).
Statistical methods are used for pharmacokinetic parameter estimation and
data interpretation.
Disease affects the way drugs are absorbed,distributed,excreted and
metabolized. Renal disease directly affects drug excretion but also affects
drug binding. Hepatic disease affects drug metabolism.
Renal dysfunction greatly impairs the elimination of drugs especially
those that are primarily excreted by the kidneys. Some of the causes
of renal failure are hypertension, diabetes mellitus, hypovolemia,
pyelonephritis, nephrotoxic agents such as amino glycosides,
phenacetin and heavy metals such as lead and mercury.
Uraemia characterized by impaired GFR and accumulation of fluids
and protein metabolites also impairs renal clearance of drugs. In both
these conditions the half lives of the drugs are incresed, as a result
drug accumulation and toxicity may result.
Glomerular filtration rate
Several drugs and endogenous substances have been used as markers to measure GFR.These
markers are carried to the kidney by the blood via the renal artery and are filtered at the
glomerulus.
Criteria necessary for using a drug to measure GFR
 The drug must be freely filtered at the glomerulus.
 The drug must not be reabsorbed nor actively secreted by the renal tubules.
 The drug should not be metabolized.
 Drug should not bind to plasma proteins.
Inulin, a fructose poly saccharide fulfills most of the criteria listed above and is
therefore used as a standard reference for the measurement of GFR.
Clearance Creatinine is used most extensively as a measurement of GFR.
In humans, creatinine is mainly filtered at the glomerulus with no reabsorption.
Blood urea nitrogen (BUN) is a commonly used clinical diagnostic laboratory
test for renal disease, urea is the end product of protein catabolism and is
excreted through the kidney, normal BUN ranges from 10-20mg/dl.
Higher BUN levels indicate the presence of renal disease.
Creatinine Clearance
It is an endogenous amine produced as a result of muscle catabolism.
Excreted unchanged in the urine by GFR.An advantage of this test is that it
can be correlated to steady state concentration of creatinine in plasma and
no needs no collection of urine.
Normal values adjusted to 1.73m2 body surface area range from 100125ml/min.
Creatinine clearance values of 20 -50 ml/min, indicates moderate renal
failure, values less than 10ml/min indicates severe renal failure.
Estimation of creatinine clearance
Population
Creatinine
clearance/
Serum creatinine
Serum creatinine
Adults(20-100yrs)
Males
(140-age)*wt/ 72*sc
1.23*(140-age)*wt/sc
Females
(140-age)*wt/ 85*sc
1.04*(140age)*wt/sc
Children(1-20yrs)
5
0.48*ht/ sc *(wt/70)0.7 42.5*ht /sc*(wt/70)0.7
TOTAL CLEARANCE,
80
60
40
C
B
A
20
3
4
5
6
8
10
15
20
30
BIOLOGIC HALF-LIFE
100
40
80
120
CREATININE CLEARANCE,
Eg: Relationship between total clearance and renal function (creatinine
clearance) for three drugs that are excreted in the urine to different degrees in
patients with normal renal function. Vertical line shows clearances and halflives when renal function is reduced to one-sixth of normal. Renal disease has
the largest effect on drug A and the smallest effect on drug C.
Nomograms
 A nomogram is a chart that displays values of three related variables in
vertical columns in such a way that when a ruler is placed across values in
any two columns the corresponding values of the variables in the third
column can be read directly from chart.
 Nomograms are used for the calculation of drug dosage regimens in patient
with renal disease.
Pharmacokinetic parameters
 Drug clearance: the volume of plasma cleared of drug per unit time. It
determines the maintenance dose rate, required to maintain a plasma
concentration.
 Clearance=rate of elimination/plasma concentration.
 Volume of distribution: it determines the loading dose(the dose required to
achieve a target plasma concentration).
 Half-life: The time for the concentration of drug in plasma(or the amount of
drug in the body) to halve.
Relationship between t1/2’ Vd and Cl
t ½ =0.693 Vd/Cl.
It indicates that the half life is dependent on Vd and Cl.
vd and Cl are the independent variables.
larger Vd
Cp
largerCl
Time
Modification of Pharmacokinetic parameters
 Patients with renal insufficiency often show modifications of pharmacokinetic
parameters which do not bear a direct relationship with the decreasing of GFR.
 Some drugs often show alteration of the volume of distribution.
 Eg: Oedema disturbs the behaviour of drugs, the volume of distribution of
wish approximately equals the extracellular space, such as sulphonamides .
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Drugs elliminated almost entirely by the kidneys
Drug cl
Creatinine clearance
Drugs elimination entirely unchanged by the kidney (fu=1) (e.g.gentamicin)
for these drugs, doses should be reduced in direct proportion to the degree
of impairment in creatinine clearance.
Drugs eliminated almost entirely by extra renal mechanism
Drugs cl
Creatinine clearance
Drugs eliminated entirely by metabolism (fu=0) (e.g.phenytoin)
Drugs that are eliminated partly by the kidney and partly by the metabolism
Drug cl
Creatinine clearance
Drug eliminated by both metabolism and by renal elimination (fu=0.5)
(e.g.captopril).
Dosage regimens
 The stategy for treating patients with drugs is to give sufficient
amounts that the required therepeutic effect.
 Increase of dosage intervals without changing the dose: it is
useful for the drug which are having long serum half life.
 Reduction of the dose without changing the frequency of
administration : the amount of drug in the body during a given
dosage interval will be the same for both types of patient, this is
reached by reducing the maintenance dose .
 Loading dose: if the initial dose is the same as the maintenance
dose,the height of peak plasma concentrations will increase
progressively to reach the steady state blood level after 6 half
lives.
Disease effects on drug binding
 The half life of most drugs depends strongly on tissue binding and protein




binding.
Albumin is considered to be the most important binding protein in plasma for
acid and neutral drugs,AAG is of prime importance in the plasma binding of
basic drugs.
Protein binding decreases the renal excretion of drugs and enhances the
biological half life.
Tetracycline's are excreted mainly by glomerular filtration, these drugs bind
to protein and results in decreased renal excretion.
In hypoalbuminaemia an acidic drug such as phenytoin will have a lower total
drug concentration because of lower protein binding.
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Contraindicated drugs
 Kidneys already suffering from a nephropathy have an increased
sensitivity to nephrotoxic drugs such as some antibiotics, phenyl
butazone, gold salts, mercurial diuretics and anaesthetics.
Conclusion
Drugs that are extensively excreted unchanged in urine, alteration of the
renal function will alter the drugs elimination rate. Many drugs or their
metabolites are eliminated partly or completely by the kidneys, thus the
usual dosage regimens may need to be adjusted to provide safe and effective
treatment for patients with impaired renal function. So i conclude that
determination of renal function is important to monitor the dosage regimen.
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REFERENCES
Gibaldi ,M, “Biopharmaceutics and Clinical Pharmacokinetics”, fourth
edition, 272-305,(2005).
Notari, E, Robert, “Biopharmaceutics and Clinical pharmacokinetics”,
fourth edition, 349-400,(1987).
Rowland M,Tozer N,Thomas, “Clinical Pharmacokinetics and
Applications” third edition,248-267,(2007).
Shargel, L, Andrew, Y, “Applied Biopharmaceutics and Pharmacokinetics",
fourth edition,531-552,(1999).
Tipnis, H.P,Amrita Bajaj “Principles and Applications of Biopharmaceutics
and Pharmacokinets”,260-272,(2002).
Venkateshwarlu V, “Biopharmaceutics and Pharmacokinetics”,110130,(2004).
www.drug interaction centre.com
www.Scottish biomedical.com
www.pharma info.net