2.2: Distribution

2.2 Overview of Distribution

After a drug has been absorbed or administered intravenously, the second phase of pharmacokinetics, distribution, begins. In this phase, the drug is distributed throughout the body and gains exposure to its target site via the circulatory system.

A medication's distribution can also cause unintended adverse or side effects, as described in Chapter 6. Drugs are designed to be selective, binding to one specific receptor and primarily causing one effect. Often, that is not the case. The likelihood of a drug binding to another receptor increases as the amount of drug in circulation increases. Side effects may occur when a drug binds to other sites in addition to the intended target. These side effects can range from tolerable to unacceptable, resulting in discontinuation of the medication (a drug given to treat a disease state). For example, a person might take ibuprofen (Advil®) for muscle soreness in their leg, and the pain may be relieved, but the side effect of gastric irritation may cause the person to stop taking the medication.

As a drug is circulated throughout the body, it crosses membranes to be dispersed into interstitial and intracellular fluids. There is often no direct way to measure the drug concentration in the target tissue. Instead, blood plasma levels are used as a surrogate to determine the concentration of a drug within the body. The amount of drug that reaches the target molecule or tissue depends upon many factors that determine how easily a drug can move through the body and cross membranes (including the blood–brain barrier and the placental barrier). These factors include blood flow, plasma protein binding, lipid solubility, drug concentration gradients, and permeability. Other factors include capillary permeability, differences between blood/tissue, and volume of distribution.

Blood Flow

Blood flow is a major regulating factor in the rate of drug uptake at a particular distribution site. Drug uptake is quicker in well-perfused tissues such as the brain, heart, kidneys, and splanchnic organs. Poor perfusion to the target organ can affect medication delivery, such as decreased blood flow in dehydration, heart failure, shock states, or other clinical scenarios involving compromised circulation. For example, when administering an antibiotic to a patient with diabetes who has an infected toe, it may be difficult for the antibiotic to reach a therapeutic concentration within the cells of the infected toe. This is because the same processes that contribute to the development of the infection, poor circulation to the foot/toe, also affect the distribution to that site.

Protein-Binding

One factor impacting the medications' distribution is the presence of plasma proteins in the blood, including albumin and glycoproteins. Albumin is the most abundant plasma protein, and its levels are decreased by malnutrition, liver dysfunction, and aging. A certain percentage of almost every drug is bound to plasma proteins once it reaches circulation. The portion of the drug that becomes “protein-bound” will be inactive while it is bound. The portion of the unbound or “free” drug is available to bind to the target tissue or target molecule and exerts its effect or blocks an action. The binding of a drug to plasma proteins is usually reversible, meaning that as a drug concentration decreases, the drug is released from the plasma protein. In contrast, an irreversibly bound drug is not released as concentration levels decrease. The drug’s affinity for a specific plasma protein or a receptor determines the probability of the drug binding to plasma proteins or a receptor.

A patient taking several highly protein-bound medications may experience a greater risk of side effects from each of these drugs. The affinity among the prescribed medications for a plasma protein (often albumin) varies. Suppose more than one medication that binds to plasma proteins is in circulation. In that case, the medications compete for the binding site, and the medication with the highest affinity will bind to the plasma protein. This action prevents other medications in the circulation from binding to plasma proteins, which float freely in the circulation and are available to bind to receptors, increasing the risk of side effects and toxicities.

Blood–Brain Barrier

Medications destined for the central nervous system (the brain and spinal cord) face an even larger obstacle than protein-binding; they must also pass through a nearly impenetrable barricade called the blood–brain barrier. This barrier is formed from a tightly woven mesh of capillaries that protects the brain from potentially dangerous substances such as microbes (viruses) and foreign molecules (drugs). Only lipid-soluble medications or medications that bind to a “carrier” or transport protein can cross the blood–brain barrier.

Pharmacologists and research scientists involved in designing and manufacturing drugs have devised ways for certain medications to penetrate the blood–brain barrier. An example is the brand-named medication Sinemet®, which is a combination of two drugs, carbidopa and levodopa, used to treat Parkinson’s Disease. Levodopa is lipid-soluble and crosses the blood–brain barrier, where it enters the brain and is converted into dopamine to exert its effect on Parkinson’s disease symptoms. However, if levodopa is given alone without carbidopa, it is degraded in the peripheral circulation, and only a small fraction of the original dose of levodopa reaches the brain. Carbidopa prevents the degradation of levodopa in peripheral circulation, allowing a larger amount of the levodopa to enter the brain and exert a therapeutic effect. This is an example of a synergistic drug combination.

Some lipid-soluble medications bypass the blood–brain barrier and impact an individual’s central nervous system function (CNS depressants). For example, diphenhydramine (Benadryl®) is an antihistamine that decreases allergy symptoms. However, because it crosses the blood-brain barrier and depresses the central nervous system, diphenhydramine causes drowsiness. This drowsy side effect may benefit a person who has difficulty falling asleep. Still, it may be problematic for another person as they try to carry out daily activities safely.

Placental Barrier

Consider the effects of medication on individuals who are or may become pregnant. The placenta is known to be permeable to substances such as alcohol, cocaine, caffeine, and certain prescription medications that cross the fetal–placental barrier. Some drugs can cause harm to the unborn fetus during any trimester, while others are teratogenic during a specific trimester. Further information is found in Chapter 7.

Tissue Differences in Rates of Drug Uptake

How quickly an organ or target tissue takes up a drug depends on the surface area of the organ or tissue. The larger the surface area, the faster the drug will be distributed to that tissue.

Capillary permeability is also tissue-dependent. Distribution rates are relatively slower or non-existent in the CNS because of the tight junction between capillary endothelial cells, the blood-brain barrier, and the presence of P-glycoproteins. These efflux proteins expel foreign molecules from the brain. Capillaries of the liver and kidneys are fenestrated or more porous, allowing for greater permeability.

Apparent Volume of Distribution

The volume of distribution (Vd) is not an actual anatomical space but a theoretical space. The volume of distribution (Vd) is the concentration of a drug spread across fluid compartments: plasma, extracellular water, and total body water. The volume of distribution is the pharmacokinetic parameter that relates the dose to the plasma concentration. Clinically, it is essential for accurately predicting how much medication we need to administer to achieve the desired therapeutic concentration in the plasma. Vd helps clinicians calculate that dose. Vd is depicted below. In the figure below (Figure 2.2.1), the Vd for the human figure on the left equals approximately 60 ml of fluid in the beaker on the right.

Vd is calculated by using the amount of the drug in the body divided by the plasma concentration of the drug (Vd = total amount of drug/plasma drug concentration).

Every drug has a different Vd and pattern of distribution. Some drugs are widely distributed in the body and cross cellular membranes to disperse into adipose tissue or bone (Figure 1.1). These drugs have a wide or large Vd. In contrast, some drugs may not distribute extensively throughout the body but stay in the plasma compartment. Such drugs may have relatively small Vd, and relatively low doses are necessary to achieve a target concentration. Other drugs may bind to plasma proteins. In this case, plasma drug levels may not accurately reflect the pharmacologic effect the drug may exert. Figure 2.2.2 below illustrates how a drug may bind and distribute throughout tissues and the subsequent relationship to the plasma concentration of a drug in circulation.

Figure 2.2.2: Drug binding and distribution. (CC-BY 4.0; Amy Hoang)

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Figure 2.2.2 depicts drug binding between the vascular and extracellular compartments under various hypothetical clinical conditions. In panel A, Drug A diffuses freely across the membrane between the two compartments. As a drug freely diffuses, it will reach equilibrium or steady state. At equilibrium, 20 mg of the drug is in the body. With 20 mg of the drug in the body, the steady-state distribution leaves a 2 mg/L plasma concentration.

In panel B, Drug B binds plasma proteins in the vascular compartment. At equilibrium, only 2 mg of the total drug is present in the extravascular compartment, while the remaining 18 mg is still in the vascular compartment. For the conditions in panels A and B, the total amount of drug in the body is the same (20 mg), but the apparent Vd is very different.

Finally, in panel C, Drug C exits the vascular compartment and strongly binds to molecules in peripheral tissues. For Drug C to reach a plasma concentration of 2 mg/L, a larger total dose of 200 mg must be given to achieve the desired plasma concentration. At equilibrium, 198 mg are bound in the peripheral tissues and only 2 mg in the plasma, so the calculated volume of distribution is greater than the physical volume of the system.

Clinicians use Vd to calculate how much drug or dose is needed to achieve a therapeutic concentration of a drug in the plasma. Another important point about understanding Vd is that it helps explain the limitations of plasma drug levels. As demonstrated in Figure 2.21, a plasma drug level doesn’t accurately reflect how much drug may be in the body. Clinicians need to be aware of the pharmacokinetic properties of individual drugs, including drugs that bind to plasma proteins such as digoxin, amiodarone, and ibuprofen. The Vd of drugs that bind to plasma proteins (albumin) can be altered by liver disease through reduced protein synthesis and kidney disease through protein loss in the urine. On the other hand, if a drug is avidly bound in peripheral tissues, the drug’s concentration in plasma may drop to very low values even though the total amount in the body is large. As a result, the Vd may greatly exceed the total physical volume of the body. For example, 50,000 liters is the average Vd for the drug quinacrine, also known as mepacrine, in persons whose average physical body volume is 70 liters.

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This chapter titled 2.2 Distribution is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Karen Vuckovic from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz (MIT OpenCourseWare) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures are by Amy Hoang and Riley Cutler.