Pharmacokinetics (PK) is the study of how the body interacts with administered substances for the entire duration of exposure (medications for the sake of this article). This is closely related to but distinctly different from pharmacodynamics, which more closely examines the drug’s effect on the body. The four main parameters generally examined by this field include absorption, distribution, metabolism, and excretion (ADME). Wielding an understanding of these processes allows practitioners the flexibility to prescribe and administer medications that will provide the greatest benefit at the lowest risk and allow them to make adjustments as necessary, given the varied physiology and lifestyles of patients.

Absorption

Absorption is the process that brings a drug from the administration, e.g., tablet, capsule, into the systemic circulation. Absorption affects the speed and concentration at which a drug may arrive at its desired location of effect, e.g., plasma. There are many possible methods of drug administration, including but not limited to oral, intravenous, intramuscular, intrathecal, subcutaneous, buccal, rectal, vaginal, ocular, otic, inhaled, nebulized, and transdermal. Each of these methods has its own absorption characteristics, advantages, and disadvantages. The process of absorption also often includes liberation or the process by which the drug is released from its pharmaceutical dosage form. This is especially important in the case of oral medications. For instance, an oral medication may be delayed in the throat or esophagus for hours after being taken, delaying the onset of effects or even causing mucosal damage. Once in the stomach, the low pH may begin to chemically react with these drugs before they even arrive in the systemic circulation.[1]

Bioavailability

Bioavailability is the fraction of the originally administered drug that arrives in systemic circulation and depends on the properties of the substance and the mode of administration. It can be a direct reflection of medication absorption. For example, when administering medication intravenously, 100% of the drug arrives in circulation virtually instantly, giving this method a bioavailability of 100%.[2] This makes intravenous administration the gold standard regarding bioavailability. This concept is especially important in orally administered medications. Oral medications, once swallowed, must navigate the acidity of the stomach and be taken up by the digestive tract. The digestive enzymes begin the process of metabolism for oral medications, already diminishing the amount of drug arriving in circulation before being taken up. Once absorbed by gut transporters, the medications then often have to undergo "first-pass metabolism." When oral medication is administered, it is often processed in large quantities by the liver, gut wall, or digestive enzymes, subsequently lowering the amount of medication that arrives in circulation; therefore, having a lower bioavailability.[2] These processes will be discussed in greater detail under metabolism. Other modes of administration may delay certain quantities of drugs to arrive in circulation at the same time (intramuscular, oral, transdermal), giving rise to the use of the area under the plasma concentration curve (AUC). The AUC is a method of calculating the drug bioavailability of substances that have different dissemination characteristics, and this observes the plasma concentration over a given time. By calculating the integral of that curve, bioavailability can be expressed as a percentage of the 100% bioavailability of intravenous administration.

Distribution

Distribution describes how a substance is spread throughout the body. This varies based on the biochemical properties of the drug as well as the physiology of the individual taking that medication. In its simplest sense, the distribution may be influenced by two main factors: diffusion and convection.[3] These factors may be influenced by the polarity, size, or binding abilities of the drug, the fluid status of the patient (hydration and protein concentrations), or the body habitus of the individual.[4] The goal of the distribution is to achieve what is known as the effective drug concentration. This is the concentration of the drug at its designed receptor site. To be effective, a medication must reach its designated compartmental destination, described by the volume of distribution, and not be protein-bound in-order to be active.

Volume of Distribution (Vd)

This metric is a common method of describing the dissemination of a drug. It is defined as the amount of drug in the body divided by the plasma drug concentration.[4] It is important to remember that the body is made up of several theoretical fluid compartments (extracellular, intracellular, plasma, etc.), and Vd attempts to describe the fictitious homogenous volume in a theoretical compartment. When a molecule is very large, charged, or primarily protein-bound in circulation, such as the GnRH antagonist cetrorelix (Vd = 0.39 L/kg), it stays intravascular, unable to diffuse, reflected by a low Vd. A different molecule that is smaller and hydrophilic would have a larger Vd reflected by its distribution into all extracellular fluid. Finally, a small and lipophilic molecule, such as chloroquine (Vd = 140 L/kg), would have a very large Vd as it can distribute throughout cells and into adipose tissues.[5] There may be multiple volumes of distribution depending on the rate of distribution within the subject.[4]

Knowledge of the volume of distribution is an important factor for a practitioner to understand dosing schemes. For example, an individual with advanced infection may require a loading dose of vancomycin to achieve desired trough concentrations. A loading dose allows the drug concentrations to rapidly achieve their ideal concentration instead of needing to accumulate before becoming effective. It is directly related to the volume of distribution and is calculated by Vd times the desired plasma concentration divided by bioavailability.[6]

Protein Binding 

In the body, a drug may be protein-bound or free. Only free drug can act at its pharmacologically active sites, eg., receptors, cross into other fluid compartments, or be eliminated. In the clinical setting, the free concentration of a drug at receptor sites in plasma more closely correlates with effect than is the total concentration in plasma.[4] The protein binding of the substance largely determines this. Any reduction in plasma protein binding increases the amount of drug available to act on receptors, possibly leading to greater effect or an increased possibility of toxicity. The principle proteins responsible for binding drugs of interest are albumin and alpha­-acid glycoprotein.[7] These proteins may fluctuate depending on the age and development of the patient, any underlying liver or kidney disease, or nutrition status. One example in which this is relevant is in renal failure. In renal failure, uremia decreases the ability of acidic drugs, such as diazepam, to bind to serum proteins. Even though the same amount of drug is initially given, there is far more drug in "active" space, unbound by serum protein. This will increase the effect of the medication and increase the possibility of toxicity, e.g., respiratory depression.[4]

Metabolism

Metabolism is the processing of the drug by the body into subsequent compounds. This is often used to convert the drug into more water-soluble substances that will progress to renal clearance or, in the case of prodrug administration such as codeine, metabolism may be required to convert the drug into active metabolites.[8] Different strategies of metabolism may occur in multiple areas throughout the body, such as the gastrointestinal tract, skin, plasma, kidneys, or lungs, but the majority of metabolism is through phase I (CYP450) and phase II (UGT) reactions in the liver. Phase I reactions generally transform substances into polar metabolites by oxidation allowing conjugation reactions of Phase II to take place.[2] Most commonly, these processes inactivate the drug, convert it into a more hydrophilic metabolite, and allow it to be excreted in the urine or bile.

Excretion

Excretion is the process by which the drug is eliminated from the body. The kidneys most commonly conduct excretion, but, for certain drugs, it may be via the lungs, skin, or gastrointestinal tract. In the kidneys, drugs may be cleared by passive filtration in the glomerulus or secretion in the tubules, complicated by reabsorption in some compounds.     

Clearance

Clearance is an essential term when examining excretion. It is defined as the ratio of the elimination rate of a drug to the plasma drug concentration. This is influenced by the drug, blood flow, and organ status (usually kidneys) of the patient. In the perfect extraction organ, in which blood would completely be cleared of medication, the clearance would become limited by the overall flow of blood through the organ.[4] An understanding of clearance allows practitioners to calculate appropriate dosing rates of medications. Maintenance dosing ideally replaces the amount of drug that was eliminated since the previous administration.[9] It is calculated by clearance times the desired plasma concentration divided by bioavailability.

Half-life (t)

The half-life is the amount of time for serum drug concentrations to decrease by 50%. Defined by the equation t=(0.693xVd)/Clearance, it is directly proportional to the volume of distribution and inversely to clearance. The half-life of medications often becomes altered from changes in the clearance parameters that come with disease or age.[4][10] 

Drug Kinetics

This is the graphical manifestation of metabolism and excretion and is depictions of a medication's half-life. The two major forms of drug kinetics are described by zero-order versus first-order kinetics. Zero-order kinetics display a constant rate of metabolism and/or elimination independent of the concentration of a drug. This is the case with alcohol and phenytoin elimination. There is a variable half-life that decreases as the overall serum concentrations decrease. In contrast, first-order kinetics relies on the proportion of the plasma concentration of the drug. First-order has a constant 't' with decreasing plasma clearance over time. This is the major elimination model of most medications. These two models are not usually independent for most drugs. However, as is the case with salicylates, at concentrations below 1.4 mmol/L, elimination is proportional to serum concentrations while, at higher concentrations, elimination is constant due to saturation of metabolic and eliminatory processes.[11]

These kinetic models can be used to estimate steady states and complete elimination of medications. Steady-state is when the administration of a drug and the clearance are balanced, creating a plasma concentration that is unchanged by time. Under ideal treatment circumstances, in which a drug is administered by continuous infusion, this is achieved after treatment has been operational for four to five half-lives. This is the point at which the system is said to be in a steady-state. This steady-state concentration can only be altered by changes in dosing interval, total dose, or changes in the clearance of the drug. Similarly, total elimination is measurable by half-lives. Upon administration of a drug that follows first-order elimination kinetics, it may be assumed that it is completely eliminated by four to five half-lives as, by that point, 94 to 97% of the medication has left the system. As an example, the 't' of morphine is 120 minutes; therefore, one may assume that there is a negligible amount of morphine in a patient's system eight to ten hours after administration.[12]

When a provider prescribes medication, it is with the ultimate goal of a therapeutic outcome while minimizing adverse reactions. A thorough understanding of pharmacokinetics is essential in building treatment plans involving medications. Pharmacokinetics, as a field, attempts to summarize the movement of drugs throughout the body and the actions of the body on the drug. By using the above terms, theories, and equations, practitioners are better able to estimate the locations and concentrations of a drug in different areas of the body. Through laboratory testing, the appropriate concentration needed to obtain the desired effect, and the amount needed for a higher chance of adverse reactions is determined. Using the equations given above, a clinician can easily estimate safe medication dosing over a period of time and how long it will take for a medication to leave a patient’s system. These are, however, statistically-based estimations, influenced by differences in the drug dosage form and patient pathophysiology. This is why a deep understanding of these concepts is essential in medical practice so that improvisation is possible when the clinical situation requires it.

The interprofessional team members caring for the patient need to work together to ensure the safety and efficacy of pharmacotherapy. The patient may require training on how to correctly self-administer and store their medications. The physician, nurse, or pharmacist can perform this education, and in fact, it may serve the patient well to hear it from multiple providers to optimize therapy and minimize toxicity. Importantly, the interprofessional team needs to monitor for signs of drug efficacy and toxicity, which are affected by the drug's pharmacokinetic parameters, e.g., half-life. The pharmacist should verify the dosing, perform a drug interaction check, and follow the plasma concentrations of medication if clinically warranted, e.g., gentamicin. Nursing can monitor adverse events and make preliminary assessments of treatment effectiveness on subsequent visits, as well as verifying patient medication adherence.

Both nurses and pharmacists need to have an open communication line to the prescribing physician so they can report or discuss any concerns regarding drug therapy, or the patient's drug regimen in general. This type of interprofessional communication is necessary to optimize patient outcomes with minimal adverse events.[13] [Level 5]