First-pass effect After the drug is absorbed across the gut wall, the drug is delivered by blood to the liver before it reaches systemic circulation. Drugs can be metabolically processed by the gut wall as well as the blood, but typically, it is the liver that is responsible for most metabolism before the drug enters systemic circulation. The liver may also excrete the drug in bile. Each of these channels may contribute to the loss in bioavailability, the sum of which is referred to as first-pass effect or elimination . This means that a drug is swallowed and absorbed with its effects diminished through processing by the liver. Because of this effect, some types of medications are administered intravenously rather than orally, so the active ingredients are utilized appropriately for therapeutic benefits rather than rendered inactive or used up through the liver’s metabolic properties. A number of interrelated factors influence an individual’s ability to metabolize drugs, including physical condition, genetic differences, and age. In cases of liver disease or dysfunction, where there is destruction of hepatocytes, metabolic action will be disturbed or slowed. Reduced hepatic blood flow may also be a result of cardiac failure or shock. Drug metabolism is largely mediated by the individual’s enzyme system functions, which is widely genetically determined. Individuals vary considerably in their response to certain drugs, especially those with hepatic metabolism. First-pass metabolism is often reduced in the elderly, resulting in greater bioavailability of the drug. The elderly may also experience delayed production and elimination of active metabolites, which can extend drug action. In such cases, reduced dosages may be necessary. Newborns—who do not have fully effective enzyme systems—may be at increased risk of toxic drug effects (Herman & Santos, 2022). Drugs in the gastrointestinal tract Many interacting factors determine how drugs are absorbed from the gastrointestinal tract. Because the gastrointestinal tract’s pH varies at different points of the route, and drug absorption varies according to environmental pH, different parts of the body with different pH values will affect how medications work. Antacids, for example, change the environmental pH of the gastrointestinal tract, tending to decrease absorption of acidic drugs and increase absorption of drugs with alkaline pH. When a drug has a higher concentration in the gastrointestinal tract than in the bloodstream, the drug will move through the cell membrane into circulation. Transport will continue until the drug’s concentration is equal on either side of the cell membrane (in both the gastrointestinal tract and the bloodstream). Drug absorption will also vary according to the amount of food and liquid in the gastrointestinal tract, as well as the amount and rate of movement or action of the digestive system. The presence of food in the gastrointestinal tract can either increase or decrease drug absorption, depending on the type of drug and type of food or fluid consumed. Medications taken with liquids are partly dissolved by them, which facilitates the drug’s passage to the small intestine. In cases where the gut’s content moves quickly through the system, there is less time for the drug to be absorbed. Where the drug is located among the food will influence how much and how quickly it is absorbed. The rate of drug absorption is greatest in the small intestine, as it has the largest surface area for absorption and also a strong blood supply—two factors that facilitate drug absorption. Gastric emptying is associated with a faster absorption rate, while delayed emptying will slow drug delivery to the intestine, reducing the rate of absorption.
Injected drugs will absorb at varying degrees according to tissue perfusion of the site. Intradermal drugs travel from the injection site into the capillaries more slowly than subcutaneously administered drugs. Drugs injected into the muscle will absorb even more quickly due to the abundant supply of blood to the muscles. Fat acts as a storage location for lipid-soluble drugs (like anticoagulants). Drugs may accumulate there, building up and remaining for an extended period, and releasing long after administration of the drug is complete. Drug distribution Distribution involves movement of the drug from the administration site to the area targeted for a specific desired effect of the drug. Distribution of drug molecules depends on many interrelated factors, including blood flow, binding of the drug, and barriers between body compartments. Some drug molecules are deposited in storage areas along the route, and some are rendered inactive or never distributed. Tissue with the most abundant blood flow tends to receive the drug first; increased blood flow to the tissue means increased uptake of a drug. Tissues receiving the most blood, like the brain and kidney, have the highest rate of uptake, while tissues with low blood supply, like fat, accumulate the drug at a slower rate. Highly vascular organs like the liver, kidney, and heart will acquire the drug more quickly than bone, muscle, fat, or skin tissues, which have low vascularity. Other characteristics of the individual, including activity level and tissue temperature, can also affect the drug’s distribution to the skin and muscle. Lipid solubility and the degree of ionization . Solubility refers to the drug’s ability to enter tissues; highly lipid- soluble drugs can travel throughout the body, while highly ionized drugs are unable to cross lipid membranes. Ion channels are selective porous passages in the cell membrane that allow ion movement in and out of the cell. Some drugs block these routes. Ability to cross barriers . Certain areas of the body, like the brain and testis, are resistant to drug penetration because these tissues are lined with capillaries made of endothelial cells; these cells create a barrier between those tissues and the rest of the body (i.e., blood-brain barrier). This issue is of special concern in the case of pregnant women, as some drugs can cross the placenta, causing harm to the fetus, or may be passed on to an infant through the mother’s breast milk. Drugs administered orally must travel through a number of cell membrane barriers before reaching circulation. Binding . Binding of the drug to other molecules in the blood and tissue limits its distribution to specific areas of the body. For example, drugs bound to plasma proteins are limited in that they can only travel where the proteins go. Rate of absorption: Zero order and first order elimination The rate of absorption is largely dictated by the route of administration and drug composition. Drug absorption can be referred to as graphically “nonlinear” or “zero-order” when the rate of drug release is not associated with the amount of drug remaining in the originating compartment, for example, in the case of a time-released drug. A model that exhibits this characteristic may also be referred to as “saturable,” “capacity-limited elimination,” “dose- dependent,” or “concentration dependent.” Graphically linear or “first order” kinetics, in contrast, refer to a rate of absorption that is typically proportional to the amount in the gastrointestinal concentration (gut) or drug concentration in the originating compartment.
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