Principles of Pharmacodynamics and Pharmacokinetics of Drugs Used in Extracorporeal Therapies

Objectives

This chapter will:

1.
Identify the major factors affecting drug removal during renal replacement therapy (RRT).
2.
Define the principles for appropriate dosage adjustments during RRT.
3.
Describe the potential relevance of RRT in modifying the pharmacodynamic behavior of antimicrobial agents during RRT.

When a drug is administered for therapeutic purposes, its pharmacodynamic effect is the result of the achievement and maintenance of therapeutically effective free concentrations at the site of action. This result depends on several complex pharmacokinetic processes occurring after drug administration according to the drug's peculiar physicochemical properties. As a consequence, a wide interindividual variability in plasma protein binding, distribution with tissue accumulation, metabolism (mainly by the liver), and/or elimination (mainly by the kidney) of drugs may exist, and appropriate dosing regimens must be defined to guarantee the therapeutic effect.

When clinicians start drug treatment, the first dose, namely the loading dose, has the intent of rapidly achieving therapeutically effective concentrations, and its amount depends on volume of distribution (Vd). The subsequent doses, namely the maintenance doses, are administered with the intent of maintaining over time these effective levels. Accordingly, their amount depends mainly on the amount that is eliminated from the body by drug clearance (K) during the dosing interval.

In the presence of acute renal failure, the application of renal replacement therapies (RRTs) may consistently alter drug clearance, especially for those compounds that are cleared normally by the kidney. Consistently, the maintenance dose, but not the loading dose, of a given drug may require significant adjustments during the application of RRT to avoid either therapeutic failure related to underexposure or toxicity risks related to overexposure, especially whenever using drugs with low therapeutic index.

The amount of drug removal may vary greatly according to several factors related to the functioning processes of RRT, the peculiar physicochemical and pharmacokinetic properties of the drug, and the properties of the device.

Factors Affecting Drug Clearance During Renal Replacement Therapy

Principles of Drug Removal

RRT may employ two different physicochemical processes, diffusion and convection, to replace renal function in the elimination of several solutes from blood through semipermeable membranes, and these processes may influence greatly drug removal by RRT ( Table 147.1 ).

TABLE 147.1

Comparison of Characteristics of Drug Removal During Renal Replacement Therapy

DIFFUSION	CONVECTION
Typical of dialysis	Typical of hemofiltration
Passive process	Active process
Movement results from concentration gradient and is countercurrent to blood flow	Movement results from pump-driven pressure gradient
Dependent on drug molecular weight	Independent of drug molecular weight
Long time to equilibrium	Rapid equilibrium
No need for replacement fluid	Need for replacement fluid to reconstitute blood volume (predilution or postdilution mode)

Diffusion is the typical working principle of hemodialysis; it occurs passively through a semipermeable membrane, according to the concentration gradient and in countercurrent respect to blood flow, and generally needs time to reach equilibrium. Diffusive clearance is correlated inversely to the molecular weight (MW) of the solutes, being especially efficient for small molecules (MW < 500 Da).

Conversely, convection represents the typical working principle of hemofiltration; it is an active process, similarly to glomerular filtration, and occurs rapidly and efficiently thanks to a pump-driven pressure gradient. Drug removal is independent of the MW, considering that almost all drug molecules are smaller than the very high hemofilter cutoffs, which are targeted expressly to allow filtration of large solutes (e.g., inflammatory cytokines). Similarly to the glomerular filtration process in the kidney, hemofiltration produces an ultrafiltrate, so that a replacement fluid must be administered to preserve adequate circulatory volume.

The most frequently applied RRTs in patients with acute renal failure are intermittent hemodialysis (IHD), continuous venovenous hemofiltration (CVVH), and continuous venovenous hemodiafiltration (CVVHDF). Whereas IHD is essentially a diffusive technique, CVVH is a convective technique, and CVVHDF is a combination of both.

Drug Properties

The drug characteristics that affect clearance during RRT are shown in Table 147.2 .

TABLE 147.2

Factors Potentially Affecting Drug Clearance During Renal Replacement Therapy

DRUG PROPERTIES	DEVICE PROPERTIES
Molecular weight	Composition
Plasma protein binding	Surface area
Volume of distribution	Pore size
Proportion of renal clearance	Adsorption

Molecular Weight

Drug removal is expected to be dependent on MW only if the filter membrane cutoff is lower than the size of the considered drug. This aspect is absolutely irrelevant for hemofiltration techniques such as CVVH or CVVHDF, because almost all of the therapeutic drugs have MW < 2000 Da, which is a value significantly lower than the hemofilter cutoffs, which are optimized to be impermeable to plasma proteins (about 30,000 to 50,000 Da). On the other hand, MW becomes relevant in IHD because the filters are optimized for small solutes, often with a cutoff value of less than 800 to 1000 Da. Accordingly, almost all drugs are expected to be removed at least partially by CVVH and CVVHDF, whereas most, but not all drugs, may be removed by IHD. For example, the glycopeptide antibiotics vancomycin and teicoplanin are not removed during classic IHD because they have an MW higher than 1500 Da.

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