94 3.3 Distribution
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The second stage of the ADME of pharmacokinetics is known as distribution. Distribution is the process by which drugs are spread throughout the body’s blood and tissues. After a drug enters systemic circulation by absorption or direct administration, it will pass from vascular spaces to tissues where a drug-receptor interaction will occur, creating the effect of the drug. Thus, the efficacy or toxicity of a drug depends on the distribution to specific tissues. This varies based on the biochemical properties of the drug as well as the physiology of the individual taking the medication. We will discuss some of these factors in the next few sections of this chapter.
3.3.1 Volume of Distribution
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One of the most important pharmacokinetic parameters of distribution is the volume of distribution. Volume of distribution (Vd) represents a drug’s propensity to either remain in the plasma or distribute to the tissue compartments. Essentially, it relates the total amount of drug in the body to the plasma concentration of the drug at a given time. It is typically represented as a volume (e.g., liters (L)). The following equation can represent Vd:
[latex]{\text {Volume of Distribution (Vd)}} = \frac{\text{Amount of drug in the body (mg)}}{\text{Plasma concentration of drug (mg/L)}}[/latex]
Based on this formula, the higher the value of Vd, the greater the propensity of the drug to leave the plasma and distribute to the tissues. This means that a higher dose of a drug is required to achieve a given plasma concentration. Conversely, a drug with a low Vd has a propensity to remain in the plasma, with less of the drug distributed to the tissues. This means that a lower dose of the drug is required to achieve a given plasma concentration.
There are features of drugs that affect the volume of distribution, including acid-base characteristics and lipophilicity. Acidic molecules typically exhibit a lower Vd compared to basic molecules, due to their attraction to plasma proteins, causing them to remain in the plasma. Basic molecules typically exhibit a higher Vd compared to acidic molecules, due to their attraction to the lipid bilayer of cells, causing them to leave systemic circulation. More lipophilic drugs tend to exhibit a higher Vd, whereas more hydrophilic drugs tend to exhibit a lower Vd. This is rooted in the fact that lipophilic drugs are more likely to pass through lipid bilayers and leave the bloodstream, whereas those that are more hydrophilic remain in systemic circulation.
3.3.2 Factors Influencing Distribution
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3.3.2.1 Blood Flow
The circulatory system transports medications throughout the body in the bloodstream. Many factors can affect the blood flow and delivery of medication, such as decreased blood flow (due to dehydration), blocked vessels (due to atherosclerosis), constricted vessels (due to uncontrolled hypertension), or weakened pumping by the heart muscle (due to heart failure). As an example, when administering an antibiotic to a patient with diabetes who has an infected toe, it may be difficult for the antibiotic to move through the blood vessels all the way to the area of the toe that is infected because of blocked vessels in the legs and feet due to atherosclerosis.
3.3.2.2 Tissue Differences
Distribution occurs most rapidly into tissues with a greater number of blood vessels that allow high blood flow (such as the lungs, kidneys, liver, and brain). Distribution occurs least rapidly in tissues with fewer numbers of blood vessels (such as fat), resulting in low blood flow. However, lipophilic drugs (i.e., drugs that dissolve in lipid environments) disproportionately distribute into adipose tissue in obese subjects.
The permeability of capillaries is tissue-dependent. Capillaries of the liver and kidney are porous, allowing for greater permeability. Distribution rates are relatively slower or nonexistent into the central nervous system because of the tight junction between capillary endothelial cells and the blood-brain barrier.
3.3.2.3 Protein Binding
After a drug enters the bloodstream, a portion of it exists as free drug, dissolved in plasma water, but a portion of it becomes bound to proteins. This is important because only free and unbound drugs will pass from the bloodstream to tissues where drug-receptor interactions will occur, thus producing the effect of a medication. The other portion of the drug that becomes “protein-bound” is inactive while it is bound. For many drugs, these bound forms can account for 95–98% of the total. Protein binding can also act as a reservoir, as the drug is released slowly, causing a prolonged action. When considering drug distribution, it is important to consider both the amount of free drug that is readily available to tissues, as well as the protein binding that causes the drug to be released over time.
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Albumin is one of the most important proteins in the blood. Albumin levels can be decreased by several factors, such as malnutrition and liver disease. Therefore, patients with low albumin levels may experience differences in the desired actions of administered medication because of the consequence effect on protein-binding and distribution. Competition for plasma binding can also impact the effects of drugs. For example, aspirin and warfarin are both anticoagulants that compete for the same plasma protein-binding site. Administering both drugs at the same time may increase the risk of severe bleeding. This is due to the ability of aspirin to displace warfarin from plasma proteins, increasing the unbound (free) concentration of warfarin in the blood. Patients taking warfarin are typically advised to reduce their aspirin intake due to this interaction.
As an analogy of how protein binding affects the distribution of medications, consider passengers at a bus stop going to their destination. Many passengers (i.e., drug molecules) want to take a ride on the bus. Everyone is eager to get to their destination (i.e., receptor sites) and tries to find a seat. Some passengers are stronger than others and take all the seats first (such as drug molecules with greater protein-binding ability). When there aren’t enough seats on the bus, some passengers are left at the bus stop and become “free” to move around or walk to their destination. In a similar way, “free” drug molecules that are not protein-bound circulate freely in the bloodstream. The “free” passengers in this analogy may go directly to their destination, or they may stop at other locations along the route. In a similar manner, “free” drug molecules produce the first intended or unintended effects in the body when they attach to receptors. Furthermore, similar to the passengers who had seats on the bus and then later got off at their destination, the medication molecules attached to proteins are eventually released and attach to the receptor sites.
3.3.2.4 Barriers
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Medications destined for the central nervous system (the brain and spinal cord) face an even larger hurdle than protein-binding; they must also pass through a nearly impenetrable barricade called the blood-brain barrier (BBB). This blockade is built from a tightly woven mesh of capillaries that protect the brain from potentially dangerous substances, such as poisons or viruses. Only certain medications made of lipids or those with a “carrier” can get through the blood-brain barrier. Scientists have devised ways for medications to penetrate the blood-brain barrier. For example, the brand-named medication Sinemet® used to treat Parkinson’s disease is a combination of two drugs: carbidopa and levodopa. Levodopa is converted to dopamine via the enzyme DOPA decarboxylase. In the central nervous system, activation of dopamine receptors leads to improvement of the symptoms of Parkinson’s disease; however, in the periphery this can lead to nausea and vomiting. Carbidopa is a DOPA decarboxylase inhibitor (DDCI) and cannot cross the BBB, thereby preventing the conversion of levodopa into dopamine in the periphery and reducing the unwanted side effects of levodopa.
Some medications inadvertently bypass the blood-brain barrier and impact an individual’s central nervous system function as a side effect. For example, diphenhydramine is an antihistamine used to decrease allergy symptoms. However, it can also cross the blood-brain barrier, depress the central nervous system, and cause the side effect of drowsiness. In the case of a person who has difficulty falling asleep, this drowsy side effect may be useful, but for a person trying to carry out daily activities, drowsiness can be problematic.
The placenta links mother and fetus, and the blood-placental barrier regulates the transfer of molecules between maternal and fetal circulation to protect the fetus. Drug transporters are involved in the transport of drugs through the placenta, affecting potential drug distribution to the fetus. The placenta is known to be permeable to some medications, which may cause significant harm to the fetus.
Many medications have not been specifically studied in pregnant patients, and their effects on the fetus are unknown. For this reason, it is always important to consider the potential effects of medication on the fetus if it is administered to a client who is pregnant or who may become pregnant.
3.3.3 Special Considerations
There are certain populations of individuals that may present a specific physiological status that can increase the risk of toxicity of certain drugs or decrease their therapeutic effects. Young (i.e., fetus, infant) children and older adults are typically most at risk.
Fat content in infants and children is decreased because of greater total body water. This leads to a higher Vd for hydrophilic drugs, which may require a higher dose to achieve therapeutic concentrations. Additionally, protein-binding capacity is decreased in infants and young children, and the developing blood-brain barrier allows more drugs to enter the central nervous system. This leads to increased free drug concentrations, which can increase the risk of adverse effects.
At the same body mass index, older adults, on average, tend to have more body fat than younger adults. This increased body fat can result in a longer duration of action for many medications that accumulate in fatty tissues. Serum albumin also decreases, resulting in more active free drug circulating within the body. For these reasons related to distribution, many older adult patients require lower dosages of medication.
