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When drugs are used to treat or prevent disease, doses must be given that achieve the necessary concentrations for the desired effects, yet remain at levels in the blood that do not cause excessive toxicity. The processes that determine this are collectively called pharmacokinetics. This involves the study of drug absorption into the body, distribution throughout the body, and metabolism and excretion to eliminate the drug from the body. Many factors contribute to variability in the pharmacokinetics of a given drug, including age, gender, body weight, and medical conditions. Sometimes, pharmacokinetics is referred to as clinical pharmacokinetics.
When a drug is given by any means other than the intravenous route, it must be absorbed across biologic membranes to reach the blood. Most often, this refers to oral drugs absorbed from the gastrointestinal (GI) tract. The percentage of a dose that reaches the blood after absorption is called bioavailability.
The most common reason for a low oral bioavailability is first-pass metabolism. All drugs absorbed from the GI tract go through the liver first. Here, drugs can be significantly broken down, or metabolized, before reaching the blood. Other reasons for decreased oral bioavailability include destruction of the drug by gastric acid and inhibition of absorption by food. Some drugs have saturable absorption, meaning that only a certain amount can be absorbed at one time.
Once the drug is in the blood, it may remain there or go into various tissues throughout the body. The volume of distribution (Vd) is an indication of the extent to which a drug is distributed outside the blood. It is a mathematical relationship between the amount of drug in the body and the concentration in the blood. This is a virtual, rather than a physiologic, volume and expresses the volume that would be needed to contain all drug in the body at any point in time.
Practically speaking, Vd is used to calculate a loading dose for a drug. This is the amount of drug that will quickly reach effective concentrations in the blood. It is the dose that fills the tank completely, if you will. A loading dose will be larger for drugs with a large Vd compared to one with a small Vd.
The half-life of a drug is the time it takes for the concentration in the blood to decrease by one-half. It is usually expressed in hours, but for some drugs, it may be a matter of minutes or as long as several days. Half-life is taken into consideration when determining how frequently to dose a drug. A longer half-life means the drug may be given less frequently.
Several organs in the body have the ability to break down drugs. This is called drug metabolism. Organs with metabolic capabilities include the liver, kidneys, GI tract, and lungs. Even the blood contains enzymes that can metabolize drugs.
The enzymes in the liver that metabolize drugs evolved long before humans took medications intentionally. These enzymes inactivate toxins that are inadvertently ingested, thereby preventing damage to the body. Since many drugs are derivatives of naturally occurring substances, they are also susceptible to breakdown by liver enzymes. Liver disease, such as cirrhosis or hepatitis, can decrease the body’s ability to metabolize drugs.
Two separate processes characterize metabolism by the liver: phase I reactions and phase II reactions. Phase I reactions usually inactivate or detoxify drugs. After inactivation, phase II reactions add molecules that make the drug more water-soluble. This enhances drug elimination by the kidneys.
The most prevalent phase I enzymes in the liver are called the cytochrome P450 enzymes. Some drugs may increase production of these enzymes by the liver, leading to a decreased concentration of the metabolized drug in the blood. This is called enzyme induction. Other drugs can inhibit cytochrome P450 enzymes. These drugs are called enzyme inhibitors, and they may cause an increased concentration of the metabolized drug.
The final step in pharmacokinetics is elimination of the drug from the body, also called excretion or clearance. For most drugs, clearance is a constant factor, regardless of how much drug remains in the body. This is called linear pharmacokinetics. For some drugs, however, clearance is saturable, usually because the metabolizing enzymes can only break down a fixed amount of drug at one time. Drugs with saturable metabolism and/or clearance exhibit non-linear pharmacokinetics.
Clearance of drugs is accomplished primarily by the kidneys. Inactivated drugs are excreted into the urine and taken out of the body. A decrease in kidney function, either as a result of age or diseases such as diabetes or high blood pressure, can decrease the body’s ability to eliminate drugs. The liver also excretes drugs, usually into the bile with elimination through the feces.
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