Pharmacokinetics, pharmacodynamics and drug monitoring in critical illness

Chapter 79 Pharmacokinetics, pharmacodynamics and drug monitoring in critical illness



Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism and elimination (ADME) of drugs, usually by measurement of drug concentrations in blood or plasma. Pharmacodynamics (PD) is the study of the effects of a drug on the body. The pharmacokinetics of a drug is one determinant of its pharmacodynamics. Pharmacokinetic-pharmacodynamic (PK-PD) analysis seeks to summarise the behaviour of a drug in the body, to understand the sources of variability in this behaviour, and to use this knowledge to design rational, and ideally individualised, dosing regimens. The aim of this chapter is to review some basic PK and PD principles, to introduce the concepts that an intensive care physician may encounter when reading a contemporary PK-PD paper, and to consider the influence of critical illness on the pharmacokinetics and pharmacodynamics of drugs used in intensive care.



DOSE–RESPONSE RELATIONSHIPS


Most drugs exert their effects by binding to receptors1 such as an enzyme or membrane ion channel. The binding to the receptor directly or indirectly triggers a chain of biological events leading to the observable effects of the drug. The magnitude of effect is a function of:






As the number of receptors present is finite, drugs have a maximum achievable effect. Classically, a plot of drug effect versus the logarithm of a wide range of doses will be described by a sigmoid-shaped dose–response curve (Figure 79.1). In practice, the range of doses used in patients is often narrower, and is confined to a smaller section of the dose–response curve.



Note that a drug effect can be plotted in individuals (e.g. mean arterial pressure vs. drug concentration) or for a population of individuals (e.g. % of patients responding to increasing doses of an antihypertensive). The shape of dose–response curves is often defined by three parameters:





Analogous curves can often be drawn for each of the adverse or toxic effects of a drug. The ratio of the median toxic dose and the median effective dose is termed the therapeutic index. The smaller the therapeutic index of a drug, the greater the potential to do harm rather than good.


Any drug should be administered with a clear understanding of the expected benefits to the patient. While it is more difficult to cause drug toxicity by administering a drug with a high therapeutic index, careless use can result in treatment failure and unnecessary cost. Drugs with a low therapeutic index should be used with considerable caution, with the assistance of titration to measured drug effects, dose nomograms or measurements of drug concentrations (therapeutic monitoring).




PHARMACOKINETICS


Key pharmacokinetic concepts include volume of distribution (V) and clearance (CL). These can be applied to individual organs or to the whole body.



VOLUME OF DISTRIBUTION IN AN ORGAN


A drug administered to a patient will directly or indirectly enter the blood and be distributed by the blood circulation around the body. Drug enters the organs of the body via the afferent arterial blood supply. Any given molecule can then either diffuse into the organ or leave via the efferent venous blood (Figure 79.2). At steady state (when the arterial concentrations are constant and the net rates of diffusion into and out of the organ are equal), the total amount of drug in the organ (A) will often be a fixed ratio of the afferent arterial concentration (C). This ratio is known as an apparent volume of distribution (V):





(1) image



The process of normalising amount (e.g. mg) for concentration (e.g. mg/l) produces a constant with the units of volume (l).


A given organ is characterised by the size of defined ‘physiological’ spaces and its relative proportions of water, lipids and drug-binding sites (Figure 79.2). The important physiological spaces are:





A drug may act on receptors in any of these spaces. The physicochemical properties of a drug dictate which physiological spaces are accessible to the drug. A drug can exist in blood in several forms: ionised or unionised (governed by the local pH and the pKa of the drug), and bound or unbound to plasma proteins.




Consequently, drugs that are highly bound or highly ionised in blood generally have smaller distribution volumes in an organ. For example, the distribution volume of propofol in the brain is less than expected based on its high lipophilicity because it is highly bound in plasma. Paradoxically, highly lipophilic drugs in general do not penetrate tissues as extensively as moderately lipophilic compounds, as high lipophilicity is correlated with high binding in plasma.33


A distribution volume (V) provides information about how much drug is in an organ at steady state, but provides no information about how quickly steady-state concentrations in the organ would be achieved. The fastest possible rate is when diffusion across the endothelium and cell membranes is significantly faster than organ blood flow (Q). In this case, the uptake into the organ is ‘flow-limited’, and the half-life of organ equilibration is given by:



(2) image



Note that if the distribution volume of an organ is relatively large or the organ blood flow is low, the time required for an organ to completely equilibrate (at least five times tt1/2) with the blood can be quite long despite flow-limited kinetics.


When the diffusion rate across the endothelium and cell membranes is significantly less than organ blood flow (Q), the uptake into the organ is ‘membrane-limited’ and less affected by changes in organ blood flow. Morphine shows membrane-limited uptake into the brain.34




CLEARANCE IN AN ORGAN


The liver and the kidney have the special (but not exclusive) role of removing drug from the body. The liver can either transport a drug from the blood into the bile or metabolise a drug into another chemical entity (metabolite). Metabolism can be Phase I (e.g. by oxidation or reduction by enzymes of the cytochrome P-450 (CYP) family, or hydrolysis by esterases) or Phase II (e.g. conjugation with another compound to form a glucuronide or sulphate). The kidney excretes drug by filtration, and potentially active secretion, into the urine. Usually metabolites are less active than their parent compound, are more polar and more readily excreted in bile or urine.


The rate (R) that the liver or kidney can remove drug from the body is usually proportional to the concentration of drug in the blood (C) (i.e. first-order kinetics). This proportionality constant is known as drug clearance (CL):



(3) image



The process of normalising rate (e.g. mg/min) for concentration (e.g. mg/l) produces a constant with the units of flow (l/min). For an organ, the clearance can be shown to be equal to the blood flow (Q) through the organ multiplied by the extraction ratio of the drug across the organ (E). If the liver, for example, completely removes all drug passing through it, then E = 1 and the clearance of the drug is hepatic blood flow. If half the drug is removed, E = 0.5 and the clearance is half the hepatic blood flow. Clearance can also be calculated for the whole body, where it represents the total rate of removal of the drug from the body.



HEPATIC DRUG CLEARANCE


There are a number of factors that affect drug metabolism by the liver, but they can be classified by the extraction ratio of the drug across the liver: high (> 0.7), intermediate or low (< 0.3).




When the concentration of some drugs is relatively high (e.g. ethyl alcohol, phenytoin, high-dose barbiturates), the metabolic pathway becomes saturated, and the drug is slowly eliminated at a fixed rate (i.e. a zero-order process). A corollary is that small increases in a dose of a drug will cause marked sustained increases in plasma concentration during zero-order kinetics compared with administration during first-order elimination kinetics.




HALF-LIFE IN THE BODY


For a given drug, each organ of the body has characteristic rates of distribution (equilibration half-life) or clearance (extraction). When these complex processes are summed together, however, the sum appears to reduce to changes in blood concentrations that can be described by one, two or three exponential functions, each with an associated half-life term. Half-lives can describe the rate of decline of the blood drug concentration following a dose, or the rate of increase in concentration during an infusion. Half-life is defined as the time taken for the drug concentration in the blood to decrease (or increase) by 50%, and when only one half-life is evident it is related to distribution volume and clearance as follows:



(4) image



In this case, clearance and distribution volume describe the apparent behaviour of the drug in the body as a whole. This volume and clearance can be used to calculate dose regimens for this special case.





The distribution volume can sometimes provide information about the location of a drug in the body:38 a drug that distributes only in the intravascular space (e.g. one that is tightly bound to plasma proteins, such as indocyanine green) will have a distribution volume of about 0.075 l/kg; a drug that distributes into the extracellular space (e.g. one that is charged and cannot cross cell membrane, such as furosemide) will have a distribution volume of about 0.21 l/kg; and a drug that distributes into the total water space (e.g. one that is uncharged, lipophilic but does not bind to proteins, such as antipyrine) will have a distribution volume of about 0.6 l/kg. Drugs with higher distribution volumes can be assumed to be bound in blood and/or tissues.


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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on Pharmacokinetics, pharmacodynamics and drug monitoring in critical illness

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