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Contents
Introduction Renal clearance
Creatinine clearance
Renal impairment Effect of renal impairment on pharmacokinetics
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-absorption hence a measure of GFR. Creatinine,inulin,mannitol,sodium thio sulphate are used to estimate GFR
Active tubular secretion occurs in the proximal tubule region of the nephron.
Tubular reabsorption
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 halflife 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
Renal clearance is the volume of blood or plasma which is
completely cleared of the unchanged drug by the kidney per unit time. 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
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
Clcr=
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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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
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10>ml/min
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(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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Renal impairment
The kidney is an important organ in regulating body fluids,
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 6089 mL/min/1.73 m2 could be normal from approximately 8 weeks to 1 year of age and in older individuals.
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Chronic overloading of the kidney with fluid and electrolytes may lead 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 kidney damageeg, the aminoglycosides, phenacetin, and heavy metals, such as mercury and lead.
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Hypovolemia Any condition that causes a reduction in renal blood flow will eventually
lead to
Neophroallergens Certain compounds may produce an immune type of sensitivity reaction with nephritic syndromeeg, quartan malaria nephrotoxic serum.
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 renal function.
Renal clearance=A* Creatinine clearance
A=Drug specific constant patients with renal disease also excrete less unchanged drug in the urine than patients with normal renal function.
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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
glomerular filtration is impaired or reduced, leading to accumulation of excessive fluid and blood nitrogenous products in the body.
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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..
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Most acidic drugs bind to the bilirubin site on albumin. The reduced binding occurs when renal function is impaired for
b)
c)
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For example phenytoin is an acidic drug showing changes in kinetics in impaired renl function.
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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bioavailability of drugs exhibiting first-pass metabolism when the function of drug metabolizing enzymes is compromised.
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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.
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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.
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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.
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THANK YOU
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