Pharmacokinetic and Pharmacodynamic Considerations for Patients Undergoing Therapeutic Hypothermia

Because many enzyme systems rely on temperature in order to function, a state of lowered temperature is expected to cause alterations in pharmacokinetics and pharmacodynamics.

Therapeutic hypothermia is mainly used as a post-cardiac arrest care method in an attempt to prevent ischemic brain injury.1 It has also been studied in neurologic conditions such as ischemic stroke, traumatic brain injury, and coronary artery surgery.

Because many enzyme systems rely on temperature in order to function, a state of lowered temperature, or hypothermia, is expected to cause alterations in pharmacokinetics and pharmacodynamics.2 This can lead to increased risk for drug toxicity or failure.

Physiologic effects of hypothermia based on organ system are summarized in the Table.3

Table: Physiological Effects of Hypothermia3

Pharmacokinetics

More trials on pharmacokinetic alterations in therapeutic hypothermia are conducted in animals (74%) than humans (26%).2

Overall, hypothermia decreases the rate of drug absorption and may delay the time to reach a maximum concentration. Greater variability in absorption exists with oral drugs than intravenous ones.

In addition, patients undergoing therapeutic hypothermia likely have neurologic dysfunction and thus decreased gut motility, which also affects drug absorption.

Drug distribution is multifactorial.

First, perfusion is altered. During hypothermia, the body shunts blood away from the gut and towards vital organs, which decreases intravascular distribution volume, and cardiac output, leading to an altered volume of distribution.

At lower temperatures, pH increases because there is greater partial pressure of carbon dioxide in arterial blood. This will consequently affect ionization of drugs depending on their acid-base properties, and thus their distribution.

Plasma protein binding may be unchanged, increased, or decreased depending on the drug. At lower temperatures, there is less drug transfer into lipid tissues, which affects distribution depending on the lipophilicity of the drug. Altered tissue-binding capacity can also be observed depending on the drug.

In a state of hypothermia, hepatic, renal, and biliary clearances have been shown to decrease. High-clearance drugs seem to be effected more than low-clearance drugs.

Pharmacodynamics

Enzymatic inactivation by hypothermia is dependent on the targets for certain drugs.

Targets of neuromuscular-acting agents have not been shown to be affected by lower temperatures, whereas cardiac targets of sympathomimetic drugs (catecholamine receptors) have increased sensitivity in the presence of lower temperatures.

Drug affinity for mu opioid receptors has also been observed to be altered in a state of hypothermia. Mu agonists have been shown to have decreased affinity in hypothermia, though antagonists have not been shown to have altered affinity.

References

1. Neumar RW, Shuster M, Callaway CW, Gent LM, Atkins DL, Bhanji F, et al. Part 1: executive summary: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015 Nov;132(18 Suppl 2):S315-367.

2. van den Broek MPH, Groenendaal F, Egberts ACG, Rademaker CMA. Effects of hypothermia on pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010;49(5):277-294.

3. Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy. 2008;28(1):102-111.