Dialysis clearance

Currently the efficiency of hemodialysis is expressed in terms of dialysis clearance. Dialysis clearance (CLd) is usually estimated from the Pick equation as follows  

Single-pass dialyzers are now standard for patient care and clearance calculations suffice for characterizing their performance. However recirculating dialyzers were used in the early days of hemodialysis. 

Dialysis bath solute concentration (Bath) had to be considered in describing the performance of recirculating dialyzers and was included in the equation for calculating diahjsance (D), as shown in the following equation (7)  

Considerable confusion surrounds the proper use of Equation 6.2 to calculate dialysis clearance. There is general agreement that blood clearance is calculated when Q is set equal to blood flow and A and V are expressed as blood concentrations. In conventional practice -plasma clearance is obtained by setting Q equal to plasma flow and expressing A and V as plasma concentrations. In facb this estimate of plasma clearance is only the same as plasma clearance calculated by standard pharmacokinetic techniques when the solute is totally excluded from red blood cells. 

This dilemma is best avoided by calculating dialysis clearance using an equation that is analogous to the equation used to determine renal clearance  

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EIGURE 6.1 Plot of dialysis clearance (CL]j) vs. dialyzer blood flow (Q). The theoretical curves were fit to experimental data points to obtain estimates of the permeability coefficient-surface area product (P-S) for each solute. Flow-limited clearance is indicated by the dashed line. The data were generated with a Kolff-Brigham type hemodialysis apparatus. (Reproduced with permission from Renkin EM. Tr Am Soc Artific Organs 1956 2 102-5.)... 

An analysis of relative dialysis clearance and dialyzer permeability coefficient-surface area products that was made for the closely related compounds procainamide (PA) and N-acetylprocainamide (NAPA) is summarized in Table 6.3. Dialyzer clearance measurements of PA (CLpa) and NAPA (CLmapa)... 

We can use these recovery clearances to examine the effective flow of plasma (Qeff) that is needed if Equation 6.2 is to yield an estimate of dialysis clearance that is consistent with the corresponding recovery clearance value. Since CLb = Qb / it follows from Equation 6.4 that ... 

Because elimination clearances are additive/ total solute clearance during hemodialysis (CLp) can be expressed as the sum of dialysis clearance (CLd), and the patienfs renal clearance (CLr) and nonrenal clearance (CLjvp) ... 

Since UFR cannot exceed blood flow through the hemofilter/ that establishes the theoretical upper limit for CLuf- The major determinants of SC are molecular size and the unbound fraction of a compound in plasma water. Values of SC may range from 0/ for macromolecules that do not pass through the pores of the hemofilter membrane/ to 1, for small-molecule drugs that are not protein bound. Although less information has been accumulated about the ultrafiltration clearance of drugs than about their dialysis clearance/ in many cases the unbound fraction of drug in plasma water can be used to approximate SC. 

The disposition of quinupristin, dalfopristin, and their primary metabolites was similar in eight non-infected patients on peritoneal dialysis compared with eight matched healthy volunteers after the administration of quinupristin + dalfopristin 7.5mg/kg (48). Since dialysis clearance was insignificant, the combination was thought to be inadequate for the therapy of dialysis-associated peritonitis. 

B. Use with caution in patients with hepatic and renal impairment. A few reports suggest that dimercaprol or its metabolites are dialyzable, and that BAL increases the dialysis clearance of mercury in patients with renal failure. 

Planning for dialysis should begin when creatinine clearance falls less than 30 mL/minute/1.73 m2 (stage 4 CKD),1 when progression to ESRD is inevitable, to allow time to educate the patient and family on the treatment modalities and establish the appropriate access for the modality of choice. Ideally, initiation of dialysis should be done at a point when the patient is ready to undergo treatment, rather than when the patient is in emergent need of dialysis. 

In general, peritoneal dialysis is less effective in removing drugs than hemodialysis and, in fact, does not contribute substantially to total body clearance. 

Total clearance during dialysis can be calculated as the sum of the patient s residual clearance during the interdialytic period (CLRES) and dialyzer clearance (CLD) ... 

Hemodialysis clearance of most drugs is dialysis-filter dependent, and a value can be extrapolated from the literature. The concentration after dialysis can be calculated as ... 

Renal function Impairment Drug elimination was related to GFR. Clearance was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. 

The terminal half-life ranges from 6.9 to 8.1 hours. During dialysis, a 2-fold increase in clearance occurs. The drug is eliminated intact by the kidneys. Approximately 70% to 80% of an IM dose is excreted in the urine during the first 24 hours, with an additional 10% excreted over the next 3 days. 

Use in patients with impaired renal function - Perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when Ccr drops below 30 mL/min. In patients with Ccr less than 30 mL/min, safety and efficacy have not been established. For patients with lesser degrees of impairment (Ccr more than 30 mL/min), the initial dosage should be 2 mg/day, and dosage should not exceed 8 mg/day because of limited clinical experience. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function. 

Renal function impairment In volunteers with severe renal impairment (Ccr 30 mL/min or less), sildenafil clearance was reduced. Consider an initial sildenafil dose of 25 mg in these patients. There is no clinical data on the safety or efficacy of vardenafil in patients with end-stage renal disease requiring dialysis. 

Renal function impairment - In patients with a creatinine clearance less than 30 mL/min, increase the dosing interval to 12 hours, with a maximum daily dose of 200 mg. Because hemodialysis only removes 7% of an administered dose, dialysis patients can receive their regular dose on the day of dialysis. 

Renal function impairment Use rizatriptan and sumatriptan with caution in dialysis patients because of a decrease in the clearance. 

Hemodialysis Topiramate is cleared by hemodialysis 4 to 6 times greater than in a healthy individual a prolonged period of dialysis may cause topiramate levels to fall below that required to maintain an antiseizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of the dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed. 

Renal function impairment Because daptomycin is eliminated primarily by the kidney, a dosage modification is recommended for patients with creatinine clearance (Ccr) less than 30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CARD). When possible, administer daptomycin following hemodialysis on hemodialysis days. 

Metabolism/Excretion - In the first 24 hours, approximately 75% of a dose is excreted in urine by glomerular filtration. Elimination half-life is 4 to 6 hours in adults and 2 to 3 hours in children. About 60% of an intraperitoneal dose administered during peritoneal dialysis is absorbed systemically in 6 hours. Accumulation occurs in renal failure. Serum half-life in anephric patients is approximately 7.5 days. Vancomycin is not significantly removed by hemodialysis or continuous ambulatory peritoneal dialysis, although there have been reports of increased clearance with hemoperfusion and hemofiltration. 

However, in patients with renal failure there is a strange and currently unexplained observation in relation to non-renal clearance. If this is measured for some compounds it also is found to be depressed even though it is the kidney that is diseased and not the liver The picture becomes a little clearer if the same non-renal (presumed hepatic) clearance is measured again in patients after renal dialysis when the hepatic clearance has been found to have risen to control values. Recent animal experiments have demonstrated that the circulating inhibitor of hepatic cytochrome P450 may be parathyroid hormone. Parathyroidectomy of rats with chronic renal failure prevented the reduction in liver cytochrome activity (see Michaud et al., 2006). 

For those who like the ability to calculate things for themselves, it is relatively easy to predict how much drug is lost in dialysis - the dialysis is effectively another clearance mechanism which operates alongside whatever remaining clearance the patient has for the dmg in question. From the equations we have used it follows that... 

If it is possible to measure the T1/2 of the drug in question during the period that the patient is hooked up to the dialysis machine, to estimate the Vj for that substance (and the existing intrinsic clearance has been measured during the non-dialysis period - from a similar exercise of repeated plasma concentration measurement), then it is possible to work out how much drug is being lost through the dialysis process itself. Even in the more sophisticated centres of the developed world this would be a heroic exercise and would seldom be done unless a fervent pharmacoki-neticist was a member of the ward team. 

Dosage in renal impairment For patients with creatinine clearance less than 30 ml/min, usual dose is given q24h. For patients on hemodialysis, usual dose is given 3 timesAwk after dialysis. 

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