altered pks in renal insufficiency

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

A Functional unit of Kidneys: Nephron:

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 extra-cellular fluid volume & osmolality Conserves important solutes Regulates acid-base balance Excretion of exogenous substance

Three Major Process of Elimination in Kidney:

Three Major Process of Elimination in Kidney 1. Glomerular filtration 2. Active tubular secretion 3. Active (or)passive tubular reabsorption

Glomerular Filtration:

Glomerular Filtration Glomerular filtration occurs in the Bowman’s 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:

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:

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 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:

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. CL R = 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). CL R = Rate of filtration+ Rate of secretion – Rate of reabsorption plasma drug concentration

Estimation of creatinine clearance:

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

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Cl cr = Rate of urinary excretion of creatinine Average serum creatinine concentration Normal value: 100-125ml/min for 1.73m 2 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 clearance U cr = urine creatinine concentration(mg/dl) V urine = volume of urine collected in ml S cr = serum creatinine T =time in min. of urine collection Crcl(ml/min)=(Ucr . V urine )/(Scr.T)

Comparison of creatinine clearance values:

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

Limitations of serum creatinine measurement:

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.

Cockcroft and Gault method::

Cockcroft and Gault method: According to this method creatinine clearance can be calculated by fallowing formulas. For males: Crcl est={(140-age)BW}/(72.S cr) For females: Crcl est={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:

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 <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:

Common Causes of Kidney Failure Hypertension 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 damage— eg , 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 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 :

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

Effect of renal disease on pharmacokinetics:

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.

Effect of renal disease on drug elimination:

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 the elimination characteristics of the drug. For many drugs CL E consists of renal(CL R ) and non renal(CL NR ) components. CL E = CL R + CL NR Non renal excretion includes Biliary excretion,Pulmonary excretion, salivery excretion etc..

Mechanisms of renal excretion of drugs :

Mechanisms of renal excretion of drugs

Effect of renal disease on drug metabolism:

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.

Effect of renal disease on drug distribution:

Effect of renal disease on drug distribution 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. Most acidic drugs bind to the bilirubin site on albumin. The reduced binding occurs when renal function is impaired for the fallowing reasons. Reduction in serum albumin concentration. Structural changes in binding sites. 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.

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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.

Effect of renal disease on drug absorption:

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.

Dose adjustment in renal disease:

Dose adjustment in renal disease In 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 clearance is <50-60mL/min. A moderate decrease in drug doses when creatinine clearance is < 25-30 mL /min. A substantial decrease in drug doses when creatinine clearance is <15mL/min.

Approaches for dose adjustment:

Approaches for dose adjustment Decrease 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.

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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 :

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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