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.
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 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 Elimination A drug’s rate of elimination refers to the disappearance of active drug molecules from the blood stream or body, which is typically associated with the end of pharmacodynamic effect. Most metabolic activity occurs in the liver, where hepatic enzymes biochemically react with drug molecules, but may also occur in the kidneys, intestines, lungs and plasma. In some cases, where drugs are administered repeatedly, metabolism becomes more efficient due to enzyme induction. This efficiency is referred to as drug tolerance , in which increasingly large doses of the drug become necessary to produce the same effect. The rate of elimination is typically discussed in terms of plasma concentrations of the drug, which characterize the intensity and duration of a drug’s effect. Drugs are most commonly eliminated by excretion, either through the kidney in the form of urine or, in small amounts, through the bile duct as feces. In order to be excreted by the kidneys, drugs must be relatively hydrophilic (readily dissolving in water) to remain in fluid state. Individuals with impaired kidney function are less able to excrete hydrophilic drugs, typically requiring adjusted dosages. The majority of drugs and metabolites are excreted by the kidneys. A number of factors influence at what rate the drug is excreted, including healthy condition or the presence of kidney disease, urine pH, renal Drug half-life Half-life is the amount of time necessary to alter the amount of drug in the body by one-half. In the simplest example, the human body is considered as a single compartment of a size equal to the volume of distribution (Vd). The time course of the drug in the body is proportional to both the volume of distribution and the clearance, or elimination, of the drug from the body. Drug metabolism and excretion dictate the drug’s half-life. Elimination half-life (signified by “t1/2”) is defined as the time taken for the concentration of the drug in the blood to fall to 50 percent of its original value (for the plasma drug concentration to reduce by 50 percent). Elimination is 94 percent complete after four half-lives. Dosage intervals are typically based on half-life estimations, and dosage regimes are developed to produce stable drug concentrations in 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. Depending 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. blood flow, and the concentration and the molecular weight of the drug. Drugs that are not excreted are metabolized in the following manner. Metabolism, or enzymatic conversion, is a process that terminates the action of many drugs, particularly lipophilic compounds, which readily dissolve in lipids. In most cases, metabolism forms a more water-soluble compound that can more easily be excreted in urine. The majority of enzymes encountered by the drug are located in the gastrointestinal tract and liver. Drugs and metabolites that are secreted by the liver into bile enter the duodenum by the common bile duct, where they pass through the small intestine. Some drugs are reabsorbed back into the blood stream and return to the liver though the process of enterohepatic circulation. The drug is further metabolized or is secreted back into bile (referred to as enterohepatic cycling , which may extend drug action). Drugs secreted into bile move into the large intestine to be excreted as fecal matter. Drugs may enter breast milk through a network of capillaries surrounding milk-producing glands. While amounts are very small, they may affect the infant, who has reduced ability to metabolize or excrete the drug. Lipid-soluble drugs may also be excreted passively though perspiration, saliva and tears. plasma, keeping the concentration at or above the minimum effective level and below toxic levels. In some circumstances, when an effective level of concentration in the plasma must be achieved quickly, a larger than normal dosage, called a loading dose , is given. Once the required plasma level of drug is reached, the normal recommended dose is repeated at regular intervals (called the maintenance dose ) to maintain a stable concentration of the drug in the plasma (plasma level). Drugs with a relatively narrow therapeutic span are typically prescribed according to the therapeutic index, which is the ratio of the drug’s toxic dose to its minimally effective dose. Plasma levels must be monitored to assess appropriate dosage.
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