Pharmacokinetics

Issues of Concern

Absorption

Absorption is the process that brings a drug from the administration, eg, tablet or capsule, into the systemic circulation. Absorption affects the speed and concentration at which a drug may arrive at its desired location of effect, eg, 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 administration method has its own absorption characteristics, advantages, and disadvantages.

The absorption process 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. Bioavailability 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.

Once swallowed, oral medications must navigate the stomach acidity and be taken up by the digestive tract. The digestive enzymes begin the process of metabolism for oral drugs, already diminishing the amount of drug arriving in circulation before being taken up. Once absorbed by gut transporters, the medications often 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 drug that arrives in circulation and, 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 from arriving 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 with 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 the 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 to be active.

Volume of Distribution (Vd)

This metric is a common method of describing the dissemination of a drug. The volume of distribution is defined as the amount of drug in the body divided by the plasma drug concentration.[4] One must 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 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. Loading doses are directly related to the volume of distribution and are 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 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 a greater effect or an increased possibility of toxicity. The principal proteins responsible for binding medications 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 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 the "active" space, unbound by serum protein. This will increase the effect of the medication and increase the possibility of toxicity, eg, 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 Phase II conjugation reactions to occur.[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. Medications may be cleared in the kidneys 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 a drug's elimination rate to the plasma drug concentration. This is influenced by the drug and the patient's blood flow and organ status (usually kidneys). In the perfect extraction organ, in which blood would completely be cleared of medication, the clearance would become limited by the overall blood flow 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 eliminated since the previous administration.[9] Maintenance doses are 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, a drug's half-life 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 depicts 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 of 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 over time. Under ideal treatment circumstances, when 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. For 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]

Clinical Significance

When a provider prescribes medication, the ultimate goal is a positive 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 can better estimate the locations and concentrations of a drug in different areas of the body.

The appropriate concentration needed to obtain the desired effect and the amount required for a higher chance of adverse reactions are determined through laboratory testing. Using the equations above, a clinician can easily estimate safe medication dosing over time and how long it will take for a drug 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, making improvisation possible when the clinical situation requires it.

Nursing, Allied Health, and Interprofessional Team Interventions

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 correctly self-administering and storing their medications. The physician, nurse, or pharmacist can perform this education. It may serve the patient well to hear this information from multiple providers to optimize therapy and minimize toxicity.

Notably, the interprofessional team needs to monitor for signs of drug efficacy and toxicity, which are affected by the drug's pharmacokinetic parameters, eg., half-life. The pharmacist should verify the dosing, perform a drug interaction check, and follow the plasma concentrations of medication if clinically warranted, eg, gentamicin. Nursing can monitor adverse events, make preliminary assessments of treatment effectiveness on subsequent visits, and verify patient medication adherence.

Both nurses and pharmacists need to have an open communication line with the prescribing physician to 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]