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1Department of Nephrology and Dialysis and 2University Department of Medicine, Sestre milosrdnice University Hospital, SUMMARY – Drug dialyzability is determined by complex interaction of many factors, including the char- acteristics of the drug and the technical aspects of the dialysis system. Numerous aspects of dialysis pre- scription, including some elaborated in this article, have the potential to influence drug removal by dialysis.
Care must be exercised when applying information from published reports of drug dialyzability to the individual patient. In order to provide the best information for individual patients, healthcare professionals should become familiar with the dialysis membranes utilized at their healthcare facility, and interpret liter- ature information in that light. This article includes a table on dialyzability of drugs during conventional and high-permeability dialysis, and during peritoneal dialysis.
Key words: Peritoneal dialysis; Kidney failure, therapy; Dialysis solutions, pharmacokinetics; Renal dialysis, trends; Renal replacement therapy, methods; Pharmaceutical preparations, administration and dosage the pore size of the membrane. As a general rule, smaller The extent to which a drug is affected by dialysis is molecular weight substances will pass through the mem- determined primarily by several physicochemical charac- brane more easily than larger molecular weight substanc- teristics of the drug. These include molecular size, protein es. Drugs of molecular weight above 1,000 daltons depend binding, volume of distribution, water solubility, and plas- less on diffusion and more on conventional dialytic clear- ance. Hemodiafiltration does not differ from convention- ma clearance. In addition to these properties of the drug, al dialysis with respect to clearance of small solutes with technical aspects of the dialysis procedure may also deter- molecular weights <500 daltons. However, the hemodia- mine the extent to which a drug is removed by dialysis.
filtration clearance of middle molecular weight molecules (500 to 5,000 daltons) exceeds that in conventional dialy- sis by 10%, and large molecular clearance (>5,000 daltons) Drug Properties That Affect Dialyzability in hemodiafiltration is increased by 24% over that in con- ventional hemodialysis1. Molecular volume is determined by the weight, shape and charge of the species in question.
One of the most reliable predictors of the dialyzability If a drug cannot fit through a dialysis membrane pore be- of a drug is its molecular weight. Dialysis is dependent on cause of its geometric proportions, it is reflected and can- the dialytic membrane used, i.e. either a synthetic mem- not be cleared by the dialyzer. The term ‘molecular size’ brane with fixed pore size, as in hemodialysis, or a natu- is used to indicate the relationship of molecular weight, rally occurring peritoneal membrane, as in peritoneal di- volume, shape, charge and steric hindrance to the ability alysis. The movement of drugs or other solutes is largely of a molecular species to permeate a membrane pore. A determined by the size of these molecules in relation to common assumption is that pore size of the peritoneal membrane is somewhat larger than that of the hemodial- Correspondence to: Siniša Šefer, M.D., Department of Nephrology and ysis membrane; this would explain the observation that Dialysis, Sestre milosrdnice University Hospital, Vinogradska c. 29, HR- larger molecular weight substances appear to cross the peritoneal membrane to a greater extent than they cross Received April 4, 2003, accepted June 2, 2003 Golper showed the addition of free fatty acids to increase the free fraction of phenytoin, a highly protein bound drug9.
Another important factor determining drug dialyzabil- Thus, any perturbation in the serum free fatty acid con- ity is the concentration gradient of unbound (free) drug centration may alter drug-protein binding and ultimately across the dialysis membrane. The bound and unbound drug clearance. Drugs with a high degree of protein bind- fractions of the total drug are in constant equilibrium. If ing will have a small plasma concentration of unbound drug the drug is tightly protein-bound, then the flux between available for dialysis. Uremia may have an effect on pro- bound and unbound drug occurs more slowly. Unbound tein binding for some drugs. Through the mechanisms not drug is the pharmacologically active form, for it can be free- yet completely understood, protein binding may decrease ly distributed to targeted tissue receptor sites, metabolic in uremic serum. Should this change in binding be sub- inactivating sites (e.g., the liver), or excretory sites (e.g., stantial, increased dialyzability of free drug may occur.
the kidneys or dialyzer). Certain conditions of uremia may Because the primary binding proteins for most drugs (al- inhibit or enhance protein binding3. Malnutrition and pro- bumin, α -acid glycoprotein) are of large molecular size, teinuria lower serum protein levels, thereby increasing the the drug-protein complex is often too large to cross the di- free fraction of a drug due to saturation of a reduced num- alysis membrane, especially in case of hemodialysis mem- ber of protein binding sites available. Consequently, dia- brane. Since peritoneal membrane does permit the pas- lyzer clearance increases and the possibility of drug toxic- sage of some proteins, there may be some limited drug- ity is enhanced, particularly if the drug has a narrow ther- protein removal with this technique. Increased protein apeutic window. Accumulation of uremic toxins decreas- concentrations have been noted in peritoneal effluent es the affinity of albumin for drugs such as penicillins, dig- itoxin, phenobarbital, phenytoin, warfarin, morphine, prim- idone, salicylates, theophylline, and sulfonamides. Acid drugs (e.g., cephalosporins, imipenem, vancomycin, and ciprofloxacin) have a higher free fraction than do basic Related to tissue compartmentalization is the phenom- drugs such as tobramycin because of the chronic organic enon of drug partitioning into red blood cells. Marbury et al. first raised this concern because ultrafiltration during acidemia that accompanies renal failure. Organic acids dialysis raises hematocrit and complicates the determina- compete with acid drugs for certain protein binding sites.
tion of intradialytic drug clearance10. The question is On the other hand, uncomplicated uremia causes few al- whether the whole blood concentration or the plasma con- terations in the protein binding of basic drugs4. Basic drugs centration is the proper reference value; this is particular- bind more avidly to nonalbumin serum proteins than to ly relevant to the clearance of ethambutol, a drug known albumin. The protein binding of basic drugs is often in- to partition into red blood cells11. Drugs that have a parti- creased owing to elevated levels of the acute-phase reac- tion coefficient (whole blood to plasma concentration ra- tant α acid glycoprotein, to which these drugs readily tio) exceeding unity (e.g., procainamide, glutethimide and bind5. These basic drugs may bind still more avidly to these acetaminophen) may have decreased clearance due to nonalbumin proteins during catastrophic illnesses6. As the hemoconcentration at the end of dialysis. Thus, for drugs result, less unbound drug is available for dialytic clearance that partition into red blood cells, total dialytic clearance or for pharmacologic activity. However, since metabolism may be reduced in these hemoconcentrated states12. Fur- is slowed by the enhanced protein binding, drug presence thermore, the issue of rapid re-equilibration between red may also be prolonged. Heparin use during hemodialysis blood cell drug and plasma drug becomes more important.
stimulates the activity of lipoprotein lipases, which break These observations were made before they had been in the down triglycerides into free fatty acids. Elevated levels of pre-erythropoietin era. Higher predialysis hematocrits will plasma free fatty acids compete with drugs such as tryp- result in greater red blood cell partitioning and in less free tophan, sulfonamides, salicylates, phenylbutazone, pheny- drug, with the potential consequences described above.
toin, thiopentone and valproic acid for protein binding Even for a drug with low red blood cell partitioning, clear- sites, causing an increase in the free fraction during and ance may be decreased in a setting of higher hematocrit after the action of heparin effect7. To illustrate the com- because, as with all plasma solutes, dialytic clearance is plexity of drug-protein interactions, free fatty acids may dependent on plasma delivery to the dialyzer. With high- displace cefamandole but may enhance the binding of er hematocrits more red cell mass and less plasma are de- other cephalosporins such as cephalothin or cefoxitin8.
ance, the contribution that dialysis may make to total drug removal is low. However, if renal (dialysis) clearance in- The volume of distribution (Vd) is a mathematically creases plasma clearance by 30% or more, dialysis clearance determined volume representing the extent of drug dis- is considered to be clinically important4.
tribution into body tissues. A drug with a large Vd (e.g., digoxin) is distributed widely throughout tissues and is present in relatively small amounts in the blood. Factors that contribute to a drug having a large Vd include a high degree of lipid solubility and low plasma protein binding.
The primary organs of drug elimination are the liver and Drugs with a large Vd are likely to be minimally dialyzed.
kidneys, with the skin, gastrointestinal tract and the lungs Despite rapid extracellular clearance with any type of also involved to an appreciable degree. Dialysis may play a short-time dialysis, intracellular equilibration with extra- significant role in drug elimination for the individual with cellular fluid can be slow, especially with middle to large end-stage renal failure. If alternative routes of elimination molecular weight solutes. This is probably related to the are not available for drug clearance, the parent drug and lipid solubility of the drug and tissue compartmentaliza- its metabolites accumulate. Thus, the quantity of drug tion. Quantitatively, postdialysis intracellular concentra- administered and/or the frequency of dosing must be con- tions may vary by only 1% to 2 %, and as the result there is sidered. Metabolic biotransformation is the chemical con- a drug concentration gradient between intracellular and version of a drug to another form. This process, occurring extracellular fluid. There may be a posthemodialysis re- mainly in the liver, results in a more polar, less lipid-solu- bound of 10%-25% with intercompartmental equilibration.
ble and more extractable metabolite, which often differs Higher ultrafiltration rates, as with short-time high-flux from the parent drug in its pharmacologic effects. Most hemodiafiltration, can aggravate this rebound phenome- metabolites are pharmacologically inert, although some non13. Matzke et al. found that for vancomycin the rebound may possess pharmacologic activity and/or toxicity (e.g., N- level was by 50% higher than the initial postdialysis drug acetylprocainamide). Hepatic metabolism of most drugs concentration. The maximum posthemodiafiltration re- is usually normal or accelerated with uremia. This may be bound time, defined as the time at which the maximum related to an increased availability of free drug because of drug plasma concentration occurred postdialysis, was high- decreased protein binding. Cytochrome P450 metabolism ly variable for vancomycin, ranging from 2.8 to 45.8 hours.
of phenytoin is accelerated in uremia, probably as the re- Therefore it would be difficult to predict this phenome- sult of enzyme induction due to the increased free frac- non for a specific patient, and it is advised to follow drug tion. The metabolism of peptides (e.g., insulin) and procaine is reduced secondary to the inhibition of ester hydrolysis, while hepatic acetylation (e.g., isoniazide) and glucuronide (e.g., acetaminophen) and sulfate conjugate hydrolysis (e.g., sulfa compounds) are usually normal.
Drugs and metabolites that have a small molecular size, The dialysate used for either hemodialysis or perito- small volume of distribution, and high water solubility are neal dialysis is an aqueous solution. In general, drugs with more likely to be eliminated by dialysis. A dialytic clear- high water solubility will be dialyzed to a greater extent ance that increases plasma clearance by more than 30% is than those with high lipid solubility. Highly lipid-soluble drugs tend to be distributed throughout tissues, and there- fore only a small fraction of the drug is present in plasma Bioavailability is defined as the fraction of administered drug that reaches the bloodstream. It is dependent on the completeness and rate of absorption. The technique of The inherent metabolic clearance – the sum of renal administration will determine how much drug is bioavail- and nonrenal clearance – of a drug is often termed the ‘plas- able. A drug’s absorption is affected by the character of the ma clearance’ of a drug. In dialysis patients, renal clearance membranes it must cross to reach the circulation, the blood is largely replaced by dialysate clearance. If for a particular flow at the site of absorption, the absorptive surface area, drug nonrenal clearance is large compared to renal clear- and the contact time between the drug and the absorp- tive area. In addition, physicochemical drug properties Dialysis Properties That Affect Drug Clearance such as molecular size and lipid solubility affect drug ab- sorption, particularly after oral administration. The routes of drug administration include the gastrointestinal tract Dialysis membrane characteristics that affect drug and injection into subcutaneous tissue, muscle and blood- clearance can be divided into five categories: membrane stream. Since maximum absorption is obtained with intra- materials, surface area, drug-membrane charge interaction, venous administration, this is the standard with which all drug-membrane binding, and dialyzer reuse.
other forms of administration are compared. Interstitial edema can retard absorption after subcutaneous or intra- muscular injection. If a dialysis patient has large interdia- lytic fluid gains, one would expect erratic or delayed ab- Dialyzer membranes are fabricated from a variety of sorption of drugs administered by either of these condi- natural and synthetic polymers: cellulose, cellulose acetate, tions of volume overload15. However, there is the poten- polysulfone, polyamide, polyacrylonitrile, and polymeth- tial for increase in either pharmacologic or toxic effect when ylmethacrylate. Concern over the possible importance of the patient approaches dry weight and absorbs the drug higher molecular weight toxins has led to the development properly. In the uremic patient three factors affect gastric of membranes with a wide range of solute permeabilities.
absorption: gastric pH, gastric motility, and mucosal integ- This development has accelerated in recent years with the rity. An increase in gastric pH as the result of urea break- availability of dialysis equipment capable of controlling down to ammonia greatly reduces absorption. Aluminum fluid removal. With polysulfone membranes, trace quan- hydroxide, used as a phosphate binder, further raises gas- tities of albumin can apper in the dialysate. Clearance of tric pH, delays gastric emptying, and forms poorly absorbed vancomycin vary with different membranes. AN69 and complexes with drugs. Drugs such as digoxin, tetracycline polysulfone membranes have the greatest clearance, while and probably ciprofloxacin may form nonabsorbable che- cuprophane has minimal clearance of this drug under sim- lation products with aluminum hydroxide. H -blockers and proton inhibitors may also rise gastric pH without concom- itant motility effects. Mucosal edema delays absorption in the same manner as interstitial edema delays absorption The removal of small solutes is dependent upon the after intramuscular and subcutaneous injection. Bioavail- concentration gradient between blood and dialysate. This ability is closely related to hepatic metabolism owing to gradient can be maximized by increasing flow rates and/ the first-pass effect of the enterohepatic circulation, which or by increasing surface area, thus dispersing the undia- the drug enters following enteral absorption. The liver can lyzed blood to areas of fresh dialysate. Both these princi- metabolize and inactivate drugs before they reach the sys- ples apply to either high-flux or high-efficiency dialysis. As temic circulation. Drugs may never reach their intended molecular size increases and diffusivity is increasingly lim- site of action due to this first-pass effect. One cannot con- ited by membrane pore size, molecular clearance becomes sistently predict how uremia will affect hepatic metabo- more dependent upon convection. The hydraulic perme- lism. Hemodialysis can indirectly alter absorption or bio- ability of high-flux membranes exceeds that of convention- availability. It can reduce edema in the bowel, muscles and al membranes, thus enhancing convective clearance of skin, as described above. Dialysis can lower urea levels and these larger molecules. When hydraulic permeability lim- can slightly reduce the need of phosphate binders, which its are achieved, larger surface area becomes the factor most may improve absorption of some drugs. On the other hand, influencing the total rate of convective clearance. Jindal hypotension associated with dialysis can impair mesenteric at al. have shown that for PAN, PMMA and polysulfone di- blood flow and may contribute to malabsorption. Remov- alyzers, surface area and ultrafiltration have great effect on al of uremic toxins may result in more available protein the clearance of β -microglobulin and phosphate, two poor- binding sites, thus increasing the drug fraction bound to ly diffusable species17. As mentioned previously, the char- protein, and this in turn may affect drug metabolism or acteristics of the dialysis membrane determine to a large extent the dialysis of drugs. Pore size, surface area and geometry are the primary determinants of the performance of a given membrane. The technology of hemodialysis continues to evolve, and new membranes continue to be introduced for clinical use. Interpretation of published lit- drug concentrations in the dialysate will increase during erature should be tempered with the understanding that the period of time in which the dialysate resides in the newer membranes may have different drug dialysis char- peritoneal cavity, thus slowing additional movement of acteristics. On the other hand, because the peritoneal drug across the membrane. More frequent exchanges will membrane is natural, little can be done to alter its charac- favor increased drug dialyzability, provided the drug’s phys- icochemical characteristics permit its movement across the Drug-membrane charge interaction and membrane binding The negative charge of the PAN membrane repels anionic solutes such as doxycycline and gentamicin. The negative charge of the membrane retarded gentamicin clearance. Other possibilities for decreased gentamicin Most of the information contained in this guide have clearance could involve drug adsorption on the dialysis been obtained from studies conducted under conditions membranes18. Drug membrane binding has also been dem- of standard hemodialysis that employed conventional di- onstrated in the absence of proteins in experimental con- alysis membranes. Recent changes in dialysis technology ditions of continuous methods of hemofiltration19.
have led to more permeable dialysis membranes and the opportunity to employ higher blood and dialysate flow rates. These new technologies are often referred to as ‘high-permeability’, ‘high-efficiency’ and ‘high-flux’ dial- Reuse may affect clearance by reduction of fiber bun- ysis. The Food and Drug Administration has proposed that dle volume (loss of surface area), by alteration in the dif- high-permeability dialysis membranes be defined as those fusive property of the membrane, or by the loss of hydrau- with in vitro ultrafiltration coefficient (CUf) above 12 mL/ lic permeability. Observations recorded during continuous mm Hg per hour (Federal Register, March 15, 1999, p.
hemodiafiltration suggest a predictable decline in ultrafil- 12776). Commonly included in this group of dialysis mem- tration with time due to either fibrin or protein adherence branes are polysulfone, polyacrylonitrile, and high-efficien- to the membrane20. Despite these observations, the role cy cuprammonium rayon dialyzers. Changes in dialysis of reuse in membrane deposition of protein has not been membranes, and changes in blood and dialysis flow rates fully elucidated and its effect on drug clearance remains may have clinically important effects on drug removal through the membrane24. There are increasing numbers of studies to examine the effects of high-permeability di- alysis on drug dialyzability. Results of these studies have confirmed predictions that drug removal from plasma is The hemodialysis prescription contains determination often enhanced as compared with more traditional dialy- of blood and dialysate flow rates. As drugs normally move sis membranes. Studies with high-permeability dialysis from blood to dialysate, the flow rates of these two sub- have also demonstrated that removal of drug from plasma stances may have a pronounced effect on dialyzability. In often exceeds the transfer of drug from tissues to plasma.
general, increased blood flow rates during hemodialysis will As a result, there is often a rebound of plasma drug con- enable greater amounts of drug to be delivered to the di- centrations following the conclusion of dialysis as blood- alysis membrane. As drug concentrations increase in the tissue drug equilibration occurs. Patients receiving high- dialysate, the flow rate of the dialysis solution also becomes permeability dialysis may require more drug compared important in overall drug removal21. Greater dialysis can be with those receiving standard hemodialysis25. Due to the achieved with faster dialysate flow rates that keep dialy- many technical and physiologic variables, individualized sate drug concentrations at a minimum. Therefore, when therapeutic drug monitoring may be necessary. The read- interpreting studies of drug dialyzability, these flow rates er is referred to the primary literature for more details.
During peritoneal dialysis, little can be done to alter blood flow rates to the peritoneum. However, dialysate flow rates are determined by the volume and frequency of di- Another therapeutic development that will affect drug alysate exchange in the peritoneum. At low exchange rates, dialyzability is continuous renal replacement therapy (CRRT), known in its various forms as continuous arteri- considerations based upon general principles of drug re- ovenous hemofiltration (CAVH), continuous venovenous moval derived from the physicochemical characteristics of hemofiltration (CVVH), continuous arteriovenous hemo- the drug and the CRRT technique employed28,29. Once dialysis (CAVHD), continuous venovenous hemodialysis again, the reader is referred to the primary literature for (CVVHD), continuous venovenous hemodiafiltration assistance with the dosing of specific drugs under condi- (CVVHDF), continuous arteriovenous hemodiafiltration (CAVHDF), slow continuous ultrafiltration (SCUF), con- tinuous arteriovenous high-flux hemodialysis (CAVHFD) and continuous venovenous high-flux hemodialysis (CV- VHFD). These various techniques are used in the man- Automated peritoneal dialysis (APD) is the fastest agement of acute renal failure in critically ill patients25.
growing renal replacement therapy by percentage in the CRRTs differ considerably from intermittent hemodialy- US, and provides dialysis exchanges via a machine while sis. Relying heavily upon continuous ultrafiltration of plas- the patient is sleeping, thereby improving patient conve- ma water, CRRT has a potential for the removal of large nience, peritoneal dialysis compliance rates, and decreas- quantities of ultrafilterable drugs contained in the plasma.
ing peritonitis rates. Well-designed pharmacokinetic stud- Unfortunately, few in vivo studies have been published, and ies involving APD have not been conducted. Consequently, very few drugs have been studied pharmacokinetically in no formal drug dosing recommendations are available for intensive care patients9,26,27. Therefore, many guidelines for APD, and pharmacists must rely on established dosing drug dosing during CRRT have been extrapolated from guidelines for continuous ambulatory peritoneal dialysis experiences with chronic hemodialysis or from theoretical when recommending dosing regimens31-34.
YES indicates supplemental dosing in conjunction with dialysis is usually required.
NO indicates supplemental dosing is not required.
U indicates significant drug removal is unlikely based on physicochemical characteristics of the drug such as protein binding, molecular size or L indicates no published data exist, but information extrapolated from studies using conventional dialysis techniques suggest significant drug removal is likely during high-permeability dialysis.
ND indicates there are no data on drug dialyzability in this type of dialysis.
NS indicates the type of high-permeability membrane was not specified.
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3. McNAMARA PJ, LALKA D, GIBALDI M. Endogenous accumula- 10. MARBURY TC, LEE CC, PERCHALSKI RJ, WILDER BJ. Hemo- tion products and serum protein binding in uremia. J Lab Clin Med dialysis clearance of ethosuximide in patients with chronic renal disease. Am J Hosp Pharm 1981;38:1757-60.
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tein binding, volume of distribution, and molecular weight on the fraction of drug eliminated by hemodialysis. Clin Nephrol 24. KES P. High flow dialyzers. Lijec Vjesn 2002;124:50-1.
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Disposition of vankomycin during hemofiltration. Clin Pharmacol 26. BELLOMO R, RONCO C. Continuous renal replacement thera- py in the intensive care unit. Intensive Care Med 1999;25:781-9.
15. MAHER JP. Principles of dialysis and dialysis of drugs. Am J Med 27. GOLPER TA, MARX MA. Drug dosing adjustment during continu- ous renal replacement therapies. Kidney Int Suppl 1998;66:165-8.
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Dijalizabilnost lijekova je odreðena složenim meðudjelovanjem mnogih èimbenika ukljuèujuæi osobine lijeka i tehnièke osobitosti sustava za dijalizu. Brojni èimbenici propisivanja dijalize navedeni u ovom èlanku imaju bitan utjecaj na odstranjivanje lijeka. Potrebna je posebna pažnja pri uporabi postojeæih informacija o dijalizabilnosti lijekova iz objavljenih izvješæa za svakoga bolesnika ponaosob. U cilju pronalaženja najbolje informacije za svakoga pojedinog bolesnika zdravstveni djelatnici trebaju dobro poznavati dijalizne membrane koje rabe i u tom svjetlu objasniti podatke iz literature. Ovaj èlanak sadrži tablicu s podacima o dijalizabilnosti lijekova tijekom konvencionalne, visokopropusne i peritonejske dijalize.
Kljuène rijeèi: Peritonejska dijaliza; Bubrežno zatajenje, lijeèenje; Dijalizne otopine, farmakokinetika; Bubrežna dijaliza, trendovi; Bubrežna zamjenska terapija, metode; Farmaceutski pripravci, davanje i doziranje

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