Basic concepts and processes

Pharmacokinetics involves drug movement through the body (ie, “what the body does to the drug”) to reach sites of action, metabolism, and excretion. Specific processes are absorption, distribution, metabolism (biotransformation), and excretion. Overall, these processes largely determine serum drug levels, onset, peak and duration of drug actions, drug half-life, therapeutic and adverse drug effects, and other important aspects of drug therapy.
Absorption is the process that occurs from the time a drug enters the body to the time it enters the bloodstream to be circulated. Onset of drug action is largely determined by the rate of absorption; intensity is determined by the extent of absorption. Numerous factors affect the rate and extent of drug absorption, including dosage form, route of administration, blood flow to the site of administration, GI function, the presence of food or other drugs, and other variables. Dosage form is a major determinant of a drug’s bioavailability (the portion of a dose that reaches the systemic circulation and is available to act on body cells). An intravenous drug is virtually 100% bioavailable; an oral drug is virtually always less than 100% bioavailable because some is not absorbed from the GI tract and some goes to the liver and is partially metabolized before reaching the systemic circulation. Most oral drugs must be swallowed, dissolved in gastric fluid, and delivered to the small intestine (which has a large surface area for absorption of nutrients and drugs) before they are absorbed. Liquid medications are absorbed faster than tablets or capsules because they need not be dissolved. Rapid movement through the stomach and small intestine may increase drug absorption by promoting contact with absorptive mucous membrane; it also may decrease absorption because some drugs may move through the small intestine too rapidly to be absorbed.
For many drugs, the presence of food in the stomach slows the rate of absorption and may decrease the amount of drug absorbed. Drugs injected into subcutaneous (SC) or intramuscular (IM) tissues are usually absorbed more rapidly than oral drugs because they move directly from the injection site to the bloodstream. Absorption is rapid from IM sites because muscle tissue has an abundant blood supply. Drugs injected intravenously (IV) do not need to be absorbed because they are placed directly into the bloodstream. Other absorptive sites include the skin, mucous membranes, and lungs. Most drugs applied to the skin are given for local effects (eg, sunscreens). Systemic absorption is minimal from intact skin but may be considerable when the skin is inflamed or damaged. Also, a number of drugs have been formulated in adhesive skin patches for absorption through the skin (eg, clonidine, estrogen, fentanyl, nitroglycerin, scopolamine). Some drugs applied to mucous membranes also are given for local effects. However, systemic absorption occurs from the mucosa of the oral cavity, nose, eye, vagina, and rectum. Drugs absorbed through mucous membranes pass directly into the bloodstream. The lungs have a large surface area for absorption of anesthetic gases and a few other drugs.
Distribution involves the transport of drug molecules within the body. Once a drug is injected or absorbed into the bloodstream, it is carried by the blood and tissue fluids to its sites of pharmacologic action, metabolism, and excretion. Most drug molecules enter and leave the bloodstream at the capillary level, through gaps between the cells that form capillary walls. Distribution depends largely on the adequacy of blood circulation. Drugs are distributed rapidly to organs receiving a large blood supply, such as the heart, liver, and kidneys. Distribution to other internal organs, muscle, fat, and skin is usually slower. Drug distribution into the central nervous system (CNS) is limited because the blood–brain barrier, which is composed of capillaries with tight walls, limits movement of drug molecules into brain tissue. This barrier usually acts as a selectively permeable membrane to protect the CNS. However, it also can make drug therapy of CNS disorders more difficult because drugs must pass through cells of the capillary wall rather than between cells. As a result, only drugs that are lipid soluble or have a transport system can cross the blood–brain barrier and reach therapeutic concentrations in brain tissue.
Metabolism is the method by which drugs are inactivated or biotransformed by the body. Most often, an active drug is changed into one or more inactive metabolites, which are then excreted. Some active drugs yield metabolites that are also active and that continue to exert their effects on body cells until they are metabolized further or excreted. Other drugs (called prodrugs) are initially inactive and exert no pharmacologic effects until they are metabolized. Most drugs are lipid soluble, a characteristic that aids their movement across cell membranes. However, the kidneys, which are the primary excretory organs, can excrete only water-soluble substances. Therefore, one function of metabolism is to convert fat-soluble drugs into water-soluble metabolites.
Hepatic drug metabolism or clearance is a major mechanism for terminating drug action and eliminating drug molecules from the body. Most drugs are metabolized by enzymes in the liver (called the cytochrome P450 [CYP] or the microsomal enzyme system); red blood cells, plasma, kidneys, lungs, and GI mucosa also contain drug-metabolizing enzymes. The cytochrome P450 system consists of 12 groups or families, nine of which metabolize endogenous substances and three of which metabolize drugs.
Excretion refers to elimination of a drug from the body. Effective excretion requires adequate functioning of the circulatory system and of the organs of excretion (kidneys, bowel, lungs, and skin). Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in the urine. Some drugs or metabolites are excreted in bile, then eliminated in feces; others are excreted in bile, reabsorbed from the small intestine, returned to the liver (called enterohepatic recirculation), metabolized, and eventually excreted in urine. Some oral drugs are not absorbed and are excreted in the feces. The lungs mainly remove volatile substances, such as anesthetic gases. The skin has minimal excretory function. Factors impairing excretion, especially severe renal disease, lead to accumulation of numerous drugs and may cause severe adverse effects if dosage is not reduced.
Pharmacodynamics involves drug actions on target cells and the resulting alterations in cellular biochemical reactions and functions (ie, “what the drug does to the body”). As previously stated, all drug actions occur at the cellular level.
Route of Administration
Routes of administration affect drug actions and responses largely by influencing absorption and distribution. For rapid drug action and response, the IV route is most effective because the drug is injected directly into the bloodstream. For some drugs, the IM route also produces drug action within a few minutes because muscles have a large blood supply. The oral route usually produces slower drug action than parenteral routes. Absorption and action of topical drugs vary according to the drug formulation, whether the drug is applied to skin or mucous membranes, and other factors.
Drug tolerance occurs when the body becomes accustomed to a particular drug over time so that larger doses must be given to produce the same effects. Tolerance may be acquired to the pharmacologic action of many drugs, especially opioid analgesics, alcohol, and other CNS depressants. Tolerance to pharmacologically related drugs is called cross-tolerance. For example, a person who regularly drinks large amounts of alcohol becomes able to ingest even larger amounts before becoming intoxicated—this is tolerance to alcohol. If the person is then given sedative-type drugs or a general anesthetic, larger-than-usual doses are required to produce a pharmacologic effect—this is cross-tolerance. Tolerance and cross-tolerance are usually attributed to activation of drug-metabolizing enzymes in the liver, which accelerates drug metabolism and excretion. They also are attributed to decreased sensitivity or numbers of receptor sites.