The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments. By definition, Vd is a proportionality constant that relates the total amount of drug in the body to the plasma concentration of the drug at a given time. The following equation can represent Vd:
Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L)
Based on the above equation:
General Principles Related to Drug Distribution
Pharmacokinetics focuses on drug movement throughout the human body via the processes of absorption, distribution, and elimination. Upon administration, a drug moves from the site of administration and gets absorbed into the systemic circulation where it will then gets distributed throughout the body. The process of distribution refers to the movement of a drug between the intravascular (blood/plasma) and extravascular (intracellular & extracellular) compartments of the body. Within each compartment of the body, a drug exists in equilibrium between a protein-bound or free form. Over time, drugs within the circulation will then be metabolized and excreted from the body by the liver & kidneys.
Single vs. Multi-compartment models of Distribution
Immediately after administration of an IV bolus, a drug enters the “central” compartment, which is composed of the plasma, highly perfused organs (liver, kidneys, etc.) and other tissues where drug distribution is instantaneous. Eventually, some drugs may begin to move from the central compartment to the “peripheral” compartment, which is composed of tissues to which drug distributes slower.
Drugs that display single compartment distribution kinetics with a straight line graph on plasma vs. time curves. Because the drug is said to distribute instantaneously, the initial plasma concentration of drug at time = 0 (Co) is difficult to measure and is therefore estimated via extrapolation to time = 0 on a plasma concentration vs. time curve.
Drugs that display multiple compartment distribution kinetics have graphs that are biphasic lines on plasma vs. time curves.
Half-life and Volume of Distribution
Half-life (t1/2) refers to the time required for plasma concentration of a drug to decrease by 50%. t1/2 is dependent on the rate constant (k), which is related to Vd & clearance (CL). Half-life can be expressed using the following equation(s):
Only the drug located in the central compartment can be eliminated from the body because the process of elimination is primarily carried out by the liver and kidneys. Drugs with a high Vd will have a large fraction of drug remaining outside of the central compartment. Meanwhile, the fraction of drug in the plasma will be eliminated, causing a shift of equilibrium resulting in drug located in the peripheral compartment to shift into the central compartment. This shift will cause the plasma concentration to remain at a steady-state concentration despite drug removal from the body. This phenomenon causes plasma concentration to decline more slowly during the elimination phase in the setting of a high Vd.
Therefore, at a constant rate of clearance, a drug with a high Vd will have a longer elimination half-life than a drug with lower Vd.
Similar to the different Vd values that exist depending on the pharmacokinetic phase, there are also two half-life values of which it is important to be aware:
Features of Drugs affecting the Volume of Distribution
As previously discussed, multiple values of Vd can be calculated depending on the intrinsic drug kinetics (single vs. multiple compartment models) as well as the phase of drug kinetics following drug administration (distribution phase vs steady state vs terminal elimination phase). However, from the clinical perspective, the single most important utility of Vd is calculating the loading dose of a drug.
The loading dose is best calculated using the Vd at steady state (Vss) as it is the most representative of the specific drugs pharmacokinetic properties at desired steady-state plasma concentration. Therefore, the loading dose can be calculated using the following equation:
After administration of a loading dose, additional maintenance doses can be administered to maintain the desired plasma concentration of the drug. Unlike, the loading dose, which is dependent on the drug's Vd, the maintenance dose is dependent on clearance (Cl). Maintenance dosing can be calculated with the following equation:
Key differences between loading doses & maintenance doses include:
Although drugs have inherent properties that govern the Vd, the patients also represent variables that can alter the apparent Vd. Therefore, the apparent Vd of certain drugs may vary significantly between patients depending on each patient’s individual physiology and/or pathophysiology. For example:
Understanding volume of distribution is important for both physicians and pharmacologist who prescribe and dose medications. Differentiating pharmacologic agents who have high versus low volume of distributions is essential in appropriately dosing medications for patients. While physicians generally dose medications in low complexity cases, patients in the intensive care unit might need their medications dosed by a pharmacist. Understanding and calculating different models of distribution, the factors that can affect the volume of distribution, loading dose, and maintenance doses can mean the difference between life and death. When dosing medication, it is of the utmost importance to promptly consult an interprofessional group of specialists.
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