Drugs are compounds almost always foreign to the body. As such, they are not continually being formed and eliminated as are endogenous substances. The processes of inputting, distributing, and eliminating drugs are therefore of paramount importance in determining the onset, duration, and intensity of effect.

The process of drug movement from the site of administration toward the systemic circulation.

Drug product: The actual dosage form of a drug, consisting of the drug itself plus other ingredients formulated into a usable medicine; eg, as a tablet, capsule, or solution. Drug products are formulated for administration by a variety of routes, including oral, buccal, sublingual, rectal, parenteral, topical, and inhalational. The physicochemical properties of drugs, their formulations, and the routes of administration are important in absorption. A prerequisite to absorption of any drug is that it be able to enter into solution. The solid drug product (eg, tablet) must undergo disintegration and deaggregation, and the active ingredients must undergo dissolution before the drug can be absorbed.

Except when given IV, a drug must traverse several semipermeable cell membranes before reaching the general circulation. These membranes act as biologic barriers that selectively inhibit the passage of drug molecules. Cell membranes are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids, in which are embedded globular protein macromolecules of random size and composition. The membrane proteins may be involved in transport processes and may also function as receptors for cellular regulatory mechanisms. Membrane lipid provides stability to the membrane and determines its permeability characteristics.

The processes by which drugs move across a biologic barrier include passive diffusion, facilitated diffusion, active transport, and pinocytosis.

Passive diffusion: Transport across a cell membrane in which the driving force for movement is the concentration gradient of the solute. Most drug molecules are transported across a membrane by simple diffusion from a high concentration area ( GI fluids) to a low concentration area (blood) without expenditure of energy. The net rate of diffusion is directly proportional to this net gradient and depends upon lipid solubility, degree of ionization, molecular size, and the area of the absorptive surface. Since the drug is rapidly removed by the systemic circulation and distributed into a large volume, the concentration of drug in blood is initially low compared with that at the site of administration. The resulting large concentration gradient serves as the driving force for absorption. However, since the cell membrane is lipoidal in nature, drugs that are lipid soluble diffuse more rapidly than drugs that are relatively lipid insoluble. Furthermore, small molecules tend to penetrate membranes more rapidly than do large ones.

Most drugs exist as weak organic acids or bases in both nonionized and ionized forms in an aqueous environment. The nonionized fraction is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility.

Facilitated diffusion: For certain molecules ( glucose), the rates of penetration are greater than expected from their low lipid solubility and the concentration gradients present. It is postulated that a "carrier component" combines reversibly with the substrate molecule at the cell membrane exterior and that the carrier-substrate complex diffuses rapidly across the membrane with release of the substrate at the interior surface. This carrier-mediated diffusion process is characterized by selectivity and saturability. The carrier mechanism accepts for transport only those substrates having a relatively specific molecular configuration, and the process is limited by the availability of carrier. No expenditureof energy is required by this process; substrate is not transported against a concentration gradient.

Active transport: In addition to selectivity and saturability, active transport requires energy expenditure by the cell, and substrates may accumulate intracellularly against a concentration gradient. Active transport processes appear to be limited to agents with structural similarities to normal body constituents. These agents are usually absorbed from specific sites in the small intestine. Active transport processes have been identified for various ions, vitamins, sugars, and amino acids.

Pinocytosis refers to the engulfing of particles or fluid by a cell. The cell membrane invaginates, encloses the particle or solute, and then fuses again, forming a vesicle that later buds off within the interior of the cell. This mechanism also requires the expenditure of energy. Pinocytosis probably plays a minor role in drug transport.

Because the oral route of administration is the most common, absorption usually refers to the transport of drugs across the membranes of the epithelial cells within the GI tract. Absorption after oral administration is confounded by differences down the alimentary canal in the luminal pH; surface area per luminal volume; perfusion of the tissue, bile, and mucus flow; and the epithelial membranes. The faster absorption of acids in the intestine compared with the stomach appears to contradict the hypothesis that the nonionized form of a drug more readily crosses membranes.

Gastric emptying and intestinal transit time: Because the absorption of virtually all compounds is faster from the small intestine than from the stomach, the rate of gastric emptying is a controlling step. Food, especially fatty foods, slows gastric emptying, which explains why some drugs are recommended to be taken on an empty stomach when a rapid onset of action is desired. The extent of absorption may be enhanced by food if the drug is poorly soluble ( griseofulvin) or reduced if degraded in the stomach (eg, penicillin G). Drugs that affect gastric emptying ( parasympatholytic agents) also affect the rate of absorption of other drugs.

Direct placement of a drug into the bloodstream (usually IV) ensures complete delivery of the dose to the general circulation. However, administration by a route that requires drug transfer through one or more biologic membranes to reach the bloodstream precludes a guarantee that all of the drug will eventually be absorbed. IM or s.c. injection of drugs bypasses the skin barrier, but the drug must penetrate the capillary walls. Because the capillaries tend to be highly porous, the perfusion (blood flow/gram of tissue) is a major factor in the rate of absorption. Thus, the injection site can markedly influence a drug's absorption rate.

Controlled-release dosage forms are designed to reduce the frequency of dosing and to maintain more uniform plasma drug concentrations, thus providing a more uniform pharmacologic effect. ounts more slowly. Reduction of the absorption rate can be achieved in various ways: by coating the drug particles with wax or related water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins.

Topical controlled-release dosage forms have been designed to provide drug release for extended periods; eg, clonidine diffusion through a membrane provides controlled drug delivery over a period of 1 wk, and nitroglycerin-impregnated polymer bonded to an adhesive bandage provides controlled drug delivery over a period of 24 h. Drugs for transdermal delivery must have suitable skin penetration characteristics and high potency.

The rate at which and the extent to which the active moiety (drug or metabolite) enters the general circulation, thereby gaining access to the site of action.

Although a drug may be absorbed completely, its rate of absorption may also be important. It may be too slow to attain a therapeutic blood level in an acceptable period of time or too rapid, resulting in toxicity from high drug levels just after each dose.

When a drug rapidly dissolves from a drug product and readily passes across membranes, absorption from most sites of administration tends to be complete. This is not always the case for drugs given orally. Before reaching the vena cava, a drug must move down the alimentary canal and pass through the gut wall and liver, which are common sites of drug metabolism ,thus, the drug may be metabolized before it can be measured in the general circulation. This cause of a decrease in drug input is called the first-pass effect. A large number of drugs show low bioavailabilities owing to extensive first-pass metabolism. In many instances, the extraction is so complete that the bioavailability is virtually zero ( isoproterenol, norepinephrine, phenacetin, and testosterone).

The 2 other most frequent causes of low bioavailability are an insufficient time in the GI tract and the presence of competing reactions. Ingested drug is exposed to the entire GI tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 h, unless gastric emptying is considerably delayed. If the drug does not dissolve readily or if the drug is incapable of penetrating the epithelial membrane (highly ionized and polar), there may be insufficient time at the absorption site. Not only is the bioavailability low in this case, but it tends to be highly variable. In addition, individual variations in age, sex, activity, genetic phenotype, stress, disease ( achlorhydria, malabsorption syndromes), and previous GI surgery can alter and further increase variability in drug bioavailability.

Reactions that compete with absorption can reduce bioavailability - include complex formation; hydrolysis by gastric pH or digestive enzymes ;conjugation in gut wall ; adsorption to other drugs and metabolism by luminal microflora.

After a drug enters the general circulation, it distributes throughout the body's tissues. Distribution is generally uneven because of differences in binding in tissues, regional variations in pH, and differences in the permeability of cellular membranes.

The extent of the distribution of drugs into tissues depends on binding to plasma proteins and tissue components.

Plasma protein binding: Drugs are transported in the bloodstream partly in solution (as free drug) and partly bound to various blood components ( plasma proteins and blood cells). Many plasma proteins can interact with drugs. Albumin, alpha1-acid glycoprotein, and lipoproteins are the most important ones. Acidic drugs are generally bound more extensively to albumin, while basic drugs often are more extensively bound to either one or both of the latter 2 proteins.

Because only the unbound form is available for passive diffusion to the extravascular or tissue sites where pharmacologic effects occur, plasma protein binding influences the distribution and apparent relationship between pharmacologic activity and plasma (total) drug concentration.

The fraction unbound (Fu) is often more useful than the fraction bound.

The substances to which drugs bind in tissue are highly varied. Often these substances are not proteins. Furthermore, they may be very specific, as is the case for the binding of chloroquine to nucleic acids. Tissue binding usually involves an association of drug with a macromolecule within an aqueous environment. Another kind of association that results in apparent tissue binding is partitioning of drug into body fat.

Drug reservoir: Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues serve as depots.

Some drugs accumulate in cells in higher concentrations than those in ECF. Such accumulation most commonly involves binding of drugs with protein, phospholipids, or nucleic acids.

Passage of drugs into the CNS takes place in the capillary circulation and the CSF. Although the brain receives a large proportion of the cardiac output (about 1/6), distribution of drugs to brain tissue is restricted. While some lipid-soluble drugs (eg, thiopental) do enter and exert their pharmacologic effects rapidly, many drugs, particularly the more water-soluble agents, enter the brain slowly. Another important barrier to water-soluble substances is the close approximation of the glial connective tissue cells (astrocytes) to the basement membrane of the capillary endothelium. The capillary endothelium and the astrocytic sheath together are referred to as the blood-brain barrier.

The sum of the processes of drug loss from the body. Removal of drugs from the body occurs by metabolism and excretion.

The process of chemical alteration of drugs in the body. The liver is the principal, but not the sole, site of drug metabolism. Some metabolites are pharmacologically active. When the substance administered is inactive and an active metabolite is produced, the administered compound is called a prodrug.

Neonates have partially developed liver microsomal enzyme systems and, consequently, have difficulty with the metabolism of many drugs. Elderly patients often show a reduced ability to metabolize drugs. The reduction varies depending on the drug and is not as severe as that in neonates.

Variability among individuals makes it difficult to predict the clinical response to a given dose of a drug. Some patients may metabolize a drug so rapidly that therapeutically effective blood and tissue levels are not achieved; in others, metabolism may be so slow that toxic effects result with usual doses. Concurrent disease states, particularly chronic liver disease, drug interactions, especially those involving induction or inhibition of metabolism, and other factors also con-tribute.

Before a drug is approved for general clinical use by the FDA, preclinical and clinical data showing substantial evidence of safety and efficacy are required by law. Drug studies proceed through various phases, as follows.

Animal studies used to determine or define the safety of a drug include studies of acute, subchronic, and chronic toxicity in several animal species.

The initial acute toxicity studies are to determine the median lethal dose (LD50), the toxic symptoms developed by the animals, and the time that they appear. At least 3 species of animals, one not a rodent, are usually used, and acute toxicity is usually determined by more than one route of administration.

Subchronic toxicity studies are conducted in at least 2 animal species and usually consist of daily administration of the test drug for up to 90 days. In each species, at least 3 dose levels are used, varying from the expected therapeutic doses to levels high enough to produce toxicity.

Chronic toxicity studies are carried out in at least 2 species, one of which is not a rodent. These studies usually last for up to the lifetime of the animal, but their length will depend on the intended duration of administration of the drug to humans.

Some adverse effects of drugs cannot be discerned in animals; eg, dizziness, nausea, headaches, ringing in the ears, heartburn, and depression. It has been estimated that >= 50% of undesirable drug effects seen most frequently can be ascertained only during human trials.

Phase 1 represents the first administration of a new drug to man. A small number of closely monitored subjects, mainly healthy volunteers, are usually involved. Initially, each receives a single dose of the drug to determine a safe dose range and assess pharmacokinetic data. The primary objective of this necessarily cautious phase of the investigation is to determine a safe and tolerated dosage in humans; however, observation of toxicity, if it occurs, and of absorption, metabolism, and excretion may also be made during Phase 1.

Phase 2 begins after satisfactory preliminary evidence regarding safety has been obtained. It involves the supervised administration of the drug to patients for treatment of, or prophylaxis against, the disease or symptoms for which the drug is intended. These studies usually are conducted in randomized clinical trials comparing the new drug with the prototype drug, if any, for a particular indication. Often this is the first opportunity to observe the effect of long-term administration of the drug to humans.

Phase 3 begins after the initial phases have provided reasonable evidence of safety and efficacy. It consists of more widespread clinical trials that may move from the realm of clinical investigators to practicing physicians. Phase 3 extends up to the time the drug is released for general use.

Phase 4 is the study of the actual use of the drug in medical practice and, though often not recognized as a phase of clinical investigation, is a most important one from a clinical standpoint

ADRs are usually classified as mild (no antidote, therapy, or prolongation of hospitalization necessary); moderate (requires a change in drug therapy, although not necessarily cessation of the drug, and may prolong hospitalization or require special treatment); severe (potentially life-threatening, requires discontinuation of the drug and specific treatment of the adverse reaction); and lethal (directly or indirectly contributes to the death of the patient).

Side effects are predictable pharmacologic effects that occur within therapeutic dose ranges and are undesired in the given therapeutic situation. Side effects may be useful under certain circumstances.

Overdosage toxicity is the predictable toxic effect that occurs with dosages in excess of the therapeutic range for a particular patient. It overlaps with side-effect toxicity to some extent, especially in drugs with a small therapeutic index. The severity of the reaction is usually dose-related.

Drug allergy: Allergic reactions depend on altered reactivity of the patient as a result of prior contact with a drug that functions as an antigen or allergen. They are not dose-related; the symptoms and signs that develop are determined by antigen-antibody interactions and are largely independent of the pharmacologic properties of the drug. Allergic reactions are not completely unpredictable; a careful clinical history may suggest at risk.

Idiosyncrasy is an imprecise term that has been used as a classification for unexpected and peculiar adverse reactions occurring in a small percentage of individuals exposed to a drug. Idiosyncratic reactions are not related to a drug's known pharmacologic effects and are not obviously allergic in nature. Idiosyncrasy has been defined by some as a genetically determined abnormal reactivity to a drug.

Drugs given during pregnancy can affect the fetus by (1) acting directly on the embryo to produce a lethal, toxic, or teratogenic effect; (2) altering placental function (constricting vessels), affecting gas and nutrition exchange between fetus and mother; (3) changing the myometrial activity (producing severe uterine hypertonia resulting in fetal anoxic injury); or (4) altering the biochemical dynamics of the mother, indirectly affecting the fetus.

There is 5 categories of safety for use in pregnancy. In category A, controlled human studies have demonstrated no fetal risks (these are the safest drugs). In category B, animal studies indicate no risk to the fetus and no controlled human studies have been done, or animal studies show a risk to the fetus but well-controlled human studies do not. In category C, no adequate studies, either animal or human, have been done, or adverse fetal effects have been shown in animals but no human data are available. In category D, positive evidence of human fetal risk exists, but benefits in certain situations (eg, life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may outweigh the risks. In category X, proven fetal risks exist that outweigh any possible benefit. These labeling definitions are universally accepted and are often helpful in directing the risk-benefit decision making encountered when prescribing drugs during pregnancy.

Antineoplastic agents, Isotretinoin, androgenic hormones and synthetic progestins, thyroid drugs: radioactive iodine, triiodothyronine, propylthiouracil, methimazole; oral hypoglycemics, narcotics, sedatives, alcohol, tranquilizers and antidepressants, tetracyclines, long-acting sulfonamides, anticoagulants ( Coumarins), caffeine, cigarette smoking.

(c) Kriger Research Center Inc. 2003