Volume of distribution

Lecture (3) Pharmacology Dr. Dalia A. Muhsin

Volume of distribution
The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C).

Although Vd has no physiologic or physical basis, it can be useful to compare The distribution of a drug with the volumes of the water compartments in the body
Distribution into the water compartments in the body:
Once a drug enters the body, from whatever route of administration, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site.
a. Plasma compartment:
If a drug has a very large molecular weight or binds extensively to plasma proteins, it will, effectively trapped within the plasma compartment. As a consequence, the drug distributes in a volume (the plasma) that is about 6 percent of the body weight or, in a70-kg individual, about 4 L of body fluid. e.g. Heparin shows this type of distribution.
b. Extracellular fluid:
If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the water phase inside the cell. Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid. This is about 20 percent of the body weight, or about 14 L in a 70kg individual e.g. Aminoglycoside .
c. Total body water: If a drug has a low molecular weight and is hydrophobic, not only can it move into the interstitium through the slit junctions, but it can also move through the cell membranes into the intracellular fluid. The drug, therefore, distributes into a volume of about 60 percent of body weight, or about 42 L in a 70-kg individual. Ethanol exhibits this apparent volume of distribution.

A drug rarely associates exclusively with only one of the water compartments Of the body. Instead, the vast majority of drugs distribute into several compartments, often avidly binding cellular components, such as, lipids (abundant in adipocytes and cell membranes), proteins (abundant in plasma and within cells), and nucleic acids (abundant in the nuclei of cells). Vd is a useful pharmacokinetic parameter for calculating a drug’s loading dose
DRUG CLEARANCE THROUGH METABOLISM
Once a drug enters the body, the process of elimination begins. The three major routes involved are: 1) hepatic metabolism, 2) elimination in bile, and 3) elimination in urine. Together, these elimination processes cause the plasma concentration of a drug to decrease exponentially. That is, at any given time, a constant fraction of the drug present is eliminated in a unit of time.
Metabolism leads to products with increased polarity, which will allow the drug to be eliminated.
Clearance (CL) estimates the amount of drug cleared from the body per unit of time. Total CL is a composite estimate reflecting all mechanisms of drug elimination and is calculated as:
where t1/2 is the drug’s elimination half-life, Vd is the apparent volume of distribution, and 0.693 is the natural log constant.

Kinetics of metabolism
1. First-order kinetics: That is, the rate of drug metabolism and elimination is directly proportional to the concentration of free drug. First-order kinetics is sometimes referred to clinically as linear kinetics.
2- Zero-order kinetics: With a few drugs, such as aspirin, ethanol , and phenytoin, when their doses are very large. The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time. This is called zero order kinetics (sometimes referred to clinically as nonlinear kinetics).
A constant amount of drug is metabolized per unit of time, and the rate of elimination is constant and does not depend on the drug concentration.
Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents must first be metabolized into more polar (hydrophilic) substances in the liver using two general sets of reactions, called Phase I and Phase II .
1. Phase I: Phase I reactions convert lipophilic molecules into more polar molecules by introducing a polar functional group, such as –OH or –NH .
The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed-function oxidases):

- Inducers: Certain drugs (for example, phenobarbital, rifampin, and carbamazepine) are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes,
- Inhibitors: Inhibition of CYP isozyme activity is an important source of drug interactions that lead to serious adverse events. The most common form of inhibition is through competition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ketoconazole), leading to drug interactions. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.
2. Phase II: This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many Phase I metabolites are too lipophilic to be retained in the kidney tubules. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are most often therapeutically inactive. Glucuronidation is the most common and the most important conjugation reaction.

Renal elimination of a drug
Elimination of drugs via the kidneys into urine involves the three processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.
1. Glomerular filtration: Drugs enter the kidney through renal arteries, which
divide to form a glomerular capillary plexus.
Free drug (not bound to albumin) flows through the capillary slits into Bowman’s
space as part of the glomerular filtrate . Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, varying the glomerular filtration rate and plasma binding of the drugs may affect this process.
2. Proximal tubular secretion:
Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier requiring) systems:
One for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system (for example, probenecid).
Distal tubular reabsorption: The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation.
** ion trapping : Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be done to minimize the amount of back-diffusion and, hence, increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine.
For example, a patient presenting with Phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If overdose is with a weak base, such as amphetamine, acidification of the urine with NHCl leads to protonation of the drug (that is, it becomes charged) and an enhancement of its renal excretion.
CLEAR ANCE BY OTHER ROUTES
Other routes of drug clearance include via intestines, the bile, the lungs, and milk in nursing mothers, among others . The feces are primarily involved in elimination of unabsorbed orally ingested drugs or drugs that are secreted directly into the intestines or in bile. While in the intestinal tract, most compounds are not reabsorbed and eliminated in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, halothane and isoflurane). Elimination of drugs in breast milk is clinically relevant as a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. However, deposition of drugs in hair and skin has been used as a forensic tool in many criminal cases.

Clinical situations resulting in changes in drug half-life
When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. It is important to be able to predict in which patients a drug is likely to have a change in half-life.
The half-life of a drug is increased by
1) diminished renal plasma flow or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage;
2) decreased ability to extract drug from plasma, for example, as seen in renal disease; and
3) decreased metabolism, for example, when another drug inhibits its biotransformation or in hepatic insufficiency, as with cirrhosis.
On the other hand, the half-life of a drug may decrease by
1) increased hepatic blood flow,
2) decreased protein binding, and
3) increased metabolism.