Expo ICYMI: What Is Pharmacokinetics, and Why Should an EMT Care?

We know not everyone can make it to EMS World Expo every year. For that reason we are pleased to offer this occasional series, Expo ICYMI (that’s In Case You Missed It, if you’re not hip to social media acronyms), in which Expo speakers summarize their presentations into short print articles. Don’t miss the fun again—this year’s EMS World Expo is October 14–18 in New Orleans.

As the role of EMS providers has progressed throughout the history of the profession, so has the complexity of the care medics provide. While early first responders had a limited arsenal of pharmacological tools at their disposal, modern paramedics deal with high-risk medications with narrow margins for error.¹ Paramedics now routinely administer drugs such as epinephrine, fentanyl, ketamine, and rocuronium—medications in which the slightest error could introduce catastrophe—as part of their care, with a high degree of competency.

Furthermore, paramedics are playing a pivotal role in the procurement of new drug knowledge through participation in clinical trials—a recent example being the aptly named PARAMEDIC2 trial.² While pharmacotherapy has increased in complexity, we are fortunate to also have experienced a concomitant expansion in our mastery of the mechanics of the drugs.

Many emergency departments staff clinical pharmacists as part of their care teams, and EMS teams can develop strong working relationships with them for training and resources. For example, our local  EMS teams from Washington's Thurston County Medic One and emergency medicine pharmacists at Providence St. Peter Hospital in Olympia have teamed up on several occasions to provide pharmacology seminars for EMTs, including lectures on pharmacokinetics. EMS will often ask our pharmacists questions regarding both the drugs in the medics' tool kit and medications taken by patients. In turn our pharmacists rely on our EMS colleagues for detailed information regarding the patients' home medications as well as medications administered in the prehospital setting. 

Definition of Pharmacokinetics

To understand why a strong knowledge of pharmacokinetics is vital to optimizing a prehospital provider’s use of medications, further exploration of pharmacokinetics as a concept is needed.

The term pharmacokinetics is said to have been first used by German pediatrician F.H. Dost in a 1953 manuscript and is defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Pharmacokinetics, then, is the lens through which we peer into the workings of pharmacologic compounds and their relationships with the human body.^3,4 Pharmacokinetics pioneer Milo Gibaldi, PhD, and the late pharmaceutical scientist Gerhard Levy, PharmD, further added to this definition to include “the relationship of these processes to the intensity and time course of therapeutic and adverse effects of drugs, [involving] the application of mathematical and biochemical techniques in a physiologic and pharmacologic context.”³  

Pharmacodynamics refers to the relationship between the drug concentration at the site of action and its resulting effect.^4,5 While the clinical effects of the medications in a medic’s tool kit may be well known, having a deeper understanding of the foundational concepts of clinical pharmacokinetics is valuable for any healthcare professional wishing to understand pharmacotherapy at its core. As healthcare providers our goal with clinical pharmacokinetics is simply to enhance efficacy and decrease toxicity of a patient’s drug therapy. To that end it is helpful to explore the concepts of absorption, distribution, metabolism, and excretion. 

Absorption

For a drug molecule to exert its effect, it must first reach the receptors upon which it acts. Thus absorption is the first concept in pharmacokinetics, as it represents the initial interaction of the drug with the body.

A number of factors may influence absorption, including the route of administration (e.g., intravenous, intramuscular, oral, intraocular, transdermal) and formulation (e.g., immediate-release vs. extended-release capsules and tablets). Of note, during oral administration blood flow often first passes through the liver, where drugs may be inactivated prior to circulating to the rest of the body. This is known as the first-pass effect and impacts bioavailability, or the fraction of drug absorbed after extravascular administration.^4,5

Lidocaine, for example, may be administered intravenously for cardiac arrhythmias, but the drug has poor systemic circulation if given orally due to biotransformation in the liver prior to further absorption.⁶ For this reason lidocaine is given orally for its topical effects but not for treating an arrhythmia.

Distribution

The one-compartment model is the most commonly used model in clinical practice. Under this model a dose of a drug is assumed to distribute instantaneously and evenly to all areas of the body. However, the reality is that drug distribution will be influenced by tissue blood flow, passive diffusion across membranes or active uptake, and plasma protein/tissue binding.

A more realistic view may be taken with multiple compartments, an example of which is the two-compartment model. In this model the first compartment is a smaller, rapidly equilibrating volume such as blood, plasma, and well-perfused organs with a high blood flow rate. The second compartment would then be the tissues to which the drug more slowly distributes over a longer period of time.^4,5,7 An example of a common drug with two-compartment distribution is digoxin, which distributes first into blood plasma (from which drug levels can be sampled), then more slowly into peripheral tissues (which cannot be sampled).⁴

Metabolism

While the liver is the primary organ for the metabolism of drugs, the intestines, kidneys, lungs, plasma, red blood cells, skin, and brain are also metabolic entities.⁸ Metabolism is generally enzymatic, whereby drug molecules are transformed to facilitate excretion into bile or urine. This process may inactivate a drug molecule or change it into a pharmacologically active metabolite, which in itself can exert an effect on the same or entirely different receptors.^5,7,8 For example, morphine is transformed into various metabolites, some of which are also pharmacologically active.⁹

Excretion

Excretion is generally accomplished through the kidneys or elimination through the gastrointestinal tract. Clearance refers to the theoretical volume of blood cleared of the drug per unit of time. The concept of drug half-life—the amount of time required for half a given amount of drug to be cleared from the body—is significantly useful in the context of pharmacokinetics.^5,7,8 In general a drug is felt to be effectively eliminated from the body after approximately six half-lives, at which point only about 1.5% of drug would theoretically remain.

It is worth noting that alterations in liver and kidney function can impact drug elimination and half-life. The metabolites of morphine mentioned above can accumulate in renal dysfunction; thus lower starting doses are recommended in patients with kidney function issues.⁹ Drugs can have widely varying half-lives—for instance, adenosine’s is less than 10 seconds, while amiodarone has a half-life of 58 days.^9,10

Conclusion

As the profession of prehospital caregivers continues to expand and new drugs are developed for use in these settings, it is incumbent on the caregiver to be competent in the concepts of basic clinical pharmacokinetics. A fuller understanding and knowledge of the underlying fundamentals of pharmacokinetic theory will result in a stronger application in the real-world setting and better patient care.¹¹ Emergency medicine pharmacists are the natural interface between prehospital providers and emergency room staff. Strengthening relationships between pharmacists and EMS can bolster knowledge for both professions and lead to opportunities for collaboration and education.

References

1. Neff C. A History of Emergency Medical Services. EMS World, www.emsworld.com/news/12130421/a-history-of-emergency-medical-services.

2. Perkins GD, Ji C, Deakin CD, et al.; PARAMEDIC2 collaborators. A randomized trial of epinephrine in out-of-hospital cardiac arrest. N Engl J Med, 2018 Aug 23; 379(8): 711–21.

3. Wagner JG. History of pharmacokinetics. Pharmacology and Therapeutics, 1981; 12(3): 537–62.

4. Winter M. Basic Clinical Pharmacokinetics. Baltimore, MD: Lippincott Williams & Wilkins, 2009.

5. Spruill WJ, Wade WE, DiPiro JT, Blouin RA, Pruemer JM. Concepts in Clinical Pharmacokinetics. Bethesda, MD: American Soceity of Health-System Pharmacists, 2014.

6. Fresenius Kabi. 2% Xylocaine Viscous (lidocaine HCl) solution, www.accessdata.fda.gov/drugsatfda_docs/label/2014/009470s025lbl.pdf.

7. DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10th ed. New York, N.Y.: McGraw-Hill, 2017.

8. Fan J, de Lannoy IA. Pharmacokinetics. Biochem Pharmacol, 2014 Jan 1; 87(1): 93–120.

9. Food and Drug Administration. Adenocard IV (adenosine injection) for Rapid Bolus Intravenous Use, www.accessdata.fda.gov/drugsatfda_docs/label/2011/019937s026lbl.pdf.

10. Food and Drug Administration. Cordarone (amiodarone HCl) tablets, www.accessdata.fda.gov/drugsatfda_docs/label/2009/018972s038s039lbl.pdf.

11. Friese G. How pharmacists improve EMS patient care. EMS1, www.ems1.com/ems-world-2018/articles/392804048-How-pharmacists-improve-EMS-patient-care/.

Daniel Hu, PharmD, BCCCP, is a critical care and emergency medicine pharmacist at Providence St. Peter Hospital in Olympia, Wash.

Ben Miller-Todd, BA, NRP, is ALS program manager for Thurston County Medic One in Olympia, Wash.