CHAPTER 13

Adverse Drug Reactions

In the early 1900s, German scientist Paul Ehrlich described an ideal drug as a “magic bullet”; such a drug would be aimed precisely at a disease site and would not harm healthy tissues. Although many new drugs are aimed more accurately than their predecessors, none of them, as of yet, hit the target precisely.

Most drugs produce several effects, but usually only one effect—the therapeutic effect—is wanted for the treatment of a disorder. The other effects may be regarded as unwanted, whether they are intrinsically harmful or not. For example, certain antihistamines cause drowsiness as well as control the symptoms of allergies. When an over-the-counter sleep aid containing an antihistamine is taken, drowsiness is considered a therapeutic effect. But when an antihistamine is taken to control allergy symptoms during the daytime, drowsiness is considered an annoying, unwanted effect.

Most people, including health care practitioners, refer to unwanted effects as side effects; another term used is adverse drug event. However, the term adverse drug reaction is technically more appropriate for drug effects that are unwanted, unpleasant, noxious, or potentially harmful.

Not surprisingly, adverse drug reactions are common. Most adverse drug reactions are relatively mild, and many disappear when the drug is stopped or the dose is changed. Some gradually subside as the body adjusts to the drug. Other adverse drug reactions are more serious

SOME SERIOUS ADVERSE DRUG REACTIONS

and last longer. About 3 to 7% of all hospital admissions in the United States are for treatment of adverse drug reactions. Adverse drug reactions occur during 10 to 20% of hospital admissions, and about 10 to 20% of these reactions are severe.

Digestive disturbances—loss of appetite, nausea, a bloating sensation, constipation, and diarrhea—are particularly common adverse drug reactions, because most drugs are taken by mouth and pass through the digestive tract. However, almost any organ system can be affected. In older people, the brain is commonly affected, often resulting in drowsiness and confusion.

Types of Adverse Drug Reactions

Many adverse drug reactions represent an exaggeration of the drug’s therapeutic effects (called type 1 or overdose reactions). For example, a person taking a drug to reduce high blood pressure may feel dizzy or light-headed if the drug reduces blood pressure too much. A person with diabetes may develop weakness, sweating, nausea, and palpitations if insulin or an oral antidiabetic drug reduces the blood sugar level too much. This type of adverse drug reaction is usually predictable but sometimes unavoidable. It may occur if a drug dose is too high, if the person is unusually sensitive to the drug, or if another drug slows the metabolism of the first drug and thus increases its level in the blood (see page 89). Type 1 reactions are usually not serious but are relatively common.

Some adverse drug reactions result from mechanisms that are not currently understood (called type 2 or idiosyncratic reactions). This type of adverse drug reaction is largely unpredictable. Examples of such adverse drug reactions include skin rashes, jaundice, anemia, a decrease in the white blood cell count, kidney damage, and nerve injury that may impair vision or hearing. These reactions tend to be more serious but typically occur in a very small number of people. Affected people may be allergic or hypersensitive to the drug because of genetic differences in the way their body metabolizes or responds to drugs.

Some adverse drug reactions are not related to the drug’s therapeutic effect but are usually predictable, because the mechanisms involved are largely understood. For example, stomach irritation and bleeding often occur in people who regularly use aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs— see page 644). The reason is that these drugs reduce the production of prostaglandins, which help protect the digestive tract from stomach acid.

Severity of Adverse Drug Reactions

There is no universal scale for describing or measuring the severity of an adverse drug reaction. Assessment is largely subjective. Reactions can be described as mild, moderate, severe, or lethal.

Reactions usually described as mild and of minor significance include digestive disturbances, headaches, fatigue, vague muscle aches, malaise (a general feeling of illness or discomfort), and changes in sleep patterns. However, such reactions can be very distressing to people who experience them. As a result, people may be less willing to take their drug as instructed, and the goals of treatment may not be achieved.

Reactions that are usually described as mild are considered moderate if the person experiencing them considers them distinctly annoying, distressing, or intolerable. Other moderate reactions include skin rashes (especially if they are extensive and persistent), visual disturbances (especially in people who wear corrective lenses), muscle tremor, difficulty with urination (a common effect of many drugs in older men), any perceptible change in mood or mental function, and certain changes in blood components, such as a temporary, reversible decrease in the white blood cell count or in blood levels of some substances, such as glucose.

Mild or moderate adverse drug reactions do not necessarily mean that a drug must be discontinued, especially if no suitable alternative is available. However, doctors are likely to reevaluate the dose, frequency of use (number of doses a day), and timing of doses (for example, before or after meals; in the morning or at bedtime). Other drugs may be used to control the adverse drug reaction (for example, a stool softener to relieve constipation).

Severe reactions include those that may be life threatening (such as liver failure, abnormal heart rhythms, certain types of allergic reactions), that result in persistent or significant disability or hospitalization, and that cause a birth defect. Severe reactions are relatively rare. People who develop a severe reaction usually must stop using the drug and must be treated. However, doctors must sometimes continue giving high-risk drugs (for example, chemotherapy to people with cancer or immunosuppressants to people undergoing organ transplantation). Doctors use every possible means to control a severe adverse drug reaction.

Benefits Versus Risks

Every drug has the potential to do harm as well as good. When doctors consider prescribing a drug, they must weigh the possible risks against the expected benefits. Use of a drug is not justified unless the expected benefits outweigh the possible risks. Doctors must also consider the likely outcome of withholding the drug. Potential benefits and risks can never be determined with mathematical precision.

When assessing the benefits and risks of prescribing a drug, doctors consider the severity of the disorder being treated and the effect it is having on the person’s quality of life. For example, for relatively minor disorders—such as coughs and colds, muscle strains, or infrequent headaches—only a very low risk of adverse drug reactions is acceptable. For such symptoms, over-the-counter drugs are usually effective and well tolerated. When used according to directions, over-the-counter drugs for treating minor disorders have a wide safety margin (the difference between the usual effective dose and the dose that produces severe adverse drug reactions). In contrast, for serious or life-threatening disorders (such as a heart attack, stroke, cancer, or organ transplant rejection), a higher risk of a severe adverse drug reaction is usually acceptable.

Risk Factors

Many factors can increase the likelihood of an adverse drug reaction. They include the simultaneous use of several drugs, very young or old age, pregnancy, and breastfeeding. Hereditary factors make some people more susceptible to the toxic effects of certain drugs. Certain diseases can alter drug absorption, metabolism, and elimination and the body’s response to drugs (see page 92), increasing the risk of adverse drug reactions. How mind-body interactions, such as mental attitude, outlook, belief in self, and confidence in health care practitioners, influence adverse drug reactions remains largely unexplored.

Use of Several Drugs

Taking several drugs, whether prescription or over-the-counter, contributes to the risk of having an adverse drug reaction. The number and severity of adverse drug reactions increase disproportionately as the number of drugs taken increases. The use of alcohol, which is technically a drug, also increases the risk. Asking a doctor or pharmacist to periodically review all the drugs a person is taking and to make appropriate adjustments can reduce the risk of an adverse drug reaction.

Did You Know…

In the United States, 3 to 7% of all hospitalizations are for treatment of adverse drug reactions.

Age

Infants and very young children are at high risk of adverse drug reactions because their capacity to metabolize drugs is not fully developed. For example, newborns cannot metabolize and eliminate the antibiotic chloramphenicol. Newborns who are given the drug may develop gray baby syndrome, a serious and often fatal reaction. If tetracycline, another antibiotic, is given to infants and young children during the period when their teeth are being formed (up to about age 8), it may permanently discolor tooth enamel. Children under age 18 are at risk of Reye’s syndrome if they are given aspirin while they have influenza or chickenpox.

Older people are at high risk of having an adverse drug reaction for several reasons (see page 1896). They are likely to have many health problems and thus to be taking several prescription and over-the-counter drugs. Also, as people age, the liver is less able to metabolize many drugs, and the kidneys are less able to eliminate drugs from the body, increasing the risk of kidney damage by a drug and other adverse drug reactions. These age-related problems are often made worse by malnourishment and dehydration, which tend to become more common as people age.

Older people are also more sensitive to the effects of many drugs. For example, older people are more likely to experience light-headedness, loss of appetite, depression, confusion, and impaired coordination, putting them at risk of falling and fracturing a bone. Drugs that can cause these reactions include many antihistamines, sleep aids, antianxiety drugs, antihypertensives, and anti-depressants (see table on page 1899).

Pregnancy and Breastfeeding

Many drugs—for example, antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers—pose a risk to the health and normal development of a fetus. To the extent possible, pregnant women should not take any drugs, especially during the first trimester (see table on page 1638). However, for some drugs, including ACE inhibitors and angiotensin II receptor blockers, risk is greatest during the last trimester of pregnancy. Use of any prescription drugs, over-the-counter drugs, and dietary supplements (including medicinal herbs) during pregnancy requires a doctor’s supervision. Social drugs (alcohol and nicotine) and illicit drugs (cocaine and opioids such as heroin) also pose risks to the pregnancy and the fetus.

Drugs and medicinal herbs may be transmitted through breast milk to a baby (see box on page 1641). Some drugs should not be taken by women who are breastfeeding, whereas others can be taken but require a doctor’s supervision. Some drugs do not usually harm the breastfed baby. However, women who are breastfeeding should consult with a health care practitioner before they take any drugs. Social and illicit drugs may harm a breastfeeding baby.

Allergies to Drugs

People sometimes mistake many adverse drug reactions for allergies. For example, people who experience stomach discomfort after taking aspirin (a common adverse reaction) often say they are “allergic” to aspirin. However, this is not a true allergic reaction. True allergic reactions involve activation of the immune system by the drug. Aspirin use can cause stomach discomfort because aspirin interferes with the stomach’s natural barrier defenses against stomach acid.

Allergic (hypersensitivity) reactions to a drug are relatively uncommon. In contrast to other types of adverse drug reactions, the number and severity of allergic reactions do not usually correlate with the amount of drug taken. For people who are allergic to a drug, even a small amount of the drug can trigger an allergic reaction (see page 1112). These reactions range from minor and simply annoying to severe and life threatening. Examples are skin rashes and itching; fever; constriction of the airways and wheezing; swelling of tissues (such as the voice box [larynx] and the opening between the vocal cords that closes to stop the flow of air to the lungs [glottis]), which impairs breathing; and a fall in blood pressure, sometimes to dangerously low levels.

Drug allergies cannot be anticipated, because reactions occur after a person has been previously exposed to the drug (whether it was applied to the skin, taken by mouth, or injected) one or more times without any allergic reaction. However, appropriate skin tests can sometimes help predict allergic adverse drug reactions. A mild reaction may be treated with an antihistamine. A severe or life-threatening reaction may require an injection of epinephrine (also called adrenaline) or a corticosteroid, such as hydrocortisone.

Before prescribing a new drug, doctors usually ask whether a person has any known drug allergies. People who have had severe allergic reactions should wear a Medic Alert necklace or bracelet inscribed with their drug allergies. This information (for example, penicillin allergy) can alert medical and paramedical personnel in case of an emergency.

Overdose Toxicity

Overdose toxicity refers to serious, often harmful, and sometimes fatal toxic reactions to an accidental overdose of a drug (because of a doctor’s, pharmacist’s, or patient’s error) or to an intentional overdose (homicide or suicide).

A lower risk of overdose toxicity is often the reason doctors prefer one drug to another when both drugs are equally effective. For example, if a sedative, antianxiety drug, or sleep aid is needed, doctors usually prescribe benzodiazepines, such as diazepam and temazepam, rather than barbiturates, such as pentobarbital. Benzodiazepines are not more effective than barbiturates, but they have a wider margin of safety and are much less likely to cause severe toxicity in case of an accidental or intentional overdose. Safety is also the reason that newer antidepressants, such as fluoxetine and paroxetine, have largely replaced older but equally effective antidepressants, such as imipramine and amitriptyline (see table on page 868).

Young children are at high risk of overdose toxicity. Brightly colored tablets and capsules, most of which are adult-dose formulations, can attract the attention of toddlers and young children. In the United States, federal regulations require that all prescription drugs taken by mouth be dispensed in childproof containers unless a person signs a waiver to the effect that such a container presents a handicap.

Most metropolitan areas in the United States have poison control centers that provide information about chemical and drug poisoning, and most telephone directories list the number of the local center. This number should be copied and placed near a telephone or programmed into an automatic-dialing telephone or cellular phone.