Factors which influence drug dosing in dialysis

Also, among his otherwise rather Spartan chapters from Oh's Manual, Rinaldo Bellomo has included a table (pp.545) titled "Drug dosage during dialytic therapy"; given the highly selective nature of the Manual, one can assume that this table is of importance. For fear of copyright-associated repercussions, the table is not reproduced below. The dialysis enthusiast with a passion for memorising long lists is also invited to review Table 263.3 on page 1451 of Critical Care Nephrology (2^nd ed), which is essentially a huge listing of antibiotics, their molecular weights, their protein binding, and so forth.

In general terms:

Drugs which rely on renal clearance should be adjusted for CRRT.
Renally adjusted antibiotics should be given after a CRRT session.
CVVHDF and IHD have different pharmacokinetic effects.
Drugs with a large volume of distribution are poorly cleared by CRRT.
Highly protein-bound drugs are poorly cleared by CRRT.
CRRT is less effective at removing drugs than normal nephrons.
In critical illness CRRT is even less effective because of haemodynamic limitations on the blood flow rate and ultrafiltration rate.

CRRT filters are less efficient at removing drugs, because they rely on ultrafiltration and countercurrent diffusion, whereas the nephron also has some active pumps. CRRT will usually be inferior to native kidneys as a means of drug clearance, and therefore renally cleared drugs will need to be adjusted.

For detailed information regarding drug pharmacodynamics, Bellomo directs the reader to "specialised texts". The specialised text he refers to is in fact Jonathan Buckmaster's chapter from Critical Care Nephrology (1998 edition). This chapter does not exist in the new edition: rather, it has been split into three, two of which deal with pharmacokinetics in general, and the other with antibiotics specifically.

For the purposes of revision, these chapters have been pulled apart into easily accessible tables:

Factors which Influence the Clearance of Drugs by CRRT
Molecular weight	Theoretically, this could be an issue, because drugs of a large molecular mass may have difficulty negotiating the membrane. Diffusion depends in part on molecular mass, and therefore there may be a decreased diffusion rate if the drug is too large, and diffuses only sluggishly. Practically, this is never an issue in modern CRRT. CVVHDF filters are optimised to excluded plasma proteins (with a molecular mass in the tens of thousands of daltons - up to 50,000Da). Virtually all therapeutic drug molecules are under 2000Da, and therefore they slip through the membrane without any problems; they don't even notice that it's there. Thus, all drug molecules will be removed to some extent by CVVHDF. This is a real practical issue in IHD. Intermittent haemodialysis filters are optimised for small solute clearance, and they tend to exclude substances larger than 800-1000 Da. Drugs like vancomycin, voriconazole, caspofungin and teicoplanin are larger than this, and will not be removed by routine haemodialysis. Thus, not all drug molecules will be removed by IHD.

Volume of distribution	Drugs with a small volume of distribution will be easily cleared. A small volume of distribution suggests that these drugs are distributed exclusively in the extracellular fluid, or even in the intravascular volume. This means the drug is easily accessible by the membrane. Most antibiotics fall into this cathegory. Drugs with a massive volume of distribution (eg. extremely lipophilic or highly protein-bound drugs) are unlikely to be removed by CRRT.

Protein binding	Only the unbound "free" fraction will be cleared by any RRT technique. The protein-bound drug molecules are stuck to the surface of large protein lumps. These are too large to penetrate the pores of the membrane. Hence, the protein-bound drugs will not be cleared. Teicoplanin and ceftriaxone are examples of such highly protein-bound drugs. Fortunately, most patients in ICU are hypoalbuminaemic and hypoprotinaemic, which increases the free fraction, and enhances drug clearance by dialysis.

Membrane adsorption	Some drugs will be cleared by adsorption to the dialyser membrane. The drug essentialyl becomes irreversibly bonded to the surface of the porous membrane. This is a saturable process (i.e. eventually the membrane becomes completely saturated with the drug) and therefore may plateau over the course of a long session. Colistin is a good example of this.

Molecular charge	The Gibbs-Donnan effect may decrease the diffusability of some drugs. Specifically, it is the negative charge of albumin which attracts strongly polycationic drugs to remain on the blood side of the dialysis membrane, directly counteracting the effects of the concentration gradient. Again, colistin is an example of one such drug.

A discussion specific to antibiotic dosing in renal replacement therapy is also available.

References

For a definitive treatment of all of this, you ought to pay homage to the gigantic and all-encompassing "Critical Care Nephrology" by Ronco Bellomo and Kellum (2009).

The Gambro and Fresenius websites have also been an excellent source of information.

Bellomo referenced the first edition of his textboook from Oh's Manual:

Buckmaster J, Davies AR. "Guidelines for drug dosing during continuous renal replacement therapies." In: Ronco C, Bellomo R, editors. Critical Care Nephrology. Dordrecht, The Netherlands: Kluwer Academic; 1998. p. 1327–34. .... The second edition does not have this chapter. Instead, it has three others.

Federico Pea and Mario Furlanut. "Principles of Pharmacodynamics and Pharmacokinetics of Drugs Used in Extracorporeal Therapies" in: Critical Care Nephrology (2009) p.1190

Dingwei Kuang, Chang Yin Chionh, and Claudio Ronco "Adjustment of Antimicrobial
Regimen in Septic Patients Undergoing Continuous Renal Replacement Therapy in the Intensive Care Unit"in: Critical Care Nephrology (2009) p.1441

Kevin M. Sowinski and Bruce A. Mueller. "Drug Dosing in Patients with Acute Kidney Injury and in Patients Undergoing Renal Replacement Therapy: In: Critical Care Nephrology (2009) p.1727

Malone, Rebecca S., et al. "Pharmacokinetics of levofloxacin and ciprofloxacin during continuous renal replacement therapy in critically ill patients."Antimicrobial agents and chemotherapy 45.10 (2001): 2949-2954.

Chien, Shu-Chean, et al. "Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses." Antimicrobial Agents and Chemotherapy 41.10 (1997): 2256-2260.

Fish, Douglas N., and Andrew T. Chow. "The clinical pharmacokinetics of levofloxacin." Clinical pharmacokinetics 32.2 (1997): 101-119.

Gasser, T. C., et al. "Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function." Antimicrobial agents and chemotherapy 31.5 (1987): 709-712.

Trotman, Robin L., et al. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy." Clinical infectious diseases 41.8 (2005): 1159-1166.

Michalopoulos, Argyris S., and Matthew E. Falagas. "Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients."Annals of intensive care 1.1 (2011): 1-6.

Markou, Nikolaos, et al. "Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study."Journal of antimicrobial chemotherapy (2012): dks257.

Bekersky, Ihor, et al. "Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans." Antimicrobial agents and chemotherapy 46.3 (2002): 828-833.

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