CHAPTER 10

Administration and Kinetics of Drugs

Drug administration is the giving of a drug by one of several means (routes). Drug kinetics (pharmacokinetics) involves what the body does to a drug, including the processes of absorption, distribution, metabolism, and elimination, and how long these processes take.

Drug treatment requires getting a drug to its target site or sites—specific sites in tissues where the drug performs its action. Typically, the drug is introduced (the process of administration) into the body far from this site. The drug must move into the bloodstream (the process of absorption) and be transported to the target sites where the drug is needed (the process of distribution). Some drugs are chemically altered (the process of metabolism) by the body before they perform their action; others are metabolized afterward; and still others are not metabolized at all. The final step is the removal of the drug and its metabolites from the body (the process of elimination).

Many factors, including a person’s genetic makeup, can influence these processes (see page 88). Changes due to aging also affect how the body processes drugs (see page 1896).

Administration

Drugs are introduced into the body by several routes. They may be taken by mouth (orally); given by injection into a vein (intravenously), into a muscle (intramuscularly), into the space around the spinal cord (intrathecally), or beneath the skin (subcutaneously); placed under the tongue (sublingually); inserted in the rectum (rectally) or vagina (vaginally); instilled in the eye (by the ocular route); sprayed into the nose and absorbed through the nasal membranes (nasally); breathed into the lungs, usually through the mouth (by inhalation); applied to the skin (cutaneously) for a local (topical) or bodywide (systemic) effect; or delivered through the skin by a patch (transdermally) for a systemic effect. Each route has specific purposes, advantages, and disadvantages.

Oral Route: Because the oral route is the most convenient and usually the safest and least expensive, it is the one most often used. However, it has limitations because of the way a drug typically moves through the digestive tract. For drugs administered orally, absorption may begin in the mouth and stomach. Usually, however, most of the drug is absorbed from the small intestine. The drug passes through the intestinal wall and travels to the liver before it is transported via the bloodstream to its target site. The intestinal wall and liver chemically alter (metabolize) many drugs, decreasing the amount of drug reaching the bloodstream. Consequently, these drugs are often given in smaller doses when injected intravenously to produce the same effect.

When a drug is taken orally, food and other drugs in the digestive tract may affect how much of and how fast the drug is absorbed. Thus, some drugs should be taken on an empty stomach, others should be taken with food, others should not be taken with certain other drugs, and still others cannot be taken orally at all.

Some orally administered drugs irritate the digestive tract. For example, aspirin and most other nonsteroidal anti-inflammatory drugs (NSAIDs—see page 644) can harm the lining of the stomach and small intestine and can cause or aggravate preexisting ulcers (see page 139). Other drugs are absorbed poorly or erratically in the digestive tract or are destroyed by the acid and digestive enzymes in the stomach.

Other routes of administration may be required when the oral route cannot be used: for example, when a person cannot take anything by mouth, when a drug must be administered rapidly or in a precise or very high dose, or when a drug is poorly or erratically absorbed from the digestive tract.

Injection Routes: Administration by injection (parenteral administration) includes the subcutaneous, intramuscular, intravenous, and intrathecal routes. A drug product can be prepared or manufactured in ways that prolong drug absorption from the injection site for hours, days, or longer. Such products do not need to be administered as often as drug products with more rapid absorption.

For the subcutaneous route, a needle is inserted into fatty tissue just beneath the skin. The drug is injected, then moves into small blood vessels (capillaries) and is carried away by the bloodstream or reaches the bloodstream through the lymphatic vessels. Protein drugs that are large in size, such as insulin, usually reach the bloodstream through the lymphatic vessels because these drugs move slowly from the tissues into capillaries. The subcutaneous route is used for many protein drugs because such drugs would be digested in the digestive tract if they were taken orally.

Certain drugs (such as progestin, used for birth control—see page 1598) may be given by inserting plastic capsules under the skin (subcutaneously). This route of administration is rarely used.

Through the Skin

Sometimes a drug is given through the skin—by needle (subcutaneous, intramuscular, or intravenous route), by patch (transdermal route), or by implantation.

The intramuscular route is preferred to the subcutaneous route when larger volumes of a drug product are needed. Because the muscles lie below the skin and fatty tissues, a longer needle is used. Drugs are usually injected into the muscle of the upper arm, thigh, or buttock. How quickly the drug is absorbed into the bloodstream depends, in part, on the blood supply to the muscle: The sparser the blood supply, the longer it takes for the drug to be absorbed.

For the intravenous route, a needle is inserted directly into a vein. A solution containing the drug may be given in a single dose or by continuous infusion. For infusion, the solution is moved by gravity (from a collapsible plastic bag) or by an infusion pump through thin flexible tubing to a tube (catheter) inserted in a vein, usually in the forearm. Intravenous administration is the best way to deliver a precise dose quickly and in a well-controlled manner throughout the body. It is also used for irritating solutions, which would cause pain and damage tissues if given by subcutaneous or intramuscular injection. An intravenous injection can be more difficult to administer than a subcutaneous or intramuscular injection, because inserting a needle or catheter into a vein may be difficult, especially if the person is obese.

When given intravenously, a drug is immediately delivered to the bloodstream and tends to take effect more quickly than when given by any other route. Consequently, health care practitioners closely monitor people who receive an intravenous injection for signs that the drug is working or is causing undesired side effects. Also, the effect of a drug given by this route tends to last for a shorter time. Therefore, some drugs must be given by continuous infusion to keep their effect constant.

For the intrathecal route, a needle is inserted between two vertebrae in the lower spine and into the space around the spinal cord. The drug is then injected into the spinal canal. A small amount of local anesthetic is often used to numb the injection site. This route is used when a drug is needed to produce rapid or local effects on the brain, spinal cord, or the layers of tissue covering them (meninges)—for example, to treat infections of these structures. Anesthetics and analgesics (such as morphine) are sometimes given this way.

Sublingual Route: A few drugs are placed under the tongue (taken sublingually) so that 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 caused by an inadequate blood supply to the heart muscle)—because absorption is rapid and the drug immediately enters the bloodstream without first passing through the intestinal wall and liver. However, most drugs cannot be taken this way because they may be absorbed incompletely or erratically.

Rectal Route: Many drugs that are administered orally can also be administered rectally as a suppository. In this form, a drug is mixed with a waxy substance that dissolves or liquefies after it is inserted into the rectum. Because the rectum’s wall is thin and its blood supply rich, the drug is readily absorbed. A suppository is prescribed for people who cannot take a drug orally because they have nausea, cannot swallow, or have restrictions on eating, as is required after many surgical operations. Drugs that are irritating in suppository form may have to be given by injection.

Vaginal Route: Some drugs may be administered vaginally to women as a solution, tablet, cream, gel, suppository, or ring. The drug is slowly absorbed through the vaginal wall. This route is often used to give estrogen to women at menopause, because the drug helps prevent thinning of the vaginal wall, an effect of menopause (see page 1514).

Ocular Route: Drugs used to treat eye disorders (such as glaucoma, conjunctivitis, and injuries) can be mixed with inactive substances to make a liquid, gel, or ointment, so that they can be applied to the eye. Liquid eye drops are relatively easy to use but may run off the eye too quickly to be absorbed well. Gel and ointment formulations keep the drug in contact with the eye surface longer. Solid inserts, which release the drug continuously and in slow amounts, are also available, but they may be hard to put in and keep in place. Ocular drugs are almost always used for their local effects. For example, artificial tears are used to relieve dry eyes. Other drugs (for example, those used to treat glaucoma [see table on page 1450], such as acetazolamide and betaxolol, and those used to dilate pupils, such as phenylephrine and tropicamide), produce a local effect after they are absorbed through the cornea and conjunctiva. Some of these drugs then enter the bloodstream and may have unwanted effects on other parts of the body.

Nasal Route: If a drug is to be breathed in and absorbed through the thin mucous membrane that lines the nasal passages, it must be transformed into tiny droplets in air (atomized). Once absorbed, the drug enters the bloodstream. Drugs administered by this route generally work quickly. Some of them irritate the nasal passages. Drugs that can be administered by the nasal route include nicotine (for smoking cessation), calcitonin (for osteoporosis), sumatriptan (for migraine headaches), and corticosteroids (for allergies).

Inhalation: Drugs administered by inhalation through the mouth must be atomized into smaller particles than those administered by the nasal route, so that the drug can pass through the windpipe (trachea) and into the lungs. How deeply into the lungs they go depends on the size of the droplets. Smaller droplets go deeper, which increases the amount of drug absorbed. Inside the lungs, they are absorbed into the bloodstream.

Relatively few drugs are administered this way because inhalation must be carefully monitored to ensure that a person receives the right amount of drug within a specified time. Usually, this method is used to administer drugs that act on the lungs, such as aerosolized antiasthmatic drugs in metered-dose containers, and to administer gases used for general anesthesia.

Cutaneous Route: Drugs applied to the skin are usually used for their local effects and thus are most commonly used to treat superficial skin disorders, such as psoriasis, eczema, skin infections (viral, bacterial, and fungal), itching, and dry skin. The drug is mixed with inactive substances. Depending on the consistency of the inactive substances, the formulation may be an ointment, a cream, a lotion, a solution, a powder, or a gel (see page 1279).

Transdermal Route: Some drugs are delivered bodywide through a patch on the skin. These drugs, sometimes mixed with a chemical (such as alcohol) that enhances penetration of the skin, pass through the skin to the bloodstream without injection. Through a patch, the drug can be delivered slowly and continuously for many hours or days or even longer. As a result, levels of a drug in the blood can be kept relatively constant. Patches are particularly useful for drugs that are quickly eliminated from the body because such drugs, if taken in other forms, would have to be taken frequently. However, patches may irritate the skin of some people. In addition, patches are limited by how quickly the drug can penetrate the skin. Only drugs to be given in relatively small daily doses can be given through patches. Examples of such drugs include nitroglycerin (for chest pain), scopolamine (for motion sickness), nicotine (for smoking cessation), clonidine (for high blood pressure), and fentanyl (for pain relief).

Absorption

Drug absorption is the movement of a drug into the bloodstream.

Absorption affects bioavailability—how quickly and how much of a drug reaches its intended target (site) of action. Factors that affect absorption (and therefore bioavailability) include the way a drug product is designed and manufactured, its physical and chemical properties, and the physiologic characteristics of the person taking the drug. Physiologic characteristics that may affect the absorption of drugs taken by mouth include how long the stomach takes to empty, what the acidity (pH) of the stomach is, and how quickly the drug is moved through the digestive tract.

A drug product is the actual dosage form of a drug—a tablet, capsule, suppository, transdermal patch, or solution. It consists of the drug (active ingredient) and additives (inactive ingredients). For example, tablets are a mixture of drug and diluents, stabilizers, disinte-grants, and lubricants. The mixture is granulated and compressed into a tablet. The type and amount of additives and the degree of compression affect how quickly the tablet disintegrates and how quickly the drug is absorbed. Drug manufacturers adjust these variables to optimize absorption.

If a tablet releases the drug too quickly, the blood level of the drug may become too high, causing an excessive response. If the tablet does not release the drug quickly enough, much of the drug may be eliminated in the feces without being absorbed, and blood levels may be too low. Drug manufacturers formulate the tablet to release the drug at the desired speed.

Capsules consist of drugs and additives within a gelatin shell. The shell swells and releases its contents when it becomes wet, usually eroding quickly. The size of the drug particles and the properties of the additives affect how quickly the drug dissolves and is absorbed. Drugs tend to be absorbed more quickly from capsules filled with liquid than from those filled with solid particles.

Because drug products that contain the same drug (active ingredient) may have different inactive ingredients, absorption of the drug from different products may vary. Thus, a drug’s effects, even at the same dose, may vary from one drug product to another. Drug products that not only contain the same active ingredient but also produce virtually the same blood levels at the same points in time are considered bioequivalent. Bioequivalence ensures therapeutic equivalence (that is, production of the same medicinal effect), and bioequivalent products are interchangeable.

If an orally administered drug can harm the stomach lining or decomposes in the acidic environment of the stomach, a tablet or capsule of the drug can be coated with a substance intended to prevent it from dissolving until it reaches the small intestine. These protective coatings are described as enteric, which refers to the small intestine. For the coatings to dissolve, they must come in contact with the less acidic environment of the small intestine or with the digestive enzymes there. However, the coatings do not always dissolve as intended. The tablet or capsule may be passed intact in the feces, especially in older people.

Some drug products are specially formulated to release their active ingredients slowly or in repeated small amounts over time—usually for a period of 12 hours or more. This dosage form is called modified-release, controlled-release, sustained-release, or extended-release.

Food, other drugs, and digestive disorders can affect drug absorption and bioavailability. For example, high-fiber foods may bind with a drug and prevent it from being absorbed. Laxatives and diarrhea, which speed up the passage of substances through the digestive tract, may reduce drug absorption. Surgical removal of parts of the digestive tract (such as the stomach or colon) may also affect drug absorption.

Where and how long a drug product is stored can affect drug bioavailability. The drug in some products deteriorates and becomes ineffective or harmful if stored improperly or kept too long. Some products must be stored in the refrigerator or in a cool, dry, or dark place. Storage directions should be followed, and expiration dates should be observed.

Distribution

Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues.

After a drug is absorbed into the bloodstream, it rapidly circulates through the body. The average circulation time of blood is 1 minute. As the blood recirculates, the drug moves from the bloodstream into the body’s tissues.

Once absorbed, most drugs do not spread evenly throughout the body. Drugs that dissolve in water (water-soluble drugs), such as the antihypertensive drug atenolol, tend to stay within the blood and the fluid that surrounds cells (interstitial space). Drugs that dissolve in fat (fat-soluble drugs), such as the anesthetic drug halothane, tend to concentrate in fatty tissues. Other drugs concentrate mainly in only one small part of the body (for example, iodine concentrates mainly in the thyroid gland), because the tissues there have a special attraction for (affinity) and ability to retain the drug.

Drugs penetrate different tissues at different speeds, depending on the drug’s ability to cross membranes. For example, the anesthetic thiopental, a highly fat-soluble drug, rapidly enters the brain, but the antibiotic penicillin, a water-soluble drug, does not. In general, fat-soluble drugs can cross cell membranes more quickly than water-soluble drugs can. For some drugs, transport mechanisms aid movement into or out of the tissues.

Some drugs leave the bloodstream very slowly, because they bind tightly to proteins circulating in the blood. Others quickly leave the bloodstream and enter other tissues, because they are less tightly bound to blood proteins. Some or virtually all molecules of a drug in the blood may be bound to blood proteins. The protein-bound part is generally inactive. As unbound drug is distributed to tissues and its level in the bloodstream decreases, blood proteins gradually release the drug bound to them. Thus, the bound drug in the bloodstream may act as a reservoir for the drug.

Some drugs accumulate in certain tissues, which can also act as reservoirs of extra drug. These tissues slowly release the drug into the bloodstream, keeping blood levels of the drug from decreasing rapidly and thereby prolonging the effect of the drug. Some drugs, such as those that accumulate in fatty tissues, leave the tissues so slowly that they circulate in the bloodstream for days after a person has stopped taking the drug.

Distribution of a given drug may also vary from person to person. For instance, obese people may store large amounts of fat-soluble drugs, whereas very thin people may store relatively little. Older people, even when thin, may store large amounts of fat-soluble drugs because the proportion of body fat increases with aging.

Metabolism

Drug metabolism is the chemical alteration of a drug by the body.

Some drugs are chemically altered by the body (metabolized). The substances that result from metabolism (metabolites) may be inactive, or they may be similar to or different from the original drug in therapeutic activity or toxicity. Some drugs, called prodrugs, are administered in an inactive form, which is metabolized into an active form. The resulting metabolites produce the desired therapeutic effects. Metabolites may be metabolized further instead of being excreted from the body. The subsequent metabolites are then excreted.

A vast majority of drugs must pass through the liver, which is the site of most drug metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes. The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized. The capacity of the enzymes to metabolize is limited, so they can become overloaded when blood levels of a drug are high (see page 89).

Because metabolic enzyme systems are only partially developed at birth, newborns have difficulty metabolizing certain drugs. As people age, enzymatic activity decreases, so that older people, like newborns, cannot metabolize drugs as well as younger adults and children do (see page 1896). Consequently, newborns and older people often need smaller doses per pound of body weight than do young or middle-aged adults.

Elimination

Drug elimination is the removal of drugs from the body.

All drugs are eventually eliminated from the body. They may be eliminated after being chemically altered (metabolized), or they may be eliminated intact. Most drugs, particularly water-soluble drugs and their metabolites, are eliminated largely by the kidneys in urine. Some drugs are eliminated by excretion in the bile (a greenish yellow fluid secreted by the liver and stored in the gallbladder).

Elimination in the Urine: Several factors, including certain characteristics of the drug, affect the kidneys’ ability to excrete drugs. To be extensively excreted in urine, a drug or metabolite must be water soluble and must not be bound too tightly to proteins in the bloodstream. The acidity of urine, which is affected by diet, drugs, and kidney disorders, can affect the rate at which the kidneys excrete some drugs. In the treatment of poisoning with some drugs, the acidity of the urine is changed by giving antacids (such as sodium bicarbonate) or acidic substances (such as ammonium chloride) orally to speed up the excretion of the drug.

The kidneys’ ability to excrete drugs also depends on urine flow, blood flow through the kidneys, and the condition of the kidneys. Kidney function can be impaired by many disorders (especially high blood pressure, diabetes, and recurring kidney infections), by exposure to high levels of toxic chemicals, and by age-related changes. As people age, kidney function slowly declines. For example, the kidneys of an 85-year-old person excrete drugs only about half as efficiently as those of a 35-year-old person.

In people whose kidney function has declined, the “normal” dosage of a drug that is eliminated primarily through the kidneys may be too much and may cause side effects. Therefore, health care practitioners sometimes must adjust the drug dosage based on the amount of decline in the person’s kidney function. Health care practitioners have several ways to estimate the decline in kidney function. Sometimes they base an estimate solely on the person’s age. However, they can get a more accurate estimate of kidney function by using the results of tests that measure the level of creatinine (a waste product) in the blood and sometimes also the urine. They use these results to calculate how effectively creatinine is removed from the body (called creatinine clearance), which reflects how well the kidneys are functioning.

Elimination in the Bile: Some drugs pass through the liver unchanged and are excreted in the bile. The bile then enters the digestive tract. From there, drugs are either eliminated in feces or reabsorbed into the bloodstream and thus recycled. Other drugs are converted to metabolites in the liver and excreted in the bile. These metabolites may be excreted in the feces or can be converted back to the drug, which is then reabsorbed into the bloodstream and recycled.

If the liver is not functioning normally, the dosage of a drug that is eliminated primarily by metabolism in the liver may need to be adjusted. However, there are no simple ways to estimate liver function quantitatively for drug metabolism comparable to those for kidney function.

Other Forms of Elimination: Some drugs are excreted in saliva, sweat, breast milk, and even exhaled air. Most are excreted in small amounts. The excretion of drugs in breast milk is significant only because the drug may affect the breastfeeding infant. Excretion in exhaled air is the main way that inhaled anesthetics are eliminated.