CHAPTER 12
Factors Affecting Response to Drugs
Everyone responds to drugs differently. The way a person responds to a drug is affected by many factors, including genetic makeup, age, body size, the use of other drugs and dietary supplements (such as medicinal herbs—see page 2067), the consumption of food (including beverages), the presence of diseases (such as kidney or liver disease), storage of the drug (whether the drug was stored too long or in the wrong environment), and the development of tolerance and resistance. For example, a large person generally needs more of a drug than a smaller person needs for the same effect. Whether people take a drug as instructed (see page 97) also affects their response to it. These factors may affect how the body absorbs the drug (see page 82), how the body breaks down (metabolizes—see page 84) and eliminates the drug (see page 84), or what effects the drug has on the body.
Because so many factors affect drug response, doctors must choose a drug appropriate for each person and must adjust the dose carefully. This process is more complex if the person takes other drugs and has other diseases, because drug-drug and drug-disease interactions are possible.
A standard or average dose is determined for every new drug. But the concept of an average dose can be like “one size fits all” in clothing: It may fit a range of people well enough, but it may fit almost no one perfectly. For some drugs, however, the dose does not have to be adjusted, because the same dose works well in virtually everyone.
Effects of Age: Infants and older people particularly have problems with drug response. Their liver and kidneys function less effectively, so drugs that are broken down by the liver or excreted by the kidney tend to accumulate, thus potentially causing problems.
Older people typically have more disorders than children and younger adults and thus usually take more drugs (see page 1896). The more drugs people take, the more likely they are to have problems caused by one drug interfering with another drug or disease. With aging, people also may have more difficulty following complicated instructions for taking drugs, such as to take the drug at very specific times or to avoid certain foods.
Genetic Makeup
Differences in genetic (inherited) makeup among individuals affect what the body does to a drug and what the drug does to the body. The study of genetic differences in the response to drugs is called pharmacogenetics.
Because of their genetic makeup, some people process (metabolize) drugs slowly. As a result, a drug may accumulate in the body, causing toxicity. Other people metabolize drugs so quickly that after they take a usual dose, drug levels in the blood never become high enough for the drug to be effective.
In about half of the people in the United States, N-acetyltransferase, a liver enzyme that metabolizes certain drugs, works slowly. Such people are called slow acetylators. Drugs, such as isoniazid (which is used to treat tuberculosis), that are metabolized by this enzyme tend to reach higher blood levels and remain in the body longer in slow acetylators than they do in people in whom this enzyme metabolizes drugs rapidly (fast acetylators).
About 1 of 1,500 people have low levels of pseudocholinesterase, a blood enzyme that inactivates drugs such as succinylcholine, which is given to temporarily relax muscles during many surgical procedures. If succinylcholine is not rapidly inactivated, muscle relaxation may be prolonged, and people may not be able to breathe on their own as soon after surgery as is usual. They may need a ventilator for an extended time.
About 10% of black men and fewer black women have a deficiency of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that protects red blood cells from certain toxic chemicals. For example, in people with G6PD deficiency, some drugs (such as chloroquine and primaquine, which are used to treat malaria) destroy red blood cells and cause hemolytic anemia (see page 1031).
About 1 of 20,000 people have a genetic defect that makes muscles overly sensitive to anesthetics such as halothane, isoflurane, and sevoflurane. When such people are given one of these anesthetics with a muscle relaxant (usually succinylcholine), a life-threatening disorder called malignant hyperthermia may develop. It produces a very high fever. Muscles stiffen, the heart races, and blood pressure falls.
Drug Interactions
The effect a drug has on a person may be different than expected because that drug interacts with
Another drug the person is taking (drug-drug interaction)
Food, beverages, or supplements the person is consuming (drug-nutrient interaction)
Another disease the person has (drug-disease interaction)
The effects of drug interactions are usually unwanted and sometimes harmful. Interactions may increase or decrease the actions of one or more drugs, resulting in side effects or failed treatment.
DRUG-DRUG INTERACTIONS
Drug-drug interactions can involve prescription or nonprescription (over-the-counter) drugs. Types of drug-drug interactions include duplication, opposition (antagonism), and alteration of what the body does to one or both drugs.
Duplication: When two drugs with the same effect are taken, their side effects may be intensified. Duplication may occur when people inadvertently take two drugs (often at least one is an over-the-counter drug) that have the same active ingredient. For example, people may take a cold remedy and a sleep aid, both of which contain diphenhydramine, or a cold remedy and a pain reliever, both of which contain acetaminophen. This type of duplication is particularly likely with the use of drugs that contain multiple ingredients or that are sold under brand names (thus appearing to be different but actually containing the same ingredients). Awareness of drug ingredients is important, as is checking each new drug to avoid duplication. For
Many Factors Affect Drug Response
example, many prescription-strength pain relievers contain an opioid plus acetaminophen. People taking such a product who do not know its ingredients might take over-the-counter acetaminophen for extra relief, risking toxicity.
Similar problems with duplication can arise when two different drugs with the same effect are taken. This is most likely to occur when people see several doctors, obtain prescriptions at more than one pharmacy, or both. Doctors who are not aware of what others have prescribed may inadvertently prescribe similar drugs. For example, excessive sedation and dizziness can occur when two doctors both prescribe a sleep aid or when one prescribes a sleep aid and the other prescribes another drug (such as an antianxiety drug) that has similar sedative effects. People can reduce this risk by keeping each doctor informed about all drugs being taken and by using one pharmacy to obtain all prescriptions. It is helpful to keep an up-to-date written list of all drugs being taken and to bring the list along on each doctor visit. Also, people should not take previously prescribed drugs (such as a sleeping pill or pain reliever) without checking with the doctor or pharmacist because that drug may duplicate or otherwise interact with one of their current drugs.
Opposition (Antagonism): Two drugs with opposing actions can interact, thereby reducing the effectiveness of one or both. For example, nonsteroidal anti-inflammatory drugs (NSAIDs—see page 644), such as ibuprofen, which are taken to relieve pain, may cause the body to retain salt and fluid. Diuretics, such as hydrochlorothiazide and furosemide, help rid the body of excess salt and fluid. If a person takes both types of drug, the NSAID may reduce the diuretic’s effectiveness. Certain beta-blockers (such as propranolol), taken to control high blood pressure and heart disease, counteract beta-adrenergic stimulants, such as albuterol, taken to manage asthma. Both types of drugs target the same cell receptors—beta-2 receptors (see table on page 86)—but one type blocks them, and the other stimulates them.
Alteration: One drug may alter how the body absorbs, distributes, metabolizes, or excretes another drug.
Acid-blocking drugs, such as histamine-2 (H2) blockers and proton pump inhibitors, raise the pH of the stomach and decrease absorption of some drugs, such as ketoconazole, a drug for fungal infections.
Many drugs are broken down and inactivated (metabolized) by certain enzymes in the liver. Some drugs affect these liver enzymes, either increasing or decreasing their activity, and may cause another drug to be inactivated more quickly or more slowly than usual. For example, by increasing the activity of liver enzymes, barbiturates such as phenobarbital cause the anticoagulant warfarin to be inactivated more quickly and thus to be less effective when taken during the same time period. Conversely, by decreasing the activity of the enzyme system, drugs such as erythromycin and ciprofloxacin can increase the activity of warfarin, risking bleeding. When drugs that affect liver enzymes are used in people taking warfarin, doctors monitor the people more closely and adjust the dose of warfarin to compensate for this effect. The warfarin dose is adjusted again when other drugs are stopped. Many other drugs affect liver enzymes.
Chemicals in cigarette smoke can increase the activity of some liver enzymes. As a result, smoking decreases the effectiveness of some drugs, including propoxyphene (an analgesic) and theophylline (a drug that widens the airways called a bronchodilator).
Some drugs affect the rate at which the kidneys excrete another drug. For example, large doses of vitamin C increase the urine’s acidity and thus may change the rate of excretion and activity of certain drugs. For example, the rate of excretion may be decreased for acidic drugs such as aspirin but may be increased for basic drugs such as pseudoephedrine.
Because there are so many drug interactions, many doctors and pharmacists reduce the risk of problems by checking reference books and computer software programs when prescribing or dispensing prescriptions for additional drugs. In most pharmacies, drug orders and prescriptions are reviewed using a computer system that automatically checks for drug interactions.
DRUG-NUTRIENT INTERACTIONS
Nutrients include food, beverages (including alcohol), and dietary supplements. Consumption of these substances may alter the effects of drugs the person takes.
How to Reduce the Risk of Drug-Drug Interactions
Consult the doctor or pharmacist before taking any new drugs, including over-the-counter drugs and dietary supplements, such as medicinal herbs.
Keep a list of all drugs being taken. Periodically discuss this list with the doctor or pharmacist.
Keep a list of all disorders. Periodically discuss this list with the doctor.
Select a pharmacy that provides comprehensive services (including checking for possible interactions) and that maintains a complete drug profile for each person. Have all prescriptions dispensed in this pharmacy.
Learn about the purpose and actions of all drugs prescribed.
Learn about the possible side effects of the drugs.
Learn how to take the drugs, what time of day they should be taken, and whether they can be taken during the same time period as other drugs.
Review the use of over-the-counter drugs with the pharmacist. Discuss any disorders present and any prescription drugs being taken.
Take drugs as instructed.
Report to the doctor or pharmacist any symptoms that might be related to the use of a drug.
If seeing more than one doctor, make sure each doctor knows all the drugs being taken.
Food: Like food, drugs taken by mouth must be absorbed through the lining of the stomach or the small intestine. Consequently, the presence of food in the digestive tract may reduce absorption of a drug. Often, such interactions can be avoided by taking the drug 1 hour before or 2 hours after eating.
Dietary Supplements: Dietary supplements, including medicinal herbs, are products (besides tobacco) that contain a vitamin, mineral, herb, or amino acid and that are intended as a supplement to the normal diet (see page 2067). Supplements are regulated as foods, not as drugs, so they are not tested as comprehensively. However, they may interact with prescription or over-the-counter drugs. People who take dietary supplements should tell their doctors and pharmacists, so that interactions can be avoided.
Alcohol: Although many people do not consider alcohol a nutrient, it affects body processes and interacts with many drugs. For example, taking alcohol with the antibiotic metronidazole can cause flushing, headache, palpitations, and nausea and vomiting. Doctors or pharmacists can answer questions about possible alcohol and drug interactions.
SOME DRUG-FOOD INTERACTIONS
| AFFECTED DRUG | INTERACTING FOOD | INTERACTION |
| Bisphosphonates (such as alendronate, ibandronate, and risedronate) | Any food | Food, even orange juice, coffee, or mineral water, may markedly reduce the absorption and effectiveness of these drugs. Alendronate and risedronate must be taken with plain water at least 1/2 hour before the first food, beverage, or drug of the day is taken, and ibandronate must be taken at least 1 hour before. |
| Anticoagulants | Foods high in vitamin K (such as broccoli, brussels sprouts, spinach, and kale) | Such foods may reduce the effectiveness of anticoagulants (such as warfarin), increasing the risk of clotting. Intake of such foods should be limited, and the amount consumed daily should remain constant. |
| Certain benzodiazepines (such as triazolam) | Grapefruit juice | Grapefruit juice inhibits enzymes involved in drug metabolism and thereby intensifies the effect of certain drugs, many of which are not listed here. |
| Calcium channel blockers (such as felodipine, nifedipine, and nisoldipine) | ||
| Cyclosporine | ||
| Estrogen and oral contraceptives | ||
| Certain statins (such as atorvastatin, lovastatin, and simvastatin) | ||
| Digoxin | Oatmeal | The fiber in oatmeal and other cereals, when consumed in large amounts, can interfere with the absorption of digoxin. |
| MAO inhibitors (such as phenelzine and tranylcypromine) | Foods high in tyramine, including many cheeses (such as American processed, cheddar, blue, brie, mozzarella, and Parmesan), yogurt, sour cream, cured meats (such as sausage and salami), liver, dried fish, caviar, avocados, bananas, yeast extracts, raisins, sauerkraut, soy sauce, fava beans, red wine, certain beers, and products containing caffeine | Severe headache and a potentially fatal increase in blood pressure (hypertensive crisis) can occur if people taking an MAO inhibitor (used most often to treat depression) consume these foods. These foods must be avoided. |
| Tetracycline | Calcium or foods containing calcium, such as milk and other dairy products | These foods can reduce the absorption of tetracycline, which should be taken 1 hour before or 2 hours after eating. |
| MAO = monoamine oxidase. | ||
DRUG-DISEASE INTERACTIONS
Sometimes, drugs that are helpful in one disease are harmful in another disorder. For example, some beta-blockers taken for heart disease or high blood pressure can worsen asthma and make it hard for people with diabetes to tell when their blood sugar is too low. Some drugs taken to treat a cold may worsen glaucoma. People should tell their doctor all of the diseases they have before the doctor prescribes a new drug. Diabetes, high or low blood pressure, an ulcer, glaucoma, an enlarged prostate, poor bladder control, and insomnia are particularly important, because people with such diseases are more likely to have a drug-disease interaction.
Drug-disease interactions can occur in any age group but are common among older people, who tend to have more diseases (see page 1896).
Tolerance and Resistance
Tolerance is a person’s diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug. Resistance refers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them.
Tolerance: A person may develop tolerance to a drug when the drug is used repeatedly. For instance, when morphine or alcohol is used for a long time, larger and larger doses must be taken to produce the same effect. Usually, tolerance develops because metabolism of the drug speeds up (often because the liver enzymes involved in metabolizing drugs become more active) and because the number of sites (cell receptors) that the drug attaches to or the strength of the bond (affinity) between the receptor and drug decreases (see page 85).
Tolerance is not the same as dependence or addiction. Dependence, which may be physical or psychologic, refers to a strong desire to experience the effects of the drug (see page 2079). In physical dependence, the person may experience symptoms of withdrawal when the drug is stopped. Addiction is compulsive use and overwhelming involvement with a drug (see page 2080).
Resistance: Strains of microorganisms (bacteria or viruses) are said to develop resistance when they are no longer killed or inhibited by the antibiotics and antiviral drugs that are usually effective against them (or, in practice, when significantly higher than normal doses are required to have an effect). Similarly, cancer cells may develop resistance to chemotherapy drugs.
Resistance appears because of the mutations that take place spontaneously in any group of growing cells, whether exposed to drugs or not. Most such mutations change the cell’s structure or biochemical pathways in a harmful way. But some mutations change the parts of the cell that are affected by drugs, decreasing the drug’s ability to work (that is, causing resistance). Because such mutations are very rare, there are normally only a few such resistant cells in any group. However, if all or many of the “normal” cells are killed by a drug, a much higher proportion of the survivors are likely to be resistant. If the resistant survivors are not killed by the body’s natural defenses, which is more likely when drugs are stopped too soon or not taken in the proper manner, they may reproduce and pass on the resistant trait to their descendants.
Prevention and Treatment
To prevent the development of resistance, doctors try to use antibiotics only when necessary (not for viral infections such as a cold) and have people take them for a full course of treatment. In the treatment of certain serious infections, such as HIV, doctors usually give two or more different drugs at the same time because it is very unlikely that a cell would spontaneously be resistant to two drugs at the same time. However, giving one drug for a short time followed by another can produce resistance to multiple drugs—this has become a problem with tuberculosis in particular.
Once tolerance or resistance has developed to a drug, doctors may increase the dose or use a different drug.