Pharmacokinetics

Next time you are reviewing the chart for your patient, take a look at the medication administration record. Every entry represents a decision – a decision to alter the physiology of your patient, with all the beneficial and adverse consequences that go along with that decision. Medication administration while on extracorporeal membrane oxygenation (ECMO) takes the weight of these decisions to another level, adding the uncertainty of how that medication will interact with the circuit itself.

This chapter will review principles to consider when making the decision to initiate, continue, or remove a medication for a patient on ECMO. First, let’s consider a couple of important caveats.

There is a relative paucity of data regarding the pharmacokinetics of drugs for patients on ECMO. How a drug interacts with the circuit, with other drugs, and with the body in the setting of severe critical illness is not completely understood, and the uniqueness of these interactions extends to all patients. Every patient may react to medications differently, and the impact of the circuit on medication effect may differ from patient to patient.

This chapter will try to introduce some basic principles that can be the framework for approaching medication administration for patients on ECMO, and how to assess the effect of these medications.

Normal effect of a drug on the body

Every time we hang an IV medication, initiate a drip, or administer a pill, there are two interactions occurring, how the drug interacts with the body and how the body interacts with the drug. Let’s consider the ways the body interacts with the drug, referred to as pharmacokinetics ( Fig. 21.1 ).

1.

Absorption: how the drug enters the body, determined by route, solubility, and presence of pumps/receptors
2.

Distribution: how the drug is disseminated to the target cells, determined by volume of distribution and how it is bound
3.

Metabolism: the conversion of drug to enhance removal
4.

Elimination: the removal of metabolized drug outside the body

These processes allow for a pattern of how much drug is present in the body based on when it is administered. What does this pattern look like? Let’s consider what happens when we administer a medication to a patient.

The first thing that happens is an increase in the amount of drug that is available to be distributed. How fast this increase happens is determined by the adsorption and distribution of the drug. Regardless, you can imagine a pattern like this, with a sharp uptick in drug available and an eventual tapering off toward the top of the curve ( Fig. 21.2 ).

As time goes on, there is less drug available for distribution and more drug begins to be metabolized and eliminated. Initially, this leads to a tapering off of the increase, and then leads to a decrease in drug available, starting slowly at first and then becoming more rapid as time goes on, giving rise to a bell curve shape.

The area under this curve represents the total drug exposure, which leads to the overall effect of the drug. This is important, as it explains the different ways that drugs can achieve their target effect – a drug that is quickly absorbed and slowly eliminated may have a very different overall effect than a drug that is slowly absorbed and quickly eliminated ( Fig. 21.3 ).

How quickly the drug is absorbed and eliminated determines the height of the bell curve, while the distribution and metabolism of the drug impacts the width of the bell curve. Distribution describes how widely the drug is dispersed throughout the body, encompassing two characteristics: volume of distribution (Vd) and binding ( Fig. 21.4 ).

Vd describes the relative fraction of drug in the blood versus the extravascular space. Drug that absorbs into the fat, muscle, or interstitium has a much wider volume of distribution, with a consequent broadening effect on the bell curve.

How the drug is bound can be classified as hydrophilic, lipophilic, and protein bound. Hydrophilic drugs have a lower Vd and are more dependent on fluid shifts, while lipophilic drugs generally have the ability to penetrate into tissues with a consequent lower Vd. Protein binding generally restricts Vd as bound drugs are less likely to cross membranes.

However, we must also put this in the context of the amount of drug that is needed to achieve the clinical effect ( minimal effective concentration ) and the amount of drug that can have an adverse effect ( toxic concentration ) ( Fig. 21.5 ).