|The Merck Manual of Medical Information--Home Edition
|Section 2. Drugs
Drug Administration, Distribution, and Elimination
Drug treatment requires getting a drug into the body (administration) so it can move into the bloodstream (absorption) and travel to the specific site where it is needed (distribution). The drug leaves the body (elimination) either in the urine or by conversion to another substance.
Drugs can be taken by several routes. They can be taken by mouth (oral route) or by injection into a vein (intravenous), into a muscle (intramuscular), or beneath the skin (subcutaneous). They can be placed under the tongue (sublingual), inserted in the rectum (rectal), instilled in the eye (ocular), sprayed into the nose (nasal) or mouth (inhalation), or applied to the skin for a local (topical) or systemic (transdermal) effect. Each route has specific purposes, advantages, and disadvantages.
Oral administration is the most convenient, usually the safest, the least expensive, and therefore the most common route. However, it has limitations. Many factors, including other drugs and food, affect how drugs are absorbed after they're taken orally. Thus, some drugs should be taken on an empty stomach while others should be taken with food; still others can't be taken orally at all.
Drugs administered orally are absorbed from the gastrointestinal tract. Absorption begins in the mouth and stomach but takes place mostly in the small intestine. To reach the general circulation, the drug must pass through first the intestinal wall and then the liver. The intestinal wall and liver chemically alter (metabolize) many drugs, decreasing the amount absorbed. In contrast, drugs injected intravenously reach the general circulation without passing through the intestinal wall and liver, so they have a quicker and more consistent response.
Some orally administered drugs irritate the gastrointestinal tract; for example, aspirin and most other nonsteroidal anti-inflammatory drugs can harm the lining of the stomach and small intestine and can cause ulcers. Other drugs are absorbed poorly or erratically in the gastrointestinal tract or are destroyed by the acidic environment and digestive enzymes in the stomach. Despite these limitations, the oral route is used much more frequently than other routes of drug administration. Other routes are generally reserved for situations in which a person can't take anything by mouth, a drug must be administered rapidly or in a precise dose, or a drug is poorly and erratically absorbed.
Administration by injection (parenteral administration) includes the subcutaneous, intramuscular, and intravenous routes. With the subcutaneous route, a needle is inserted beneath the skin. After being injected subcutaneously, the drug moves into small blood vessels and is carried away by the bloodstream. The subcutaneous route is used for many protein drugs, such as insulin, which would be digested in the gastrointestinal tract if taken by mouth. Drugs can be prepared in suspensions or in relatively insoluble complexes so that their absorption is prolonged for hours, days, or longer, and they don't need to be administered as often.
The intramuscular route is preferred to the subcutaneous route when larger volumes of a drug are needed. Because the muscles lie deeper than the skin, a longer needle is used.
With the intravenous route, a needle is inserted directly into a vein. An intravenous injection can be more difficult to administer than other parenteral injections, especially in people who are obese. Intravenous administration, whether in a single dose or a continuous infusion, is the best way to give drugs quickly and precisely.
Some drugs are placed under the tongue (given sublingually) so they can be absorbed directly into the small blood vessels that lie beneath the tongue. The sublingual route is especially good for nitroglycerin, which is used to relieve angina (chest pain), because absorption is rapid and the drug immediately enters the general circulation without first passing through the intestinal wall and liver. However, most drugs can't be given this way because absorption is often incomplete and erratic.
Many drugs that are administered orally can also be administered rectally in suppository form. In this form, a drug is mixed with a waxy substance that dissolves after it's inserted into the rectum. With the rectum's thin lining and rich blood supply, the drug is readily absorbed. A suppository is prescribed when a person can't take a drug orally because of nausea, an inability to swallow, or a restriction on eating, as after surgery. Some drugs are irritating in suppository form; for such drugs, the parenteral route may have to be used.
Some drugs can be given by applying a patch to the skin. These drugs, sometimes mixed with a chemical that enhances penetration of the skin, pass through the skin to the bloodstream without injection. The transdermal route allows the drug to be delivered slowly and continuously over many hours or days, or even longer. However, some people develop irritation where the patch touches the skin. In addition, the transdermal route is limited by how quickly the drug can move through the skin. Only drugs to be given in relatively small daily doses can be delivered transdermally. Examples of such drugs include nitroglycerin (for angina), scopolamine (for motion sickness), nicotine (for smoking cessation), clonidine (for hypertension), and fentanyl (for pain relief).
Some drugs, such as gases used for anesthesia and aerosolized asthma drugs in metered-dose containers, are inhaled. These drugs travel through airways directly to the lungs, where they're absorbed into the bloodstream. Relatively few drugs are taken this way because inhalation must be carefully monitored to ensure that a person gets the right amount of drug within a specified time. Metered-dose systems are useful for drugs that act directly on the channels carrying air to the lungs. Because absorption into the bloodstream is highly variable with aerosol inhalation, this method is seldom used to administer drugs that act on tissues or organs other than the lungs.
Bioavailability refers to the rate and extent to which a drug is absorbed into the bloodstream. Bioavailability depends on a number of factors, including the way a drug product is designed and manufactured, its physical and chemical properties, and the physiology of the person taking the drug.
A drug product is the actual dosage form of a drug, such as a tablet, capsule, suppository, transdermal patch, or solution. It usually consists of the drug combined with other ingredients. For example, tablets are a mixture of drug and additives that function as diluents, stabilizers, disintegrants, and lubricants. The mixtures are granulated and compressed into tablet form. The type and amount of additives and the degree of compression affect how quickly the tablet dissolves. Drug manufacturers adjust these variables to optimize the rate and extent of the drug's absorption.
If a tablet dissolves and releases the drug too quickly, it may produce a blood level of the active drug that provokes an excessive response. On the other hand, if the tablet doesn't dissolve and release the drug quickly enough, much of the drug may pass into the feces without being absorbed. Laxatives and diarrhea, which speed up passage through the gastrointestinal tract, may reduce drug absorption. Therefore, food, other drugs, and gastrointestinal diseases can influence drug bioavailability.
Consistency of bioavailability among drug products is desirable. Drug products that are chemically equivalent contain the same active drug but may have different inactive ingredients that can affect the rate and extent of absorption. The drug's effects, even at the same dose, may not be the same from one drug product to another. Drug products are bioequivalent when they not only contain the same active ingredient but also produce virtually the same blood levels over time. Bioequivalence thereby ensures therapeutic equivalence, and bioequivalent products are interchangeable.
Some drug products are specially formulated to release their active ingredients slowly--usually over 12 hours or more. These controlled-release dosage forms slow or delay the rate at which a drug is dissolved. For example, drug particles in a capsule may be coated with a polymer (a chemical substance) of varying thicknesses designed to dissolve at different times in the gastrointestinal tract.
Some tablets and capsules have protective (enteric) coatings that are intended to prevent irritants, such as aspirin, from harming the stomach lining or from decomposing in the acidic environment of the stomach. These dosage forms are coated with a material that doesn't begin to dissolve until it comes in contact with the less acidic environment or digestive enzymes of the small intestine. Such protective coatings don't always dissolve properly though, and many people, especially the elderly, pass such products intact in their feces.
Many other properties of solid dosage forms (tablets or capsules) affect absorption after oral administration. Capsules consist of drugs and other substances within a gelatin shell. The gelatin swells and releases its contents when it becomes wet. The shell usually erodes quickly. The size of the drug particles and other substances affects how fast the drug dissolves and is absorbed. Drugs from capsules filled with liquids tend to be absorbed more quickly than those from capsules filled with solids.
After a drug is absorbed into the bloodstream, it rapidly circulates through the body, as blood has an average circulation time of 1 minute. However, the drug may move slowly from the bloodstream into the body's tissues.
Drugs penetrate different tissues at different speeds, depending on their ability to cross membranes. For example, the anesthetic thiopental rapidly enters the brain, but the antibiotic penicillin does not. In general, fat-soluble drugs can cross cell membranes more quickly than water-soluble drugs can.
Once absorbed, most drugs don't spread out evenly through the body. Some drugs tend to stay within the watery tissues of the blood and muscle while others concentrate in specific tissues such as the thyroid gland, liver, and kidneys. Some drugs bind tightly to blood proteins, leaving the bloodstream very slowly, while others escape from the bloodstream quickly into other tissues. Some tissues build up such high levels of a drug that they serve as reservoirs of extra drug, thereby prolonging the drug's distribution. In fact, some drugs, such as those that accumulate in fatty tissues, leave these tissues slowly and consequently circulate in the bloodstream for days after a person has stopped taking the drug.
Distribution of a given drug may also vary among different persons. For instance, people with large body frames, who have greater amounts of tissue and circulating blood, may require larger amounts of a drug. Obese people may store large amounts of drugs that concentrate in fat, while very thin people may store relatively little. This distribution is also seen in older people, because the proportion of body fat increases with age.
All drugs are either metabolized or excreted intact. Metabolism is the process by which a drug is chemically altered by the body. The liver is the principal, but not the only, site of drug metabolism. The products of metabolism, metabolites, may be inactive, or they may have similar or different degrees of therapeutic activity or toxicity than the original drug. Some drugs, called prodrugs, are administered in an inactive form; their metabolites are active and achieve the desired effects. These active metabolites are either excreted (mainly in the urine or feces) or converted further to other metabolites, which are ultimately excreted.
The liver has enzymes that facilitate chemical reactions such as oxidation, reduction, and hydrolysis of drugs. It has other enzymes that attach substances to the drug, producing reactions called conjugations. The conjugates (drug molecules with the attached substances) are excreted in the urine.
Because metabolic enzyme systems are only partially developed at birth, newborns have difficulty metabolizing many drugs; therefore they require less drug in proportion to body weight than adults do. On the other hand, young children (2 to 12 years of age) require more drug in proportion to body weight than adults do. Like newborns, the elderly also have reduced enzymatic activity and aren't able to metabolize drugs as well as younger adults and children do. Consequently, newborns and the elderly often need smaller, and children larger, doses per pound of body weight.
Excretion refers to the processes by which the body eliminates a drug. The kidneys are the major organs of excretion. They are particularly effective in eliminating water-soluble drugs and their metabolites.
The kidneys filter drugs from the bloodstream and excrete them into the urine. Many factors can affect the kidneys' ability to excrete drugs. A drug or metabolite must be soluble in water and not bound too tightly to plasma proteins. The acidity of the urine affects the rate at which some acidic and alkaline drugs are excreted. The kidneys' ability to excrete drugs also depends on urine flow, blood flow through the kidneys, and the condition of the kidneys.
As people age, kidney function decreases. The kidney of an 85-year-old person is only about half as efficient in excreting drugs as that of a 35-year-old. Many diseases--especially high blood pressure, diabetes, and recurring kidney infections--and exposure to high levels of toxic chemicals can impair the kidneys' ability to excrete drugs.
If the kidneys aren't functioning normally, a doctor may adjust the dosage of a drug that's eliminated primarily through the kidneys. The normal decrease in kidney function with age can help the doctor determine an appropriate dosage based solely on a person's age. However, a more accurate way to determine an appropriate dosage is to assess kidney function with a blood test (measuring the amount of creatinine in serum), either alone or in combination with a urine test (measuring the amount of creatinine in urine collected for 12 to 24 hours).
The liver excretes some drugs through bile. These drugs enter the gastrointestinal tract and end up in the feces if they aren't reabsorbed into the bloodstream or decomposed. Also, small amounts of some drugs are excreted in saliva, sweat, breast milk, and even exhaled air. The administration of a drug eliminated primarily by metabolism in the liver may need to be adjusted for a person with liver disease. There are no simple measures of liver function (for drug metabolism) comparable to those for kidney function.