Dose adjustment in Renal & Hepatic failure

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Presentation Description

Renal impairment, Pharmacokinetic considerations, General approach for dosage adjustment in Renal disease, Measurement of Glomerular Filtration rate and creatinine clearance, Dosage adjustment for uremic patients, Extracorporeal removal of drugs, Effect of Hepatic disease on pharmacokinetics, Useful for PharmD students in India and abroad

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Dosage adjustment in renal and hepatic failure:

Dosage adjustment in renal and hepatic failure Dr. P. R. Deshpande

Overview :

Basics of kidney Hazards of uremia Longer t1/2 Metabolic changes Distribution and excretion Therapeutic and toxic effects may be altered Pyelonephritis P. malariae Common causes of kidney failure Pyelonephritis HTN DM Nephrotoxic drugs, hypovolemia , allergens Overview

Slide 3:

Secondary uremic features PK considerations in RF BA Vd Cl Limitations General approaches in dosing RF pt CrCl accurate PK constant Dose Adjustment Based on Drug Clearance Changes in the Elimination Rate Constant

Slide 4:

Measurement of GFR Criteria Inulin Cr.Cl Why not BUN? Cr. Cl Def, unit, precautions, normal value CG formula

Slide 5:

The kidney is an important organ in regulating body fluids, electrolyte balance, removal of metabolic waste, and drug excretion from the body. Impairment or degeneration of kidney function affects the PK of drugs. Some of the more common causes of kidney failure include disease, injury, and drug intoxication.

Hazards of uremia:

Acute diseases or trauma to the kidney can cause uremia (urea in the blood), in which glomerular filtration is impaired or reduced, leading to accumulation of excessive fluid and blood nitrogenous products in the body. Uremia generally reduces glomerular filtration and/or active secretion, which leads to a decrease in renal drug excretion resulting in a longer elimination half-life of the administered drug. Hazards of uremia

Slide 7:

In addition to changing renal elimination directly, uremia can affect drug PK in unexpected ways . For example, declining renal function leads to disturbances in electrolyte and fluid balance , resulting in physiologic and metabolic changes that may alter the PKPD of a drug. PK processes such as drug distribution (including both the Vd and protein binding) and elimination (including both biotransformation and renal excretion) may also be altered by renal impairment. Both therapeutic and toxic responses may be altered as a result of changes in drug sensitivity at the receptor site. Overall, uremic patients have special dosing considerations to account for such PKPD alterations.

Pyelonephritis :

It is an inflammation of the kidney tissue, calyces, and renal pelvis . It is commonly caused by bacterial infection that has spread up the urinary tract or travelled through the bloodstream to the kidneys. A similar term is " pyelitis " which means inflammation of the pelvis and calyces. In other words, pyelitis together with nephritis is collectively known as pyelonephritis . Severe cases of pyelonephritis can lead to pyonephrosis (pus accumulation around the kidney), sepsis (a systemic inflammatory response of the body to infection), kidney failure and even death. Pyelonephritis

P. malariae:

It causes fevers that recur at approximately three-day intervals (a quartan fever), longer than the two-day (tertian) intervals of the other malarial parasites, hence its alternative names quartan fever and quartan malaria. P. malariae

Secondary uremia- features:

Anemia CV system (fluid retention) Respiratory system: pulmonary congestion, edema GIT: NVD, ulcers Skeletal: osteomalacia , osteitis fibrosa Secondary uremia- features

PK considerations:

Uremic patients may exhibit PK changes in BA, Vd , clearance . PK considerations

Oral BA:

The oral BA of a drug in severe uremia may be decreased as a result of disease-related changes in GI motility and pH caused by nausea, vomiting, and diarrhea. Mesenteric (small intestine) blood flow may also be altered. However, the oral BA of a drug such as propranolol (which has a high first-pass effect) may be increased in patients with renal impairment as a result of the decrease in first-pass hepatic metabolism. Oral BA

Protein binding and Vd:

The apparent Vd depends largely on drug protein binding in plasma or tissues and total body water . Renal impairment may alter the distribution of the drug as a result of changes in fluid balance, drug protein binding, or other factors that may cause changes in the apparent Vd . The plasma protein binding of weak acidic drugs in uremic patients is decreased, whereas the protein binding of weak basic drugs is less affected . The decrease in drug protein binding results in a larger fraction of free drug and an increase in the Vd . However, the net elimination half-life is generally increased as a result of the dominant effect of reduced glomerular filtration. Protein binding of the drug may be further compromised due to the accumulation of metabolites of the drug and accumulation of various biochemical metabolites, such as FFA and urea, which may compete for the protein-binding sites for the active drug. Protein binding and Vd

Clearance :

Total body clearance of drugs in uremic patients is also reduced by either a decrease in the GFR and possibly active tubular secretion or reduced hepatic clearance resulting from a decrease in intrinsic hepatic clearance. In clinical practice, estimation of the appropriate drug dosage regimen in patients with impaired renal function is based on an estimate of the remaining renal function of the patient and a prediction of the total body clearance. Clearance

Limitations :

A complete PK analysis of the drug in the uremic patient is not possible. Moreover, the patient's uremic condition may not be stable and may be changing too rapidly for PK analysis. Each of the approaches for the calculation of a dosage regimen have certain assumptions and limitations that must be carefully assessed by the clinician before any approach is taken. Dosing guidelines for individual drugs in patients with renal impairment may be found in various reference books. Limitations

General Approaches for Dose Adjustment in Renal Disease:

Most of these methods assume that the required therapeutic plasma drug concentration in uremic patients is similar to that required in patients with normal renal function. Uremic patients are maintained on the same C ∞ av after multiple oral doses or multiple IV bolus injections. For IV infusions, the same C SS is maintained. ( C SS is the same as C ∞ av after the plasma drug concentration reaches steady state.) General Approaches for Dose Adjustment in Renal Disease

Slide 19:

The design of dosage regimens for uremic patients is based on the PK changes that have occurred as a result of the uremic condition. Generally, drugs in patients with uremia or kidney impairment have prolonged elimination half-lives and a change in the apparent Vd . In less severe uremic conditions there may be neither edema nor a significant change in the apparent Vd . Consequently, the methods for dose adjustment in uremic patients are based on an accurate estimation of the drug clearance in these patients. Several specific clinical approaches for the calculation of drug clearance based on monitoring kidney function are presented later in this chapter. Two general PK approaches for dose adjustment include methods based on drug clearance methods based on t1/2

Dose Adjustment Based on Drug Clearance :

F= Fraction D=Dose Cl = clearance T=Time Dose Adjustment Based on Drug Clearance

Slide 21:

For patients with a uremic condition or renal impairment, total body clearance of the uremic patient will change to a new value, Cl u T . Therefore, to maintain the same desired C ∞ av , the dose must be changed to a uremic dose, D u 0 or the dosage interval must be changed to u , as shown in the following equation:

Dose Adjustment Based on Changes in the Ke:

Dose Adjustment Based on Changes in the Ke The overall elimination rate constant for many drugs is reduced in the uremic patient. A dosage regimen may be designed for the uremic patient either by reducing the normal dose of the drug and keeping the frequency of dosing (dosage interval) constant, or by decreasing the frequency of dosing (prolonging the dosage interval) and keeping the dose constant. Doses of drugs with a narrow therapeutic range should be reduced particularly if the drug has accumulated in the patient prior to deterioration of kidney function.

Slide 25:

When the elimination rate constant for a drug in the uremic patient cannot be determined directly, indirect methods are available to calculate the predicted elimination rate constant based on the renal function of the patient. The assumptions on which these dosage regimens are calculated include the following.

Slide 26:

The renal elimination rate constant (k R) decreases proportionately as renal function decreases. (Note that k R is the same as k e as used in previous chapters.) The nonrenal routes of elimination (primarily, the rate constant for metabolism) remain unchanged. Changes in the renal clearance of the drug are reflected by changes in the creatinine clearance.

Measurement of GFR:

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 . Several criteria are necessary to use 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 . The drug should not bind significantly to plasma proteins . The drug should not have an effect on the filtration rate nor alter renal function . The drug should be nontoxic . The drug may be infused in a sufficient dose to permit simple and accurate quantitation in plasma and in urine. Measurement of GFR

GFR by Inulin :

Therefore, the rate at which these drug markers are filtered from the blood into the urine per unit of time reflects the GFR of the kidney. Changes in GFR reflect changes in kidney function that may be diminished in uremic conditions. Inulin , a fructose polysaccharide, fulfills most of the criteria listed above and is therefore used as a standard reference for the measurement of GFR. In practice, however, the use of inulin involves a time-consuming procedure in which inulin is given by IV infusion until a constant steady-state plasma level is obtained. Clearance of inulin may then be measured by the rate of infusion divided by the steady-state plasma inulin concentration. Although this procedure gives an accurate value for GFR, inulin clearance is not used frequently in clinical practice. GFR by Inulin

GFR by CrCl:

The CrCl is used most extensively as a measurement of GFR. Creatinine is an endogenous substance formed from creatine phosphate during muscle metabolism. Creatinine production varies with the age, weight, and gender of the individual. In humans, creatinine is filtered mainly at the glomerulus , with no tubular reabsorption . However, a small amount of creatinine may be actively secreted by the renal tubules, and the values of GFR obtained by the creatinine clearance tend to be higher than GFR measured by inulin clearance. Creatinine clearance tends to decrease in the elderly patient. As mentioned in , the physiologic changes due to aging may necessitate special considerations in administering drugs in the elderly. GFR by CrCl

Why not BUN?:

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 levels range from 10 to 20 mg/ dL . Higher BUN levels generally indicate the presence of renal disease. Why not BUN?

Slide 31:

However, other factors, such as excessive protein intake, reduced renal blood flow, hemorrhagic shock, or gastric bleeding , may affect increased BUN levels. The renal clearance of urea is by glomerular filtration and partial reabsorption in the renal tubules. Therefore, the renal clearance of urea is less than creatinine or inulin clearance and does not give a quantitative measure of kidney function.

Serum Creatinine Conc. :

Under normal circumstances, creatinine production is roughly equal to creatinine excretion, so the serum creatinine level remains constant. In a patient with reduced glomerular filtration, serum creatinine will accumulate in accordance with the degree of loss of glomerular filtration in the kidney. The serum creatinine concentration alone is frequently used to determine creatinine clearance. Serum Creatinine Conc.

CrCl:

CrCl from the serum creatinine concentration is a rapid and convenient way to monitor kidney function. CrCl may be defined as the rate of urinary excretion of creatinine /serum creatinine . CrCl can be calculated directly by determining the patient's serum creatinine concentration and the rate of urinary excretion of creatinine . The approach is similar to that used in the determination of drug clearance. In practice, the serum creatinine concentration is determined at the midpoint of the urinary collection period and the rate of urinary excretion of creatinine is measured for the entire day (24 hr) to obtain a reliable excretion rate. CrCl is expressed in mL /min and serum creatinine concentration in mg/ dL or mg%. Other Cl Cr methods based solely on serum creatinine are generally compared to the creatinine clearance obtained from the 24-hour urinary creatinine excretion. CrCl

Slide 35:

Cr.Cl = rate of unrinary excretion of Cr./Serum conc of Cr. Creatinine is eliminated primarily by glomerular filtration. A small fraction of creatinine also is eliminated by active secretion and some nonrenal elimination. Therefore, Cl Cr values obtained from creatinine measurements overestimate the actual glomerular filtration rate. Cr. Cl has been normalized both to body surface area, using 1.73 m2 as the average, and to body weight for a 70-kg adult male. Creatinine distributes into total body water, and when clearance is normalized to a standard V D, similar drug half-lives in adults and children correspond to identical clearances. Creatinine clearance values must be considered carefully in special populations such as the elderly, obese, and emaciated (abnormally thin/weak) patients .

Slide 36:

In elderly and emaciated patients, muscle mass may have declined, thus lowering the production of creatinine . However, serum creatinine concentration values may appear to be in the normal range, because of lower renal creatinine excretion. Thus, the calculation of creatinine clearance from serum creatinine may give an inaccurate estimation of the renal function. For obese patient, generally defined as patients more than 20% over ideal body weight, IBW, creatinine clearance should be based on ideal body weight. Estimation of creatinine clearance based on total body weight, TBW, would exaggerate the Cl Cr values in the obese patient. Women with normal kidney function have smaller creatinine clearance values than men, approximately 80–85% of that in men with normal kidney function.

Slide 37:

Several empirical equations have been used to estimate lean body weight, LBW, based on the patient's height and actual (total) body weight (see ). The following equations have been used to estimate LBW in renally impaired patients: LBW (M)= 50kg+2.3kg for each inch over 5ft LBW (F)= 45.5kg+2.3kg for each inch over 5ft

Slide 38:

For the purpose of dose adjustment in renal patients, normal creatinine clearance is generally assumed to be between 100 and 125 mL /min per 1.73 m 2 for a subject of ideal body weight: for a female adult, Cl Cr = 108.8 ± 13.5 mL /1.73 m 2 , and for an average adult male, Cl Cr = 124.5 ± 9.7 mL /1.73 m 2 ( Scientific Table , 1973). Cr.Cl is affected by diet and salt intake. As a convenient approximation, the normal clearance has often been assumed by many clinicians to be approximately 100 mL /min.

CrCl in children :

CrCl = 0.55. body length (cm)/ Ccr The nomogram method of Siersback -Nielsen et al (1971) CrCl in children

Slide 41:

Nomogram for evaluation of endogenous creatinine clearance. To use the nomogram , connect the patient's weight on the second line from the left with the patient's age on the fourth line with a ruler. Note the point of intersection on R and keep the ruler there. Turn the right part of the ruler to the appropriate serum creatinine value and the left side will indicate the clearance in mL /min.

Dose Adjustment for Uremic Patients :

Dose Adjustment for Uremic Patients

Overview :

Doubt Loading dose Maintenance dose Basis in uremic patients Nomograms Fe method General clearance method Wagner method (total elimination rate constant) Dialysis Types PD HD Overview

Slide 46:

Factors affecting dialysis Drug related Water solubility Protein binding Mw Large Vd Machine related Blood flow rate Diasylate Dialysis membrane Transmembrane pressure

Loading dose:

A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level. Drugs which may be started with an initial loading dose include digoxin , teicoplanin , voriconazole and procainamide . Loading dose

Maintenance dose :

A maintenance dose is the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state. This is not to be confused with dose regimen, which is a type of drug therapy in which the dose [mg] of a drug is given at a regular dosing interval on a repetitive basis. Continuing the maintenance dose for about 4 to 5 half lives (t½) of the drug will approximate the steady state level. One or more doses higher than the maintenance dose can be given together at the beginning of therapy with a loading dose. Maintenance dose

Introduction :

Dose adjustment for drugs in uremic or renally impaired patients should be made in accordance with changes in PKPD of the drug in the individual patient. Active metabolites of the drug may also be formed and must be considered for additional pharmacologic effects when adjusting dose. The following methods may be used to estimate an initial and maintenance dose regimen. After initiating the dosage, the clinician should continue to monitor the PKPD of the drug. He or she should also evaluate the patient's renal function, which may be changing. Introduction

Basis for Dose Adjustment in Uremia :

The loading drug dose is based on the apparent Vd of the patient. It is generally assumed that the apparent Vd is not altered significantly, and therefore that the loading dose of the drug is the same in uremic patients as in subjects with normal renal function . The maintenance dose is based on clearance of the drug in the patient. In the uremic patient, the rate of renal drug excretion has decreased, leading to a decrease in total body clearance. Most methods for dose adjustment assume nonrenal drug clearance to be unchanged. Basis for Dose Adjustment in Uremia

Slide 51:

The fraction of normal renal function remaining in the uremic patient is estimated from creatinine clearance. After the remaining total body clearance in the uremic patient is estimated, a dosage regimen may be developed by decreasing the maintenance dose, increasing the dosage interval, or changing both maintenance dose and dosage interval. Although total body clearance is a more accurate index of drug dosing, the elimination half-life of the drug is more commonly used for dose adjustment because of its convenience . Clearance allows for the prediction of steady-state drug concentrations, while elimination half-life yields information on the time it takes to reach steady-state concentration.

Slide 52:

Nomograms are charts available for use in estimating dosage regimens in uremic patients. The nomograms may be based on serum creatinine concentrations, patient data (height, weight, age, gender), and the PK of the drug. Each nomogram has errors in its assumptions and drug database. Most methods for dose adjustment in renal disease assume that nonrenal elimination of the drug is not affected by renal impairment and that the remaining renal excretion rate constant in the uremic patient is proportional to the product of a constant and the creatinine clearance, Cl Cr:

Slide 53:

Ku= knr + α ClCr where k nr is the nonrenal elimination rate constant and α is a constant. The graph shows a graphical representation of Equation for four different drugs, each with a different renal excretion rate constant. The fractions of drug excreted in the urine unchanged, fe , for drugs A, B, C, and D are 5%, 50%, 75%, and 90%, respectively.

Fraction of Drug Excreted Unchanged (fe) Methods:

For many drugs, the fraction of drug excreted unchanged ( fe ) is available in the literature. The fe method for estimating a dosage regimen in the uremic patient is a general method that may be applied to any drug whose fe is known. Fraction of Drug Excreted Unchanged ( fe ) Methods

Slide 59:

The Giusti–Hayton (1973) method assumes that the effect of reduced kidney function on the renal portion of the elimination constant can be estimated from the ratio of the uremic creatinine clearance, Cl u Cr , to the normal creatinine clearance, Cl N Cr :

General Clearance Method:

The general clearance method is based on the methods discussed above. This method is popular in clinical settings because of its simplicity. The method assumes that creatinine clearance, Cl Cr , is a good indicator of renal function and that the renal clearance of a drug, Cl R , is proportional to Cl Cr . Therefore, renal drug clearance, Cl u R , in the uremic patient is General Clearance Method

The Wagner Method:

The methods for renal dose adjustment discussed in the previous sections all assume that the Vd and the fraction of drug excreted by nonrenal routes are unchanged. These assumptions are convenient and hold true for many drugs. However, in the absence of reliable information assuring the validity of these assumptions, the equations should be demonstrated as statistically reliable in practice. A statistical approach was used by , who established a linear relationship between creatinine concentration and the first-order elimination constant of the drug in patients The Wagner Method

Slide 62:

This method takes advantage of the fact that the elimination constant for a patient can be obtained from the creatinine clearance, as follows: The values of a and b are determined statistically for each drug from pooled data on uremic patients

Extracorporeal Removal of Drugs :

Extracorporeal Removal of Drugs

Slide 64:

Patients with ESRD and patients who have become intoxicated with a drug as a result of a drug overdose require supportive treatment to remove the accumulated drug and its metabolites. Several methods are available for the extracorporeal removal of drugs, including hemoperfusion , hemofiltration , and dialysis . The objective of these methods is to rapidly remove the undesirable drugs and metabolites from the body without disturbing the fluid and electrolyte balance in the patient. Patients with impaired renal function may be taking other medication concurrently. For these patients, dosage adjustment may be needed to replace drug loss during extracorporeal drug and metabolite removal.

Overview :

Dialysis Types Dialysate Dialyzer Overview

Dialysis:

Dialysis is an artificial process in which the accumulation of drugs or waste metabolites is removed by diffusion from the body into the dialysis fluid. Two common dialysis treatments are peritoneal dialysis and hemodialysis . Both processes work on the principle that as the uremic blood or fluid is equilibrated with the dialysis fluid across a dialysis membrane, waste metabolites from the patient's blood or fluid diffuse into the dialysis fluid and are removed. The dialysate contains water, dextrose, electrolytes ( K, Na, Cl , bicarbonate, acetate, Ca, etc ), and other elements similar to normal body fluids without the toxins. Dialysis

Peritoneal dialysis :

It uses the peritoneal membrane in the abdomen as the filter. The peritoneum consists of visceral and parietal components. The peritoneum membrane provides a large natural surface area for diffusion of approximately 1–2 m 2 in adults; the membrane is permeable to solutes of molecular weights 30,000 Da . Total splanchnic flow is 1200 mL /min at rest, but only a small portion, approximately 70 mL /min, comes into contact with the peritoneum. Placement of a peritoneal catheter is surgically simpler than hemodialysis and does not require vascular surgery and heparinization . The dialysis fluid is pumped into the peritoneal cavity, where waste metabolites in the body fluid are discharged rapidly. Peritoneal dialysis

Slide 68:

The dialysate is drained and fresh dialysate is reinstilled and then drained periodically. Peritoneal dialysis is also more amenable to self-treatment. However, slower drug clearance rates are obtained with peritoneal dialysis compared to hemodialysis , and thus longer dialysis time is required. Continuous ambulatory peritoneal dialysis (CAPD) is the most common form of peritoneal dialysis. Many diabetic patients become uremic as a result of lack of control of their diabetes.

Procedure :

About 2 L of dialysis fluid is instilled into the peritoneal cavity of the patient through a surgically placed resident catheter. The objective is to remove accumulated urea and other metabolic waste in the body. The catheter is sealed and the patient is able to continue in an ambulatory mode. Every 4–6 hours, the fluid is emptied from the peritoneal cavity and replaced with fresh dialysis fluid. The technique uses about 2 L of dialysis fluid; it does not require a dialysis machine and can be performed at home. Procedure

Hemodialysis:

Hemodialysis uses a dialysis machine and filters blood through an artificial membrane. Hemodialysis requires access to the blood vessels to allow the blood to flow to the dialysis machine and back to the body. For temporary access, a shunt is created in the arm, with one tube inserted into an artery and another tube inserted in a vein. The tubes are joined above the skin. Hemodialysis

Slide 72:

For permanent access to the blood vessels, an arteriovenous fistula or graft is created by a surgical procedure to allow access to the artery and vein. Patients who are on chronic hemodialysis treatment need to be aware of the need for infection control of the surgical site of the fistula. At the start of the hemodialysis procedure, an arterial needle allows the blood to flow to the dialysis machine, and blood is returned to the patient to the venous side. Heparin is used to prevent blood clotting during the dialysis period.

Slide 73:

During hemodialysis , the blood flows through the dialysis machine, where the waste material is removed from the blood by diffusion through an artificial membrane before the blood is returned to the body. Hemodialysis is a much more effective method of drug removal and is preferred in situations when rapid removal of the drug from the body is important, as in overdose or poisoning . In practice, hemodialysis is most often used for patients with ESRD. Early dialysis is appropriate for patients with acute renal failure in whom resumption of renal function can be expected and in patients who are to be renally transplanted. Other patients may be placed on dialysis according to clinical judgment concerning the patient's quality of life and risk/benefit ratio.

Slide 74:

Dialysis may be required from once every 2 days to 3 times a week, with each treatment period lasting 2 to 4 hours. The time required for dialysis depends on the amount of residual renal function in the patient, any complicating illness ( eg , diabetes mellitus), the size and weight of the patient, including muscle mass, and the efficiency of the dialysis process. Dosing of drugs in patients receiving hemodialysis is affected greatly by the frequency and type of dialysis machine used and by the physicochemical and PK properties of the drug.

Slide 77:

In hemodialysis , blood is pumped to the dialyzer by a roller pump at a rate of 300–450 mL /min. The drug and metabolites diffuse from the blood through the semipermeable membrane. In addition, hydrostatic pressure also forces the drug molecules into the dialysate by ultrafiltration . The composition of the dialysate is similar to plasma but may be altered according to the needs of the patient. Many dialysis machines use a hollow fiber or capillary dialyzer in which the semipermeable membrane is made into fine capillaries, of which thousands are packed into bundles with blood flowing through the capillaries and the dialysate is circulated outside the capillaries. The permeability characteristics of the membrane and the membrane surface area are determinants of drug diffusion and ultrafiltration .

Slide 78:

The efficacy of hemodialysis membranes for the removal of vancomycin by hemodialysis has been reviewed by . Vancomycin is an antibiotic effective against most Gram-positive organisms such as Staphylococcus aureus , which may be responsible for vascular access infections in patients undergoing dialysis. In De Hart's study, vancomycin hemodialysis in patients was compared using a cuprophan membrane or a cellulose acetate and polyacrylonitrile membrane. The cellulose acetate and polyacrylonitrile membrane is considered a "high-flux" filter. Serum vancomycin concentrations decreased only 6.3% after dialysis when using the cuprophan membrane, whereas the serum drug concentration decreased 13.6–19.4% after dialysis with the cellulose acetate and polyacrylonitrile membrane.

Slide 79:

In dialysis involving uremic patients receiving drugs for therapy, the rate at which a given drug is removed depends on the flow rate of blood to the dialysis machine and the performance of the dialysis machine.

Overview :

Dialysance ( Cld ) Inter & during HD HD vs PD(speed, cost, expertise, home based, frequency, physiologic AE, dialyzer) Dialysate - composition and differences Overview

Dialysance:

Syn = Dialysis clearance The term is used to describe the process of drug removal from the dialysis machine. Dialysance is a clearance term similar in meaning to renal clearance, and it describes the amount of blood completely cleared of drugs (in mL /min). Dialysance is defined by the equation Dialysance

Slide 82:

C a = drug concentrations in arterial blood (blood entering kidney machine), C v = drug concentration in venous blood (blood leaving kidney machine), Q = rate of blood flow to the kidney machine, Cl D = dialysance . Dialysance is sometimes referred to as

Overview :

Ab vs Adsorption Activated charcoal HP- what is this?, principle, adsorbent, amberlite types, factors affecting HP vs HD (HP, protein bound drugs, lipid soluble, preferred) HF- Wht is this, principle, <10,000, problems Examples of the drugs- HD and HF- Li, Theo, Vancomycin HP- Barbiturates, CBZ Overview

Activated charcoal:

Syn =activated carbon It has oxygen added to it to increase its porosity, thereby, adding to its surface area. Activated charcoal

Hemoperfusion:

It is the process of removing drug by passing the blood from the patient through an adsorbent material and back to the patient. It is a useful procedure for rapid drug removal in accidental poisoning and drug overdosage . Because the drug molecules in the blood are in direct contact with the adsorbent material, any molecule that has great affinity for the adsorbent material will be removed. The two main adsorbents used in hemoperfusion include Activated charcoal , which adsorbs both polar and nonpolar drugs, Amberlite resins Hemoperfusion

Slide 91:

Amberlite resins, such as Amberlite XAD-2 and Amberlite XAD-4, are available as insoluble polymeric beads, each bead containing an agglomerate of cross-linked polystyrene microspheres. The Amberlite resins have a greater affinity for nonpolar organic molecules than does activated charcoal.

Slide 93:

The important factors for drug removal by hemoperfusion include affinity of the drug for the adsorbent, surface area of the adsorbent, absorptive capacity of the adsorbent, rate of blood flow through the adsorbent, and the equilibration rate of the drug from the peripheral tissue into the blood

Hemofiltration:

An alternative to hemodialysis and hemoperfusion is hemofiltration . Hemofiltration is a process by which fluids, electrolytes, and small-molecular-weight substances are removed from the blood by means of low-pressure flow through hollow artificial fibers or flat-plate membranes. Because fluid is also filtered out of the plasma during hemofiltration , replacement fluid is administered to the patient for volume replacement. Hemofiltration is a slow, continuous filtration process that removes nonprotein bound, small molecules (<10,000 Da ) from the blood by convective mass transport . Hemofiltration

Slide 97:

The clearance of the drug depends on the sieving coefficient and ultrafiltration rate. Hemofiltration provides a creatinine clearance of approximately 10 mL /min and may have limited use for drugs that are widely distributed in the body, such as aminoglycosides , cephalosporins , and acyclovir . A major problem with this method is the formation of blood clots within the hollow filter fibers.

Agenda :

RRT Types CRRT vs IRRT Advantages of CRRT CRRT def Predilution CAVH vs CVVH Drug removal by CRRT (S) Agenda

Renal replacement therapy (RRT) :

It is therapy that replaces the normal blood-filtering function of the kidneys. It is used when the kidneys are not working well, which is called renal failure and includes AKI and CKD. RRT includes dialysis (HD or PD), HF, and HDF, which are various ways of filtration of blood with or without machine. RRT also includes kidney transplantation, which is the ultimate form of replacement in that the old kidney is replaced by a donor kidney. Renal replacement therapy (RRT)

Types :

HD, HF, and HDF can be continuous or intermittent and can use an arteriovenous route (in which blood leaves from an artery and returns via a vein) or a venovenous route (in which blood leaves from a vein and returns via a vein). This results in various types of RRT, as follows: Types

Slide 103:

continuous renal replacement therapy (CRRT ) intermittent renal replacement therapy (IRRT) continuous hemodialysis (CHD) continuous arteriovenous hemodialysis (CAVHD) continuous venovenous hemodialysis (CVVHD) continuous hemofiltration (CHF) continuous arteriovenous hemofiltration (CAVH or CAVHF) continuous venovenous hemofiltration (CVVH or CVVHF) continuous hemodiafiltration (CHDF) continuous arteriovenous hemodiafiltration (CAVHDF) continuous venovenous hemodiafiltration (CVVHDF) intermittent hemodialysis (IHD) intermittent venovenous hemodialysis (IVVHD) intermittent hemofiltration (IHF) intermittent venovenous hemofiltration (IVVH or IVVHF) intermittent hemodiafiltration (IHDF) intermittent venovenous hemodiafiltration (IVVHDF)

Adv of CRRT vs IHD:

Adv of CRRT vs IHD CRRT IHD Better hemodynamic tolerability More efficient solute clearance Better control of intravascular volume Better clearance of middle and large mw substances

Slide 105:

CRRT IHD Better hemodynamic stability Improved efficiency of solute removal More costly Hypotension in 20-30% cases Less Less

CRRT:

It is any extracorporeal blood purification therapy intended to substitute for impaired renal function over an extended period of time and applied for, or aimed at being applied for, 24 hours per day. CRRT

Continuous Renal Replacement Therapy (CRRT) :

Because of the initial loss of fluid that results during hemofiltration , intermittent hemofiltration results in concentration of RBCs in the resulting reduced plasma volume . Therefore, viscous blood with a high hematocrit and high colloid oncotic pressure results at the distal end of the hemofilter . Predilution may be used to circumvent this problem, but this method is rarely used because of cost and inefficiency. Continuous replacement therapy allows ongoing removal of fluid and toxins by relying on a patient's own blood pressure to pump blood through a filter. The continuous filtration is better tolerated by patients than intermittent therapy, provides optimal control of circulating volumes, and provides ongoing toxin removal. Continuous Renal Replacement Therapy (CRRT)

Slide 110:

Because CRRT are hemofiltration methods, replacement fluid must be administered to the patient to replace fluid lost to the hemofiltrate , though the volume of fluid removed can be easily controlled compared to intermittent hemofiltration . Heparin infusions are also provided for anticoagulation. Continuous renal replacement therapy (CRRT) includes continuous veno -venous hemofiltration (CVVH) and continuous arteriovenous hemofiltration (CAVH).

CAVH:

In CAVH, blood passes through a hemofilter that is placed between a cannulated femoral artery and vein. A dialysis filter may be added to CAVH to improve small-molecule clearance. Circulating dialysate on the outside of the filters allows more efficient toxin removal. However, this method is inefficient (10–15 mL filtered per minute) and complex , and is not widely used in comparison to CVVH. CAVH

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Adv of CAVH gradual, continuous therapy, which is ideal in hemodynamically unstable patients; control of fluid balance ease of administration in the ICU volume depletion. Disadv of CAVH a requirement for arterial access, the need for anticoagulation, the risks of infection from long-term indwelling vascular lines the potential for significant volume depletion

CVVH :

CVVH provides a hemofilter that is placed between cannulated femoral, subclavian , or internal jugular veins. Rather than relying on arterial pressure to filter blood, a pump can be used to provide filtration rates greater than 100 mL /min. Like CAVH, a dialysis filter may be added to CVVH to improve clearance of small molecules. As with other extracorporeal removal systems, hemofiltration methods can alter drug pharmacokinetics. CVVH

Drug Removal during CRRT :

During CAVH, solutes are removed by convection, in which a sieving coefficient, S , reflects the solute removal ability during hemofiltration and is equal to the ratio of solute concentration in the ultrafiltrate to the solute concentration in the retentate . When S = 1, solute passes freely through the membrane, when S = 0, the solute is retained in the plasma. S is constant and independent of blood flow; therefore, Drug Removal during CRRT

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where rate uf if the ultrafiltration rate. The concentration of drug in the ultrafiltrate is also equal to the unbound drug concentration in the plasma, and so the amount of drug removed during CAVH is where α = the unbound fraction.

Overview :

Dosing considerations in HI pt Drug markers Nature and severity of liver disease Drug elimination constant ROA Protein binding Hepatic blood flow Intrinsic clearance Biliary obstruction PD changes Therapeutic range Overview

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Fraction of drug metabolized Active drug metabolite CP scale (E, As, B, Al, PT; 5-6, 7-9, 10-15) Hormonal influence Liver function tests AST ALT ALP Bi PT

Effect of Hepatic Disease on PK:

Drugs are often metabolized by one or more enzymes located in cellular membranes in different parts of the liver. Drugs and metabolites may also be excreted by biliary secretion. Hepatic disease may lead to drug accumulation, failure to form an active or inactive metabolite, increased bioavailability after oral administration, and other effects including possible alteration in drug protein binding, and kidney function . The major difficulty in estimating hepatic clearance in patients with hepatic disease is the complexity and stratification of the liver enzyme systems. In contrast, creatinine clearance has been used successfully to measure kidney function and renal clearance of drugs. Clinical laboratory tests measure only a limited number of liver functions. Effect of Hepatic Disease on PK

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Some clinical laboratory tests, such as the aspartate aminotransferase (AST) and alanine aminotransferases (ALT), are common serum enzyme tests that detect liver cell damage rather than liver function. Other laboratory tests, such as serum bilirubin , are used to measure biliary obstruction or interference with bile flow. Presently, no single test accurately assesses the total liver function. Usually, a series of clinical laboratory tests are used in clinical practice to detect the presence of liver disease, distinguish among different types of liver disorders, gauge the extent of known liver damage, and follow the response to treatment. Examples of these tests include the ability of the liver to eliminate marker drugs such as antipyrine , indocyanine green, monoethylglycine-xylidide , and galactose . Furthermore, endogenous substrates such as albumin or bilirubin , or a functional measure such as prothrombin time, have been used for the evaluation of liver impairment.

Dosage Considerations in Hepatic Disease :

Several physiologic and PK factors are relevant in considering dosage of a drug in patients with hepatic disease. Chronic disease or tissue injury may change the accessibility of some enzymes as a result of redirection of hepatic blood circulation. Liver disease affects the quantitative and qualitative synthesis of albumin, globulins, and other circulating plasma proteins that subsequently affect drug plasma protein binding and distribution (). As mentioned, most liver function tests indicate only that the liver has been damaged; they do not assess the function of the CYP-450 enzymes or intrinsic clearance by the liver . Dosage Considerations in Hepatic Disease

Intrinsic clearance:

 it is the ability of the liver to remove drug in the absence of flow limitations and binding to cells or proteins in the blood. Intrinsic clearance

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Because there is no readily available measure of hepatic function that can be applied to calculate appropriate doses, enzyme-dependent drugs are usually given to patients with hepatic failure in half-doses, or less. Response or plasma levels then must be monitored. Drugs with flow-dependent clearance are avoided if possible in patients with liver failure. When necessary, doses of these drugs may need to be reduced to as low as one-tenth of the conventional dose, for an orally administered agent. Starting therapy with low doses and monitoring response or plasma levels provides the best opportunity for safe, efficacious treatment.

Fraction of Drug Metabolized:

Drug elimination in the body may be divided into: (1) fraction of drug excretion unchanged, fe , and (2) fraction of drug metabolized. The latter is usually estimated from 1 – fe ; alternatively, the fraction of drug metabolized may be estimated from the ratio of Cl h / Cl , where Cl h is hepatic clearance and Cl is total body clearance. Knowing the fraction of drug eliminated by the liver allows estimation of total body clearance when hepatic clearance is reduced. Drugs with low fe values (or, conversely, drugs with a higher fraction of metabolized drug) are more affected by a change in liver function due to hepatic disease. Fraction of Drug Metabolized

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Equation assumes that all metabolism occurs in the liver, and all the unchanged drug is excreted in the urine.

Active Drug and the Metabolite:

For many drugs, both the drug and the metabolite contribute to the overall therapeutic response of the patient to the drug. The concentration of both the drug and the metabolite in the body should be known. When the PK parameters of the metabolite and the drug are similar, the overall activity of the drug can become more or less potent as a result of a change in liver function; that is, when the drug is more potent than the metabolite, the overall pharmacologic activity will increase in the hepatic-impaired patient because the parent drug concentration will be higher; when the drug is less potent than the metabolite, the overall pharmacologic activity in the hepatic patient will decrease because less of the active metabolite is formed. Active Drug and the Metabolite

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Changes in pharmacologic activity due to hepatic disease may be much more complex when both the PK parameters as well as the PD of the drug change as a result of the disease process. In such cases, the overall PD response may be greatly modified, making it necessary to monitor the response change with the aid of a PD model

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In practice, patient information about changes in hepatic blood flow may not be available, because special electromagnetic () or ultrasound techniques are required to measure blood flow and are not routinely available. The clinician/pharmacist may have to make an empirical estimate of the blood flow change after examining the patient and reviewing the available liver function tests

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While chronic hepatic disease is more likely to change the metabolism of a drug (), acute hepatitis due to hepatotoxin or viral inflammation is often associated with marginal or less severe changes in metabolic drug clearance (). The clinician may make an assessment based on acceptable risk criteria on a case-by-case basis. list useful endpoints for assessing the extent of hepatic dysfunction (). In general, basic PK treats the body globally and more readily applies to dosing estimation. However, drug clearance based on individual eliminating organs is more informative and provides more insight into the PK changes in the disease process. A practical method for dosing hepatic-impaired patients is still in its early stages of development.

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While the hepatic blood flow model () is useful for predicting changes in hepatic clearance resulting from alterations in hepatic blood flow, Q a , and Q v , extrahepatic changes can also influence PK in hepatic-impaired patients. Global changes in distribution may occur outside the liver. Extrahepatic metabolism and other hemodynamic changes may also occur and can be accounted for more completely by monitoring total body clearance of the drug using basic pharmacokinetics. For example, lack of local change in hepatic drug clearance should not be prematurely interpreted as "no change" in overall drug clearance. Reduced albumin and acid glycoprotein (AAG), for example, may change the volume of distribution of the drug and therefore alter total body clearance on a global basis.

Hormonal Influence:

Hormones can also affect the rate of metabolism. In hyperthyroid patients, the rate of metabolism of many drugs is increased, as are, for example, the rates for theophylline , digoxin , and propranolol . In hypothyroid disease, the rate of metabolism of these drugs may be decreased. In children with human growth hormone (HGH) deficiency, administration of HGH decreases the half-life of theophylline . Hormonal Influence

Liver Function Tests and Hepatic Metabolic Markers:

Drug markers used to measure residual hepatic function may correlate well with hepatic clearance of one drug but correlate poorly with substrate metabolized by a different enzyme within the same cytochrome P-450 subfamily. Some useful marker compounds are listed below. Liver Function Tests and Hepatic Metabolic Markers

Aminotransferase:

normal ALT, male, 10–55 U/L; female, 7–30 U/L; normal AST, male, 10–40, U/L; female, 9–25 U/L Aminotransferases are enzymes found in many tissues that include serum glutamic oxaloacetic transaminase (AST, formerly SGOT) and alanine aminotransferase (ALT, formerly SGPT). ALT is liver-specific, but AST is found in liver and many other tissues, including cardiac and skeletal muscle. Leakage of aminotransferases into the plasma is used as an indicator of many types of hepatic disease and hepatitis. The AST/ALT ratio is used in differential diagnosis. In acute liver injury, AST/ALT is 1, whereas in alcoholic hepatitis the AST/ALT > 2. Aminotransferase

Alkaline phosphatase :

(male, 45–115 U/L; female, 30–100 U/L). Like aminotransferase , alkaline phosphatase (AP) is normally present in many tissues, and is present on the canalicular domain of the hepatocyte plasma membrane. Plasma AP may be elevated in hepatic disease because of increased AP production and released into the serum. In cholestasis , or bile flow obstruction, AP release is facilitated by bile acid solubilization of the membranes. Marked AP elevations may indicate hepatic tumors or biliary obstruction in the liver, or disease in other tissues such as bone, placenta, or intestine. Alkaline phosphatase

Bilirubin :

(normal total = 0–1.0 mg/ dL , direct = 0–0.4 mg/ dL ). Bilirubin consists of both a water-soluble, conjugated, "direct" fraction and a lipid-soluble, unconjugated , "indirect" fraction. The unconjugated form is bound to albumin and is therefore not filtered by the kidney. Since impaired biliary excretion results in increases in conjugated (filtered) bilirubin , hepatobiliary disease can result in increases in urinary bilirubin . Unconjugated hyperbilirubinemia results from either increased bilirubin production or defects in hepatic uptake or conjugation. Conjugated hyperbilirubinemia results from defects in hepatic excretion. Bilirubin

Prothrombin time:

(PT; normal, 11.2–13.2 sec). With the exception of Factor VIII, all coagulation factors are synthesized by the liver. Therefore, hepatic disease can alter coagulation. Decreases in PT (the rate of conversion of prothrombin to thrombin) therefore is suggestive of acute or chronic liver failure or biliary obstruction. Vitamin K is also important in coagulation, so vitamin K deficiency can also decrease PT . Prothrombin time

References :

Applied Biopharmaceutics and pharmacokinetics by Shargel , Wu Pong and Yu A. Fifth edition. www.wikipedia.org Textbook of pathology by Harsh Mohan. Sixth edition. https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc https://en.wikipedia.org/wiki/Loading_dose https://en.wikipedia.org/wiki/Maintenance_dose https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100283/ http://www.tynesidekpa.org.uk/peritoneal-dialysis/ References

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http://www.edenos.com/Peritoneal-Dialysis-more-convenient-than-Hemodialysis--0 https://www.slideshare.net/exactlyurs/artificial-kidney http://www.joacp.org/article.asp?issn=0970-9185;year=2012;volume=28;issue=3;spage=386;epage=396;aula https://www.fastbleep.com/medical-notes/gi-and-renal/12/589 http://rvcjr88.tripod.com/Tx.htm

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http://www.differencebtw.com/difference-between-absorption-and-adsorption/ http://www.webmd.com/vitamins-and-supplements/activated-charcoal-uses-risks#1 https://gardenrain.wordpress.com/2009/04/24/hemoperfusion/ https://www.ebmedicine.net/topics.php?paction=showTopicSeg&topic_id=17&seg_id=202 http://crashingpatient.com/intensive-care/renal-replacement-therapy-rrt.htm/ http://www.baxter.com/products-expertise/renal-failure-treatments/expertise/crrt.page http://www.medscape.com/viewarticle/840300 https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-016-0345-0

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http://tmedweb.tulane.edu/pharmwiki/doku.php/hepatic_drug_clearance https://muggerboard.wordpress.com/2015/11/21/child-pugh-score/ https://de.slideshare.net/PallaviKurra/dose-adjustment-in-renal-and-hepatic-failure

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