Pharmacology is the study of drugs and their actions. Pharmacologists, those who study drugs and their actions, consider a drug to be any chemical substance that produces a measurable biological response. So drugs include not only prescription medications but also nonprescription medications, botanicals, drugs of abuse, and poisons.

As we consider the variety of drugs and the measurable responses they produce, it will be helpful to think about what we would like to see in an ideal drug (Box 2-1). There are no perfect drugs—yet. But defining what would make an ideal drug will help us understand how medicines have developed over time, and what properties to consider as we compare one drug with another to choose the best medication.

HOW NEW DRUGS ARE DEVELOPED

Drugs are developed by pharmaceutical companies to help patients and to make money. The early part of the drug development process is called the preclinical stage. Identification of promising drugs and their testing in animals occur during this stage. Pharmaceutical companies will identify a drug target, starting sometimes with ingredients isolated from a plant (or organism in the case of antibiotics) with desirable medicinal properties, sometimes with a molecular target identified in the body to produce the desired response, and sometimes with a disease in need of treatment. It is common for companies to enlist medicinal chemists, who specialize in designing and synthesizing new drugs. Medicinal chemists can provide many new chemical compounds for the preclinical process. Each drug might have a small difference in its chemical structure that will change its drug properties. Many drugs are examined as pharmaceutical companies seek the elusive perfect drug with just the right combination of properties. Preclinical studies are performed on cells, isolated tissues and organs, and in laboratory animals to identify promising compounds.

BOX 2–1 IDEAL DRUG PROPERTIES

• Convenient route of administration, probably taken by mouth

• Established dosage

• Immediate onset of action

• Produces a single desired biological action

• Produces no unwanted effects

• Convenient duration of action

• Dosage unaffected by loss of kidney or liver function or by disease state

• Improves quality of life

• Prolongs patient survival

Drugs approved by the Food and Drug Administration (FDA) must be both safe and effective and are screened by pharmacologists specializing in various aspects of drug activity. Toxicologists specialize in understanding the harmful effects of drugs and predicting as early as possible if a drug will be likely to harm patients. Ideally, drugs will produce their desired effects at dosages well below those needed to produce toxicity.

During the clinical stage of new drug development, pharmaceutical companies must establish the safety and effectiveness of new products in humans. Phase I clinical trials typically establish biological effects as well as safe dosages and pharmacokinetics in a small number of healthy patients. During phase II clinical trials, new drugs are used to treat disease in a small number of patients and to establish the potential of the drug to improve patient outcomes. If the drug still looks promising, phase III clinical trials will compare the new medication to standard therapy in a larger number of patients studied by at sites across the country. New drugs must be at least as good as, and it is hoped better than, other available therapies. Throughout the process, pharmaceutical companies work with the FDA.

After being approved by the FDA, drugs are continuously monitored through post-marketing surveillance, in which health professionals are encouraged to report adverse events, which are studied by both pharmaceutical companies and the FDA. During clinical trials, only several thousand patients receive a new drug. During the post-marketing period, a larger population of patients receives the drug, and sometimes much is learned about additional adverse effects that occur infrequently with use of the drug. Pharmacogenomics is the study of how individual variations in drug targets or metabolism affect drug therapy. Pharmacogenomic studies can identify factors that are responsible for beneficial or adverse effects in individual patients.

DRUG RESPONSES

Homeostasis is the tendency of a cell, tissue, or the body not to respond to drugs but instead to maintain the internal environment by adjusting physiological processes. Before a medication can produce a response, it often must overcome homeostatic mechanisms.

Drug effects depend on the amount of drug that is administered. If the dose is below that needed to produce a measurable biological effect, then no response is observed; any effects of the drug are not sufficient to overcome homeostatic capabilities. If an adequate dose is administered, there will be a measurable biological response. With an even higher dose, we may see a greater response. At some point, however, we will be unwilling to increase the dosage further, either because we have already achieved a desired or maximum response or because we are concerned about producing additional responses that might harm the patient.

Because pharmacology is the study of substances that produce biological responses, measurement of what happens when we administer medications is important. We will need ways to express and compare drug activity so that we can describe the action or effect of drugs, compare the effects of different drugs, and predict their pharmacological effects.

Dose–Response Curves

Drugs produce responses as a result of their chemical interactions with living systems. The relationship between the dose or concentration of a drug and its biological response follows the laws of chemistry. The law of mass action defines chemical interactions and forms the theoretical foundation for drug responses that occur through receptors that mediate drug responses. Simply stated, the higher the concentration of a drug at its site of action, the more the drug will bind to the receptor and the greater will be the response. With a greater number of drug molecules in the vicinity, more of them are likely to interact with the receptor.

It is simplest to think that drug responses are directly related to the fraction of receptors that are occupied, or bound, by a drug, so that 50% of the maximum response occurs at a blood level or concentration at which a drug occupies 50% of its receptors. But depending on the number of receptors in a tissue and the ability of drug binding to produce a change in the receptor conformation, far fewer receptors (less than 10%) may be needed to produce a maximum effect.

Types of Drug Responses

There are two basic types of drug responses: quantal and graded. These responses differ in how they are measured and dictate dosing decisions to achieve the desired effect.

Graded responses are biological effects that can be measured continually up to the maximum responding capacity of the biological system (Box 2-2). Most drug responses are graded. For example, changes in blood pressure are measured in millimeters of mercury (mm Hg), and patients may experience small or large changes in blood pressure following treatment with drugs. Graded responses are easier to manage clinically because we can see how each patient responds to a particular dose of medication and, if appropriate, alter the dosage to achieve a greater or lesser response. So if a patient’s blood pressure is too low or too high when a particular blood pressure medication is administered, we can adjust the dosage based on the patient’s individualized response to the medication.

BOX 2–2 EXAMPLES OF GRADED RESPONSES TO DRUGS

• Blood pressure

• Heart rate

• Diuresis

• Bronchodilation

• FEV1

• Pain (scale 1–10)

• Coma score

Quantal effects are responses that may or may not occur (Box 2-3). For example, seizures either occur or they do not. The same is true for pregnancy, sleep, and death. If we designate a response as either occurring or absent, it is a quantal response. Prediction of drug dosages or blood levels that produce quantal effects is much more reliable for a population of patients than for an individual patient. Data from a population of patients must be used to establish appropriate doses or blood levels to predict quantal effects in a large number of patients. For example, oral contraceptive doses are high enough to prevent pregnancy (a quantal response!) in over 99% of women. Note that, even with anticonvulsants or oral contraceptives, we do not achieve a 100% response. Because of natural variation in drug metabolism and responses to drugs, there may always be individuals who fail to respond, even at higher dosages. In general, responses that are far outside the typical dose or concentration range occur in patients with unusual drug metabolism or receptor mutations.

The distinction between graded and quantal responses is not always fixed. Certainly, patients are either pregnant or not and either dead or alive. However, for some other quantal responses such as seizures, you can also count the number of occurrences. This can be helpful in adjusting medications to improve patient response with fewer or shorter seizures (a graded response), even though the goal is a seizure-free (quantal response) patient. We can also make graded responses quantal by considering such issues as “Did drug therapy lower blood pressure into the target range?” or “How many patients were headache-free?”

BOX 2–3 EXAMPLES OF QUANTAL RESPONSES TO DRUGS

• Convulsions

• Pregnancy

• Rash

• Sleep

• Death

Expressing Drug Responses

Pharmacologists show the relationship between dose or concentration and drug effect using graphs that show the dose–response relationship, or dose–response curve. Graphs showing drug responses will show the response on the vertical axis and the concentration or dose on the horizontal axis. And for statistical reasons, because drug dosages extend over a large range, the horizontal axis is logarithmic, which means that it covers a larger dosage range and that numbers are distributed along the axis so that moving a certain distance right or left represents multiplying or dividing the dosage or blood level concentration by a fixed amount. Most dosage changes in patients are doubled or halved: a “logarithmic” adjustment.

Dose–response curves provide information on the relationship between dosage or concentration and responses for one or more drugs. To “read” a concentration–effect or dose–response curve, move from left to right along the horizontal axis; this represents an increasing dosage or concentration. At each dosage, the level of effect is shown by the vertical height of the curve. When concentration–response data are shown for two drugs or two responses on the same graph, we can compare the effects at each dose level.

Pharmacologists compare drugs and their actions in several ways, including potency, efficacy, intrinsic activity, and selectivity. Potency is the expression of how much drug is needed to produce a biological response (Fig. 2-1). Potency describes the difference in concentration or dosage of different drugs required to produce a similar effect. Drugs that are more potent require a lower dosage or concentration to produce the same response. For example, compare doses of nonprescription drugs that relieve headache: 200 mg ibuprofen, 325 mg aspirin, and 50 mg ketoprofen. Because ketoprofen requires the lowest dose, it has the highest potency. Drugs that differ in potency differ in their horizontal position on the dose–response curve.

Figure 2–1. Concentration–effect curves for three drugs that differ in potency (i.e., the dose or concentration required to produce an effect). The drug concentration on the x-axis is expressed in molar units, representing the number of molecules in each liter of solution. The graded response is expressed as a percentage of maximum effect.

Efficacy expresses the ability of a drug to produce a maximum effect at any dosage. Efficacy is the expression of the maximum effect a drug can produce. For example, consider the treatment of pain. There are many drugs that will relieve mild pain. No matter how high we increase the dosage, drugs that work well for mild to moderate pain are usually ineffective for treating more severe cancer-related pain, for example. Treatment of severe pain requires the use of stronger drugs, such as the opioid analgesics morphine or oxycodone. Morphine or oxycodone have higher efficacy for pain relief than ibuprofen. Drugs with high efficacy can produce greater effects than lower-efficacy drugs can.

Intrinsic activity is very similar to efficacy in that it represents the ability of a drug to produce a large response. Intrinsic activity, however, is used to describe the ability of a drug to produce a response once it has occupied specific receptors. Some drugs produce the maximum receptor stimulation once they occupy receptors; their response is limited by how many drug molecules occupy receptor sites. Other drugs with lower intrinsic activity can occupy the same number of receptors but will produce a lesser response. Drugs can also occupy receptors and produce no receptor stimulation; they merely block the action of neurotransmitters or other drugs.

Drug Selectivity

In clinical use, drugs produce responses that are desired and responses that are unwanted. Of course, we should be administering drugs with a goal in mind, and that goal should include a level of response, either graded or quantal. The level of unwanted response we are willing to accept typically depends on what we are treating and the type of undesired effect. Patients regularly accept all kinds of adverse effects from cancer chemotherapy when their life is on the line; cancer patients tolerate hair loss, nausea, vomiting, and generally feeling miserable because that is what goes along with killing cancer cells. Sometimes patients make surprising decisions regarding drugs that produce both desirable and undesirable effects; for example, some patients will live in severe pain rather than take an analgesic that causes constipation. For hypertension and other symptomless disease states, patients are often reluctant to accept even minor adverse effects. Patients receiving pharmacotherapy present the opportunity and challenge to adjust medications and dosages to achieve optimal results with minimal adverse effects and to educate patients to continue therapy even if minor adverse effects appear.

There are challenges to expressing drug selectivity. The most reasonable way to express selectivity is as a ratio of the dose or concentration producing the undesired effect to the dose or concentration producing the desired effect. This is the same as determining how many times the therapeutic dosage needs to be increased to produce the undesired effect. A medication that requires one tablet to produce the desired response and does not produce undesirable effects unless five tablets are used would have a selectivity ratio of 5. That is not a bad drug. But many drugs produce significant undesired effects at or slightly above the therapeutic dosage.

It would be nice if we could describe drug selectivity in a way to encourage optimal drug use. Would not a medication that has high selectivity and produces only the desired effects be the treatment of choice? There are problems, though, with consistently expressing selectivity based on desired and undesired effects. Medications often have more than one effect and might be used for any of their effects, so sometimes a particular effect is desired and sometimes it is undesired. Diphenhydramine is a very nice drug that is used as an antipruritic for itching, as an antihistamine for allergies, as an anticholinergic that dries secretions, and as a sleeping aid that produces drowsiness. Desired and undesired effects can differ for each patient, and if we compare dosages, there are several selectivity ratios.

The therapeutic index is a special ratio describing drug selectivity. The therapeutic index is the ratio of the lethal dose of a drug to the therapeutic dose of a drug. There are some limitations to the therapeutic index: it uses death, a really unacceptable adverse effect, and it uses data from animal studies. But the therapeutic index provides a fixed comparison for drug safety. The therapeutic index of drugs on the market is, of course, always greater than 1; a therapeutic index of less than 1 means that the drug kills before it cures. The therapeutic index ranges from 2 for some drugs (cancer chemotherapy, lithium carbonate) to 6,000 for others (penicillin in nonallergic patients).

Drug Responses in the Real World

Pharmacotherapy in real patients is different than what has already been described. The placebo effect is a pharmacological effect that is not due to the active ingredient. Placebos are tablets or capsules that contain no active ingredient; they are sometimes called “sugar pills” because they used to be filled with sugar. It is common for drug studies to have a placebo group to see if patients are responding to the active drug or just to the act of taking a medication (Fig. 2-2). The placebo group will also be monitored for adverse effects, which establishes the level in untreated patients. Placebo effects are relatively high in some disease states, such as depression, and very low in other disease states, such as cancer.

Dose–effect relationships in the real world do not start at zero response; they start at the response associated with the placebo effect. The level of response increases as the dose increases but rarely reaches 100%. Instead, the risk of toxicity will limit the maximum dosage, or another drug will be used if there is no satisfactory effect.

Brand Versus Generic Drugs

New drugs are patented to protect the innovator company for a period during which only it can manufacture the drug. New drugs are given a generic name that anyone can use to market the drug, but innovator companies will make up a brand name that only they can use to market their drug. During the years after a drug is released, it is marketed under the brand name, and patients and practitioners often become familiar with the product under its brand name. Once the patent on the original drug expires, other companies can manufacture generic products that are designed to imitate the brand product. Once competition is allowed, generic manufacturers formulate similar dosage forms with the same active ingredient in the same amount.

Figure 2–2. Theoretical representation of how drugs produce effects in clinical practice. Drug concentration (x-axis) increases from left to right. Some patients will respond at low dosages, either because of the placebo effect or sensitivity to the drug. As drug concentrations increase, greater numbers of patients will respond favorably but some will also respond adversely. At some dosage or concentration, the presence of toxic effects precludes the use of higher doses in patients.

Patients often wonder about the relationship between the effects of brand and generic preparations. Since brand and generic preparations contain the same active ingredient, the body treats the two exactly the same. Differences between brand and generic preparations can occur in the inactive ingredients of the tablet or capsule, such as coloring or filler materials.

Generic products are supposed to provide patients with the same dosage as brand-name products. Differences between brand and generic formulations result from differences in the time it takes for the different formulations to break apart in the stomach and dissolve prior to absorption. There are always differences in the speed, or rate, of absorption. The FDA rates generic formulations in its Orange Book, and products with an AB rating are considered to be similar enough to use as generic substitutes for brand-name products.

Because the differences between brand and generic products occur in the tablet/capsule disintegration and dissolution steps prior to absorption, brand and generic preparations in which the drug is already in solution, such as injectables, are similar in their rate and extent of absorption.

RECEPTORS

We can think of drug responses in a simple way. A favorite cartoon shows a mathematician solving a problem. The solution begins with an equation that states the problem, and a gap follows in which the mathematician writes “and then a miracle happens,” followed by the result. If we choose to think of drug responses as the predictable miracles that follow drug administration, then pharmacology would be no more than memorizing which responses go along with which drugs. A century ago, medical schools and pharmacy schools had departments of materia medica, a Latin way of describing the pairing of a drug with a response without necessarily knowing what happens in between. Today, we encounter the same knowledge level for many botanicals, and patients and health professionals alike will often consult manuals that list symptoms to be treated and the plant product that can produce that action.

If we choose to actually understand drug action and why drugs produce predictable sets of responses, we need to look at the biological molecules and the chemical principles that underlie responses to drugs. Almost all drugs act through receptors. Receptors are the large molecules, usually proteins, that interact with and mediate the action of drugs. Receptors are important because they determine the relationship between dose and effect, the selectivity of drugs, and the actions of pharmacological antagonists.

Pharmacologists tend to organize drug activity based on the receptors through which individual drugs act. There are several benefits to organizing the study of pharmacology around receptors. It simplifies the amount of material that needs to be memorized. Receptors provide a theoretical framework for understanding and predicting drug actions and the relationship between dose (or concentration) and effect. Also, receptors within the same “superfamily” often share properties.

Drug targets include enzymes, ion channels, cell surface receptors, nuclear hormone receptors, transporters, and DNA. In each case, chemical interactions take place between drug and receptor molecules. Receptors act through a number of mechanisms, including those described in the following sections. Chemical energy from the drug–receptor interaction is used to change the receptor in some way that alters physiological processes to produce cellular changes that result in a measurable response.

Because chemical interactions determine the activity of a drug at a particular receptor type, changes in chemical structure result in changes in pharmacological activity. The correlation of chemical structure with pharmacological activity is called the structure-activity relationship (SAR). SARs can be helpful in understanding receptors and for developing new drugs. There are separate, independent SARs for different drug properties (e.g., potency, selectivity, toxicity), so the fact that any one drug property changes for the better (or worse) does not necessarily mean that the change affects the other properties of the drug.

Ion Channel Receptors

Ion channel receptors transmit signals across the cell membrane by increasing the flow of ions and altering the electrical potential or separation of charged ions across the membrane. Ion channel receptors can produce responses with a rapid onset and short duration. For example, activation of ion channels by nicotinic receptors is responsible for muscle contraction. Muscle movement needs to start immediately and must stop at will to be effective. The nicotinic receptor consists of five subunits, which form a cylindrical structure with a hole in the center. When acetylcholine (ACh) binds to the two alpha subunits, a conformational change occurs, which momentarily opens the central channel, permitting sodium to enter and potassium to leave the cell (Fig. 2-3). Two binding sites for ACh result in a very steep concentration–effect curve, so a very small change in ACh concentration at the neuromuscular junction will produce dramatic openings in ion channels. Notice that the two ACh sites are a certain distance apart. This is important for the structure–activity relationship of drugs that blocks nicotinic receptor sites.

Figure 2–3. The nicotinic acetylcholine (ACh) receptor comprises five subunits that come together to form an ion channel receptor. When ACh binds to two sites on the receptor, the ion channel opens to let sodium (Na+) and potassium (K+) cross the cell membrane to initiate a response.

Figure 2–4. G-protein–coupled receptors are proteins that cross the cell membrane 7 times, creating a pocket in which drugs can interact. Bound drugs may stimulate the receptor to release a G protein that can interact with various effector proteins to produce physiological responses.

Ion channel receptors include receptors for ACh (nicotinic), gamma-aminobutyric acid (GABA), and excitatory amino acids (glycine, aspartate, glutamate, etc.).

Receptors Coupled to G Proteins

A number of different guanine nucleotide regulatory proteins (or G proteins) are present in cell membranes. G proteins share a similar structure in which seven regions of protein span the cell membrane to create a pocket (in which drugs can bind) and end with a receptor “tail” inside the cell (Fig. 2-4). Individual G protein receptors have the general G-protein structure but differ in their “binding site,” the area that recognizes and binds to drugs, and in the intracellular portions of the G protein that control what happens after a drug is bound. Receptors are activated when specific drugs interact with the binding site, producing a conformational change, a sort of twist, in the G protein. Activation of receptors then produces intracellular changes in the binding of the G-protein receptor to other proteins that control response through other molecules called second messengers.

Second messengers include molecules such as cAMP (cyclic adenosine monophosphate), Ca++, phosphoinositides, and diacylglycerols; each can be produced as a result of stimulating different G-protein–linked receptors. The conformational change in the G-protein receptor can also make intracellular parts of the receptor available for enzymes to phosphorylate. Phosphorylation, placing a phosphate group on a protein, is a way of marking it for activation or inactivation.

G proteins are made up of three major subunits (alpha [α], beta [β], gamma [γ]); minor variations (isotypes) of each subunit can result in a great deal of variation in G proteins just from different combinations of alpha, beta, and gamma subunits. Variation in G-protein subunits and receptors allows them to interact with a variety of drugs and produce different responses depending on which drug is recognized by the receptor, which subunits are involved, and which effector protein is altered. Individual cells and tissues can produce various types and amounts of G proteins. This is a homeostatic mechanism used by the body to adapt to disease states and drug treatment.

Receptors coupled to G proteins mediate the level of second messengers following the extracellular interaction of drug with the receptor. This receptor superfamily includes a large number of different receptors that recognize different drugs and activate or inhibit different second messengers. For example, beta-adrenoceptors mediate the effects of epinephrine (also called adrenaline) on the heart and make our hearts beat faster and stronger at scary movies.

In the prototype beta-adrenoreceptor system, interaction of epinephrine with the receptor displaces guanosine diphosphate (GDP) from the G protein, and its replacement by guanosine triphosphate (GTP) activates the G protein. The G protein uncouples from the receptor and stimulates the enzyme adenylyl cyclase to generate intracellular second messenger cAMP. Intracellular cAMP produces the pharmacological effect, such as making the heart beat stronger and faster, until the cAMP breaks down. Caffeine produces similar effects by inhibiting the breakdown of cAMP.

Changes in the number of receptors alter responsiveness to drugs. The number of available G-protein receptors decreases when the receptors are stimulated. Receptors in the cell membrane are phosphorylated at specific intracellular sites, which can lead to desensitization, or loss of receptors or responsiveness following receptor activation. These receptor changes influence drug treatment by limiting the time in which certain drugs can be used clinically and by placing patients at risk for rebound effects when certain drugs are discontinued.

Transmembrane Receptors

Transmembrane receptors consist of an extracellular hormone-binding domain and an intracellular enzyme domain that phosphorylates the amino acid tyrosine. When an active hormone binds to the extracellular binding site, the receptor conformation changes and two receptors bind to one another, activating the enzyme and sustaining the effect (Fig. 2-5). Different receptors catalyze the phosphorylation of tyrosine residues on various downstream signaling proteins.

The protein tyrosine kinase includes receptors for insulin, epidermal growth factor, and platelet-derived growth factor.

Intracellular Receptors Regulating Gene Expression

Lipid-soluble hormones can pass through the cell membrane and bind to intracellular receptors. The glucocorticoid receptor resides in the cytoplasm until it binds with a drug having glucocorticoid activity; binding of the drug displaces a stabilizing protein and permits the folding of the receptor into its active conformation. The receptor then moves to the nucleus, where it controls the transcription of genes by binding to specific DNA sequences (Fig. 2-6). Hormone receptors of this type include corticosteroids, mineralocorticoids, sex steroids, vitamin D, and thyroid hormones; these produce more sustained responses.

Figure 2–5. The insulin receptor is prototypical of tyrosine kinase receptors. These receptors are brought together by extracellular drug binding (insulin in the case of the insulin receptor), which activates the intracellular enzyme tyrosine kinase. Tyrosine kinase receptors activate one another by adding a phosphorus (P) to select sites on cellular proteins, which in turn activates a physiological response.

Figure 2–6. Steroid hormones diffuse through the cell membrane to interact with steroid receptors in the cytoplasm. The hormone–receptor pair relocates to the nucleus, where it can interact with DNA to effect RNA transcription and the synthesis of proteins.

Enzymes

Enyzmes are biological molecules that encourage specific chemical reactions in the body. For example, the enzyme acetylcholinesterase breaks a chemical bond in ACh to terminate its action and make acetic acid and choline (Fig. 2-7). A different enzyme can reassemble these molecules into ACh. Drugs can act to stimulate or inhibit specific enzymes. The anticoagulant heparin binds to an enzyme called antithrombin-III and increases its inactivation of clotting factors. The anticholesterol “statin” drugs are inhibitors of the enzyme HMG-Co-A (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase, which controls cholesterol synthesis in the body. Antibiotics are frequently inhibitors of enzymes that are essential for bacteria to remain alive.

Drug Action at Receptors

Drugs can do three basic things once they bind to a receptor. Agonists, or full agonists, are drugs that produce receptor stimulation and a conformational change every time they bind. Full agonists do not need all of the available receptors to produce a maximum response. Some agonists can produce their maximum response by binding to less than 10% of the available receptors. The receptors that are left over and not needed for a response are called spare receptors.

Figure 2–7. Enzymes bind to substrates and speed up biochemical reactions. Enzymes can serve as receptors to the substrate, which binds at the active site, or to drugs that control enzyme activity through binding at a different site.

Antagonists are drugs that occupy receptors without stimulating them. Antagonists occupy a receptor site and prevent other molecules, such as agonists, from occupying the same site and producing a response. Antagonists produce no direct response. The response we see following administration of antagonists results from their inhibiting receptor stimulation by agonists. For example, beta blockers such as propranolol and atenolol act as antagonists at the beta-adrenoceptor. Adrenergic nerve activity can raise heart rate, and patients with high heart rates experience a significant drop in heart rate following administration of beta blockers. The same administration may have little effect on patients who lack adrenergic nerve activity and already have a lower heart rate. The effect of antagonists is dependent on the background receptor activity that it can block.

Antagonists produce a shift in the concentration–effect relationship for agonists acting at that same specific receptor as the antagonist; they make agonists for the same receptor appear less potent. The effect of an antagonist is dependent on its blood levels and its affinity for the receptor. Most antagonists in clinical use are competitive reversible antagonists, and it is possible to overcome the antagonist effects with higher concentrations of the competing agonist. A very small number of antagonist drugs (e.g., echothiophate, phenoxybenzamine) act by irreversibly binding to the receptor; their antagonism remains until new receptors can be produced by the cell.

Partial agonists are drugs that have properties in between those of full agonists and antagonists. Partial agonists bind to receptors but when they occupy the receptor sites, they stimulate only some of the receptors. This is sometimes called intrinsic activity. So they can act as part agonist and part antagonist. Partial agonists would require all of the available receptors to produce their full response, and the maximum response for a partial agonist is less than that for a full agonist. The beta blockers acebutolol, penbutolol, and pindolol are partial agonists. Administration can block the effects of adrenergic nerves on heart rate, but partial agonist activity keeps heart rate from falling too low, as might occur following administration of a pure beta-adrenoceptor antagonist. So beta blockers with intrinsic sympathomimetic activity control heart rate within a range that is higher than the response to an antagonist and lower than the response to an agonist.

Disease States and Receptors

Disease states or drug treatment can selectively alter the number of receptors in various tissues throughout the body. For example, hyperthyroidism upregulates, or increases, the number of beta-adrenoceptors, making hyperthyroid patients more likely to have hypertension and a rapid heart rate. Treatment with some agonist drugs can cause the receptors to downregulate, or decrease, in response to receptor stimulation; this can limit the duration over which the drug can be clinically useful. Treatment with some antagonist drugs can cause receptors to upregulate in response to the decrease in receptor stimulation; this can produce rebound effects if the antagonist is abruptly withdrawn.

Because the maximum response to partial agonists depends on the number of receptors, an increase in receptor number will increase the response of partial agonists.

Non-receptor Mechanisms

Not all drugs act through receptors. General anesthetics, sodium bicarbonate (which neutralizes stomach acid), and chelating agents (which bind to and remove metal ions in the blood) are some examples of drugs whose action is based on their physicochemical properties rather than interaction with receptors.

PHARMACOKINETICS

Pharmacokinetics is the branch of pharmacology dealing with the absorption, distribution through the body, metabolism, and excretion of drugs. Ideally, drugs will enter the body readily, go directly to their site of action, and have a favorable combination of metabolism and excretion that will make it easy to manage patients, even in the presence of kidney or liver disease.

Absorption

Medications produce little clinical effect when they remain inside the prescription bottle. To produce a biological effect, drugs must enter the body. Once inside the body, drugs can interact with various receptor molecules to produce physiological changes that result in clinical effectiveness.

The way in which medications are presented to the body affects the speed, the extent, and the duration of drug absorption. The route of administration also affects patient compliance, that is, their willingness to follow recommendations for taking a medication (Box 2-4). So choosing the route of administration can have important implications for drug therapy, and it is not surprising that a variety of routes of administration can be chosen based on the chemical properties of an individual drug, the condition of an individual patient, and the goal of drug treatment.

There is more to it than just having a medication enter the body. Patients can swallow a poorly formulated dosage form that travels through the intestines and arrives unchanged in the toilet. There is little biological effect from these “bedpan bullets” if the active medication never reaches its site of action.

BOX 2–4 EFFECTS OF ROUTE OF ADMINISTRATION

• Compliance

• Bioavailability

• Onset of action

• Duration of action

Parenteral Administration

Medications may be administered parenterally, or by injection, when immediate effect is required, when the active ingredients are destroyed or not absorbed in the gastrointestinal tract or other routes, or when the patient is unable to take an oral medication. A major limitation of parenteral administration is that it requires needles, syringes, and sterile technique.

Drug absorption is greatest for intravenous (IV) injection. IV preparations use drugs that have been dissolved in aqueous solution and are sterile and ready to enter the bloodstream. Intramuscular or subcutaneous preparations may use drugs suspended in sterile media, which is usually aqueous but occasionally oil-based. When administered by IV injection, all the drug enters the bloodstream immediately. IV administration serves as the standard to which other routes of administration are compared when we consider bioavailability, the percentage of the administered drug that is absorbed. Although there are drawbacks to needles and the need for sterility, IV administration is used for its advantages of rapid or complete absorption and immediate drug action. A major disadvantage of IV administration is that, once administered, the dosage cannot be slowed or removed. IV administration is common for emergency drugs and in the hospital setting.

Oral Administration

Oral administration is the most convenient and common route of administration. In contrast to IV administration, orally administered drugs must go through a number of steps on their way to the bloodstream. Following oral administration, dosages, as tablets, capsules, or liquid, make their way to the stomach and continue to move into and through the small and large intestines on their way to the colon. Tablets or capsules must break apart, and their drug contents must dissolve in stomach acid or intestinal fluid before the drug can be absorbed. This takes time, so orally administered drugs may not act as fast as some other routes of administration. Orally administered drugs must pass through the lining of the intestines to enter the systemic circulation. Once absorbed, orally administered drugs travel to the liver, where they may be metabolized on their way to the bloodstream.

A number of related routes of administration overcome some of the problems encountered with oral dosing. Sublingual administration (under the tongue) and buccal administration (between the cheek and gum, as with chewing tobacco) allow drugs to have a more rapid onset of action and to avoid liver metabolism as they enter the bloodstream. Nitroglycerin sublingual tablets are used to treat chest pain; they can act within a minute or two and can help stop an anginal attack and avoid an emergency room visit. Buccal administration is not very common but is used with methyltestosterone and nicotine preparations.

Some medications are destroyed by stomach acid following oral administration or are absorbed too rapidly to be convenient medications. Enteric-coated formulations protect the medication in the stomach and only disintegrate and dissolve when they reach the gentler conditions of the intestinal tract. Sustained-release preparations allow a drug to dissolve slowly in the intestines so that medication is absorbed over a period of time. It is important not to crush these preparations before administration because that would destroy the formulation and speed absorption.

The use of oral medications may be limited when patients are nauseous, vomiting, or uncooperative. Administration of suppository preparations into the rectum allows drug absorption that is similar to oral administration. While rectal administration is appropriate for some medications and is used for some pediatric medications, it is not universally welcomed by patients.

Site of Administration

Administration of medication close to where it will act has some notable theoretical advantages. When medications are administered near their site of action, higher concentrations may be achieved while minimizing unwanted effects in other parts of the body. Topical administration allows medication to be concentrated in the skin when patients need an anti-inflammatory (e.g., hydrocortisone) or an antifungal (e.g., clotrimazole) medication for a skin condition. This is particularly advantageous in that drugs pass more easily through damaged skin, so more drug is available to the areas of the skin that need the medication. Multidose inhalers and nebulizers are commonly used to administer drugs (e.g., albuterol) directly into the lungs. Ophthalmic preparations are sterile preparations suitable for administration to the eye. Because the eye is particularly sensitive, ocular medications are typically buffered and isotonic so that they do not cause discomfort when administered. Aural preparations, intended for administration into the ear canal, do not meet the buffering and isotonicity requirements for ophthalmic administration.

Bioavailability

Because not all of the administered dosage may be dissolved or absorbed or survive liver passage, only a fraction of an administered dosage makes it to the bloodstream. This percentage of the administered dose that does enter the bloodstream is called the bioavailability of the dosage form. Bioavailability can range from less than 10% to more than 90% for oral dosing. When the bioavailability of an oral preparation is low, a higher dose will be given so that the amounts reaching the bloodstream are similar. For example, an oral dose of 500 mg of ciprofloxacin can be substituted for a 400 mg IV dose; ciprofloxacin has about 80% oral bioavailability.

Peak Blood Levels

The speed at which drugs enter the bloodstream affects the maximum blood level that is achieved following drug administration (Fig. 2-8). Rapid absorption leads to higher peak blood levels, with a risk of greater toxicity and side effects. So rapid IV administration (e.g., “IV push”) produces immediate drug effects but increases the risk of toxicity and adverse effects. For these reasons, some medications, such as aminoglycoside antibiotics, are administered by slow IV infusion over 30 to 60 minutes. This allows distribution to occur, keeps the blood level from getting too high, and minimizes toxicity.

Figure 2–8. Blood levels for the same dose absorbed with peak-times of 20 minutes, 60 minutes, or 120 minutes. Rapid absorption results in faster effect, but blood levels are higher with a greater likelihood of toxicity.

Distribution

After a drug is absorbed, it still must reach its site of action to produce an effect. The process of drugs moving throughout the body is called distribution. Distribution of drugs can occur by transfer through the bloodstream and passive diffusion, or their distribution can be promoted or limited by the presence of transport systems that may selectively transport or exclude drugs based on size, charge, or chemical structure. Diffusion can influence the action of drugs; drugs can be effective only if they reach their site of action in adequate concentrations before they are metabolized.

Properties That Affect Distribution

Drugs can passively diffuse most readily when they are small and uncharged and also have the right balance between water and lipid solubility. Some of these properties will be related to the drug (e.g., molecular size and lipid:water solubility). Others will reflect drug properties as they present in an individual patient, such as pH, the acidity of the environment in which the drug finds itself. pH affects ionization of the drug. Of course, the drug may find itself in an acidic environment (pH ~2) in the stomach and more neutral environments in the intestine (pH 6–8) and blood (pH 7.4). The patient will also bring an environment that includes proteins inside the body to which the drug may bind.

Since passive diffusion represents transfer through partially permeable barriers, smaller molecules are better able to diffuse than larger molecules. Molecules with molecular weights of 500 or less are the best candidates for passive diffusion. Molecules with molecular weights above 5,000 are expected to diffuse poorly.

Henderson–Hasselbalch Relationship

Acidity is an important property of biological environments. Acidity is measured as pH, defined as –log[H–]; lower pH is more acidic. Normal pH in the body is around 7.4; under conditions consistent with life, pH can range only about 0.3 units in either direction. Each 1 unit of pH change represents a 10-fold increase or decrease in the concentration of hydrogen ions, and each 0.3 pH unit change represents a 2-fold change in acidity.

Most drugs contain chemical functional groups, such as carboxylic acids and amines, that can exist in a neutral, uncharged form or as a charged form. The balance between the charged and uncharged forms depends on pH. At higher acidity, or lower pH, carboxylic acid groups are uncharged, but amine groups are charged. At low acidity, at higher pH under basic conditions, the amine groups are uncharged, but the carboxylic acid groups are charged. Each drug is unique, and the pH at which it exists half in the charged state and half in the uncharged state is defined as its pKa.

It is an important principle in pharmacology that passive diffusion through biological barriers occurs most readily when drugs are in the uncharged state. Since the pH of body fluids is limited to a relatively narrow range and the pKa is a fixed property for an individual drug, we can calculate the percentage of charged and uncharged molecules for a drug if we know its pKa. The pKa can be an important drug property that influences absorption, distribution, and excretion of the drug.

Passive diffusion is a process by which drugs cross some type of biological barrier, such as a cell membrane or through a layer of cells, based on the concentration difference on the two sides of the barrier. We expect that passive diffusion will proceed until the concentration of drug is equal on both sides, but that is not quite what happens. Instead, passive diffusion proceeds until the concentration of unionized drug is the same on both sides. As a result of this, pH differences can cause more drug to accumulate based on the fraction of unionized and ionized molecules. This is called ion trapping.

Protein Binding

Drugs passively diffuse and distribute when they are unbound and uncharged. Drugs can bind to a variety of proteins that are present in the bloodstream. These are often called plasma proteins. Many plasma proteins are produced in the liver, and their presence in the blood reflects liver function, nutritional status, and the effect of aging and disease. Albumin is a major protein in the blood and is measured as part of a typical blood analysis. Albumin has a molecular weight of 66,500 and is too large to be excreted by the kidneys in healthy patients, although in renal disease albumin is lost in the urine. Other plasma proteins include alpha-1-acid glycoprotein, cortisol-binding globulin, sex hormone–binding globulin, and lipoproteins.

Binding to plasma proteins serves several important functions. Drugs bound to plasma proteins can freely circulate in the bloodstream rather than be distributed by passive diffusion from their site of absorption, so plasma protein binding helps normalize concentrations throughout the body. Drugs that are bound to plasma protein can be protected from metabolism in the liver and from excretion by the kidneys, so plasma protein binding can extend the period of time that drugs remain in the body.

Plasma proteins can be altered by disease states. Patients with poor nutrition may not have the protein building blocks to produce adequate amounts of plasma proteins. Patients with cancer can be undernourished as the cancer cells feed off the body. Patients with liver disease may lack the cellular function to produce one or more of the plasma proteins. Plasma proteins can be affected by myocardial infarction, stress, and infection as well.

Plasma protein binding has advantages and disadvantages. As mentioned above, binding to plasma proteins can protect drugs from metabolism and excretion, extending the time the drugs remain in the body. But remember the general principle that drug action occurs through free, unbound drug. Protein binding, which may include binding to proteins that are not in the plasma, also prevents the interaction of drug molecules with their site of action. Plasma protein binding creates a reservoir of bound drug molecules that can unbind at any time to interact with drug receptors and produce responses.

Plasma protein binding occurs in the plasma and encourages retention of drug in the systemic circulation. So it may appear that blood levels of a drug are high, even if the drug is not at its active site. For example, when patients receiving digoxin, a cardiac glycoside used to slow and strengthen the heart, have clinical signs of toxicity and high blood levels, they can be given antibody fragments to digoxin (Digibind). The antibody fragments remain in the central circulation and bind to digoxin in the bloodstream, essentially pulling digoxin back into the bloodstream from its sites of action throughout the body. But since digoxin is binding to its antibody in the bloodstream, the blood concentration of digoxin rises even though there is much less free digoxin to produce pharmacological effects and toxicity. This illustrates how plasma protein binding holds drugs in the circulation and prevents their distribution to other sites in the body.

Binding to proteins is also the basis for a number of drug interactions. Drugs bound to plasma proteins cannot interact with their receptor. If a drug is very strongly bound to plasma proteins, then even a small change in the fraction that is bound can have significant pharmacological effects. Warfarin is an oral anticoagulant that is used to slow blood clotting in patients at risk for thrombosis. Warfarin is about 98% bound to plasma proteins; this means that only 2% of the drug is unbound and available to produce a pharmacological effect. What if the patient takes another drug that also binds to plasma proteins? If the binding of the second drug to plasma proteins displaces even a small fraction of warfarin, it can have a dramatic effect. If only an additional 2% of warfarin is displaced, for example, it would mean a doubling of circulating warfarin activity.

Transport Systems

Drug distribution is also influenced by transporters, membrane proteins that facilitate the movement of molecules across the cell membranes. Transport systems are often directional, and they can transport drugs into (influx) or out of (efflux) cells. In either case, the transport system can transfer molecules and can create and maintain a concentration difference between two sides of the cell membrane. For example, when some antibiotics diffuse into cancer cells, they are transported out by the multidrug resistance protein (MRP1), which maintains a concentration gradient with the drug outside the cell. The presence of MRP1 suggests that a variety of drugs that require intracellular access for activity will be ineffective because the transporter removes molecules from inside the cell as quickly as they can diffuse in.

Transport systems also form the basis for distribution into protected tissues. p-Glycoprotein, an efflux secretory transporter, is widely distributed and limits the entry of drugs into the brain, testes, intestines, and other sites. Depending on the site, inhibition of p-glycoprotein can result in increased intestinal absorption or distribution into the brain or testes.

Transport systems also affect distribution to sites of metabolism. Transport or diffusion of a drug into cells is required for intracellular metabolism, and transport systems can control how much of a drug is available to an intracellular enzyme for metabolism.

Volume of Distribution

The volume of distribution (VD) is a hypothetical value that reflects the volume in which a drug would need to be dissolved to explain the relationship between dosage and blood levels. If we administer a dose of 100 mg and the plasma concentration is 2 mg/L, then it appears as though the drug is distributed in 50 liters. If we administer the same dose and the plasma concentration is 20 mg/L, then it appears as though the drug is distributed in a volume of 5 liters (Fig. 2-9).

Volume of distribution is important not only because it relates dosage to blood level but because it tells us something about where a drug might be distributed. Drugs that are confined to the bloodstream will have a volume of distribution equal to the blood volume. The plasma volume is really the smallest volume of distribution we will encounter, since it is not possible for drugs to confine themselves to part of the circulation volume. Plasma makes up about 4.5% of body weight, or about 3 L for an average person. Total body water is about 50% to 60% of body weight (35 to 40 L), depending on gender and body fat. Total body water is about two-thirds intracellular and one-third extracellular.

Volume of distribution is hypothetical, however, so it may also be higher than the amount of volume. For example, a volume of distribution can represent distribution into an amount of water greater than the total body volume; this suggests that much of the drug is bound somewhere outside the bloodstream.

Figure 2–9. Drug concentration in the plasma following administration depends on the volume of distribution. If a drug is confined to plasma (A), then plasma concentration will be higher compared with distribution into extracellular fluid (B) or intracellular fluid (C). Dilution in increasing volumes is shown by shading of the areas containing a drug.

Metabolism

Metabolism is an important factor in determining drug activity. When drugs are metabolized, they are chemically altered by enzymes into new molecules, called metabolites. Metabolism can increase or decrease the onset, duration of action, and toxicity of a medication. So it is important to know how metabolism affects drug activity and pharmacokinetics and how other drugs might interact to alter drug metabolism.

The body is a large container of enzymes that catalyze many different chemical reactions that are required to maintain life. If you think about it, one of the requirements for sustainable life is the ability to maintain a constant internal environment. All organisms are exposed to molecules that cannot be used for food or energy. If an organism cannot rid itself of a certain molecule, then that molecule can accumulate until it causes some sort of toxicity. Therefore, the human body has developed a series of enzymatic reactions directed at all sorts of molecules encountered during life. Drugs that are lipid soluble or weakly acidic or basic may not readily be excreted from the body. In general, the idea is to make these molecules more water soluble so they can be excreted by the kidneys.

Metabolism is the process of changing one chemical into another, and the process usually either creates or uses energy. Metabolism of drugs can occur in every biological tissue, but it occurs mostly in the smooth endoplasmic reticulum of cells in the liver. The liver is a major organ for drug metabolism because it contains high amounts of drug-metabolizing enzymes and because it is the first organ encountered by drugs once they are absorbed from the gastrointestinal tract. Metabolism by the liver following oral administration is called first-pass metabolism and is important in determining whether a drug can be orally administered.

Figure 2–10. Metabolism of phenobarbital. Phase I metabolism adds an –OH to the molecule. A water-soluble glucuronide molecule is linked to this site during phase II metabolism.

There is a “family” of enzymes, cytochrome P450 (CYP; pronounced sip), that metabolizes drugs. Each of these CYP enzymes is responsible for a single type of metabolic reaction. A drug may undergo several of these biological transformations, or biotransformations, sometimes in different body tissues, before being excreted. Understanding drug metabolism through these CYPs can provide a framework for understanding metabolism in individual patients, as well as drug interactions with other medications and with food.

Phase I and Phase II Metabolism

Drug metabolism utilizes two types of reactions that prepare and tag molecules for excretion. Phase I reactions, or nonsynthetic reactions, involve oxidation, reduction, and hydrolysis reactions, which prepare the drug molecule for further metabolism. Phase I reactions introduce or unmask polar groups that, in general, improve water solubility and prepare drug molecules for further metabolic reactions. Phase I metabolism can result in metabolites with greater or lesser pharmacological activity. Many phase I metabolites are rapidly eliminated, whereas others go on to phase II reactions (Fig. 2-10).

Phase II reactions are called synthetic or conjugation reactions because drug molecules are metabolized and something is added to the drug to synthesize a new compound. Metabolites are linked, or conjugated, to highly polar molecules such as glucuronic acid, glycine, sulfate, or acetate by specific enzymes. Conjugation to these molecules makes metabolites more water soluble and more easily excreted by the kidneys. So the presence or activity of these enzymes can influence the pattern of drug activity and the duration of action for drugs.

Cytochrome P450

The most thoroughly studied drug metabolism reaction is the CYP P450 mixed-function oxidase reaction. This reaction catalyzes the metabolism of a large number of diverse drugs and chemicals that are highly lipid soluble. CYP transfers electrons from the oxidation of drugs to the electron transport system of the endoplasmic reticulum, a cell organelle. There are many forms of CYP that are products of separate and distinct genes and that catalyze different reactions. Over 50 human CYPs have been isolated so far. The CYPs are organized into numbered families based on their function. For example, the CYP1, CYP2, and CYP3 families metabolize a variety of drugs and steroids (Box 2-5). Subfamilies are designated by additional letters and individual enzymes by numbers. The CYP3As are the major subfamily expressed in the human liver and consist of three forms: CYP3A4, CYP3A5, and CYP3A7. The CYP3A7 enzyme is present in the fetus and appears to be discontinued after birth. CYP3A4 is a major drug-metabolizing enzyme, whereas CYP3A5 metabolizes the same drugs but is less active.

Single nucleotide polymorphisms (SNPs) are minor mutations in proteins that can result in metabolic activity changes. These alterations in DNA are sometimes associated with population groups and help explain why certain groups of patients are more or less sensitive to certain drugs. When SNP variations exist in the individual CYP enzyme, they are named by an asterisk and a number showing the order in which each SNP was identified. For example, there are several CYP2D6 isoforms: CYP2D6*1 (with no mutation), CYP2D6*3, CYP2D6*4, and up to CYP2D6*17. Metabolic activity for each isoform may be decreased, normal, or increased. We inherit our drug-metabolizing enzymes from our parents, so it is possible to have two isoforms that differ in expression and activity. About 7% of the U.S. population lacks the CYP2D6 enzyme activity. Other patients exhibit a range of enzyme activities, with some ethnic groups having a significant percentage of ultrafast metabolizers. As you can imagine, there is the potential for a good deal of variability between individual patients.

BOX 2–5 DRUG-METABOLIZING ENZYMES (LISTED IN ORDER OF IMPORTANCE)

CYP3A

CYP2C

CYP1A

CYP2E

CYP2D

CYP3A4 is a prominent enzyme that is responsible for metabolism of a number of drugs. It serves as an example of a CYP enzyme. Drugs that are metabolized by CYP3A4 include azole antifungals; the statin drugs that inhibit HMG-CoA (5-hydroxy-3-methylglutaryl-coenzyme A) reductase and lower cholesterol; the corticosteroids prednisone, prednisolone, and dexamethasone; the anticonvulsant carbamazepine; and many other drugs. Note the variety of drug classes and chemical structures that are metabolized by this enzyme.

Variations in CYPs and in their activity can result in marked differences in drug metabolism between individuals. Individual variation in drug metabolism contributes to drug–drug and some drug–food interactions. Enzyme induction occurs when drug treatment results in an increase in enzyme activity, usually limited to the enzymes responsible for metabolizing the drug. Enzyme induction results in an increase in metabolism that decreases the amount of drug and increases the amount of metabolite in the body.

Competition occurs when two different drugs are metabolized by the same enzyme. Often the enzyme can metabolize both drugs, but sometimes one drug will be preferentially metabolized, delaying the metabolism and extending the half-life of the competing drug.

Metabolism and Half-Life

The rate of drug metabolism depends on the blood levels of drug in relation to the affinity of the drug for its metabolism enzymes. Most drugs are present at concentrations below their Km for metabolism (the concentration at which metabolism is half of maximum). Under these conditions, metabolism is related to drug concentration so that a fixed fraction of drug is metabolized per hour. This is called first-order metabolism and is characterized by a half-life, the time period over which the drug concentration will decrease by half. So, blood levels decrease 50% in one half-life, 75% in two half-lives, and 87.5% in three half-lives. As a general rule, drugs tend to be administered at dosing intervals that are close to their half-life.

Some drugs—ethanol is the prototype—are present at concentrations well above their Km for metabolism. When this happens, enzymes act near to their maximal metabolic capacity and metabolize a constant amount of drug each hour. This is called zero-order metabolism.

Rarely but importantly, some drugs are present at blood concentrations that range from below to above the Km for their metabolism. At lower doses or concentrations, they are metabolized like typical drugs, but at higher doses or concentrations their metabolism is limited. Phenytoin is a prototypical example of a drug with “mixed-order” or Michelis–Menten, pharmacokinetics. Above a certain level of phenytoin dosing (about 300 mg/day in adults), dosage must be adjusted by small amounts, which can produce disproportional increases in blood levels as metabolism changes from first order to zero order.

Patterns of Metabolism

It is important to remember that metabolism can change the pharmacological activity of drugs. We typically consider that drugs are pharmacologically active and that metabolism decreases the activity and promotes excretion (Fig. 2-11), so we expect to see inactive metabolites that have short half-lives and are rapidly excreted. This is not always the case, however.

Prodrugs are inactive compounds that rely on metabolism to become active. Prodrugs have advantages and disadvantages. The advantages may be in terms of their absorption or distribution. L-DOPA is a prodrug used to treat Parkinson’s disease. The problem in Parkinson’s disease is a lack of dopamine in the striatum of the brain. Dopamine, however, cannot pass through the blood–brain barrier, so it cannot be used to treat the neurotransmitter shortage in the brain. L-DOPA can pass into the brain and enter into cells, where it can be converted into dopamine.

Prodrugs can also have disadvantages. Terfenadine was one of the first nonsedating antihistamines and was quite popular at one time. First-pass metabolism by CYP3A4 biotransforms terfenadine, which is cardiotoxic, into fexofenadine, an effective antihistamine. When it was realized that inhibition of CYP3A4 could result in toxicity and death in some patients, terfenadine was withdrawn and replaced with fexofenadine, its active metabolite.

The prodrug terfenadine is cardiotoxic and relies on metabolism to produce more active antihistamine that is less cardiotoxic. Other prodrugs are pharmacologically inactive and rely on biotransformation to an active metabolite. Codeine is metabolized to the 12 times more potent opioid morphine by CYP2D6. Hydrocodone is metabolized to the more potent opioid hydromorphone by CYP2D6 as well. About 7% of the Caucasian population lack CYP2D6 activity. Administration of a prodrug requiring metabolism by CYP2D6 creates a situation in which the patient is receiving an inactive or poorly active drug. In the case of pain relievers, patients may be seeking stronger drugs, not because of abuse but because the drugs are not being biotransformed into their active metabolites. In contrast, patients with highly active CYP2D6 are at greater risk for toxicity following administration of codeine or hydrocodone.

Figure 2–11. Typical effect of metabolism (solid arrows) on drug activity. Prodrugs are metabolized to active drugs that can undergo phase I and phase II metabolism, with metabolites varying in activity, compared with the parent drug, and in solubility, which increases the likelihood of renal elimination. Sometimes metabolism produces unusual effects (dashed arrows), such as drug metabolites that retain drug activity or accumulate in the body.

Meperidine is an opioid analgesic that is used parenterally and orally to treat pain as well as post-operative shivering. It is metabolized by CYP2B6, 2C19, and 3A4. Meperidine remains present in the body a relatively short period of time; its half-life is 3 to 4 hours. Meperidine’s metabolite, normeperidine, is more toxic and remains in the body for a much longer period of time; its half-life is 14 to 21 hours in patients with normal renal function and even longer in those with poor kidney function. This difference in half-lives creates a clinical situation in which meperidine is administered frequently and levels of normeperidine will rise until toxicity presents as irritability, tremors, delirium, and seizures in patients with poor renal function. The solution is to limit administration of meperidine so that normeperidine does not accumulate and to avoid meperidine use in at-risk patients.

Drug Interactions

Alterations in biotransformation are responsible for many drug–drug and drug–food interactions. There are a limited number of drug-metabolizing enzymes, and these enzymes can metabolize only one drug molecule at a time. Compounds compete for enzymes based on their chemical affinity; chemicals with higher affinity for a particular CYP or drug metabolism enzyme will be preferentially metabolized. So a drug that can be metabolized by multiple enzymes will be biotransformed by each enzyme in proportion to the affinity. When several drugs are metabolized by a single enzyme, each of the drugs will be metabolized in proportion to the affinity of each of the drug–enzyme interactions. If one drug monopolizes the enzyme, then it can block the biotransformation of other drugs, extending their time in the body and contributing to toxicity. So when we look for drug interactions, we often look for drugs that are metabolized by the same CYPs.

CYP3A4 is particularly problematic because it metabolizes so many different drugs. Consequently, there is a greater likelihood of interference with metabolism when a patient receives a number of drugs. In addition to other sites in the body, such as the liver, CYP3A4 activity is present in the cells lining the gastrointestinal tract and can be influenced by food as well as drugs. Grapefruit juice contains a substance that inhibits CYP3A4 and can sometimes markedly increase blood levels of drug in patients consuming grapefruit juice. Surprisingly, this interaction extends to patients consuming grapefruit juice within about a day prior to drug administration. This interaction can affect a number of drugs, such as several older statin drugs that have increased blood levels in the presence of grapefruit juice. Higher blood levels are not always bad, but it is appropriate to counsel patients to avoid potential toxicity resulting from CYP3A4 interactions and inhibition.

Some drugs increase the expression of drug-metabolizing enzymes; this is called enzyme induction. Induction can be due to either increased enzyme synthesis or decreased enzyme degradation. Pharmacotherapy with phenobarbital, for example, effectively induces CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4. Induction increases the biotransformation of drugs and can encourage variations in metabolism and generally increase the removal of drugs by metabolism.

In clinical practice, transport systems and metabolic enzymes work together in the biotransformation of drugs. Drugs are transported into cells where they can be metabolized. Patients can have genetic differences in their ability to transport drugs through cell membranes, leading to additional variation in metabolism and drug response.

We generally assume that metabolism of drugs results in a product that has less pharmacological activity and is more likely to leave the body. Metabolism, or biotransformation, can actually result in either an inactive or an active metabolite. Metabolites are generally excreted more rapidly, but sometimes metabolite excretion is delayed. Drugs may interact with more than one CYP enzyme to produce multiple metabolites with different levels of activity and excretion.

Excretion

Excretion is the process in which drugs are transferred from inside the body to outside the body. This makes excretion or elimination the opposite of absorption. Just as drugs pass a biological boundary between inside and outside for absorption, so they must pass in the opposite direction, though not necessarily in the same location, for elimination.

The locations at which drugs can pass from inside the body to outside include some sites that are familiar as sites of absorption, such as lung, skin, and intestines. There are also some unique sites where drugs are excreted but not absorbed. These include the kidney and the gallbladder. The principal organs for drug elimination are considered to be the kidneys, lung, biliary system, and intestines. Any individual drug may rely on one or more of these sites for elimination or on a different site, such as skin excretion or excretion into saliva or breast milk.

Renal Excretion

The kidney is the primary organ of excretion for most drugs. The general theme of metabolism is to produce drug metabolites that are more water soluble and more easily removed by the kidneys. The kidney can then remove these substances from the plasma and excrete them in the urine.

The kidney is a complex organ with several important functions, including excretion of waste products and maintenance of fluid and electrolyte balance in the body. The strategy of the kidney is to allow removal of a large volume of plasma and then to take back the substances that the body needs. The result is urine. There are also transport mechanisms that can secrete substances into the urine. We will consider how drugs manage to end up in the urine.

Production of urine begins in the glomerulus of the kidney. The operational unit of the kidney is the nephron, and each of the approximately 1 million nephrons begins with a glomerulus (Fig. 2-12). The glomerulus is a specialized area of the nephron adapted for ultrafiltration, a process in which substances in the plasma pass through small holes, or pores, in the glomerular capillary membrane based on their size and charge. The structure of the glomerular capillary membrane permits filtration of smaller molecules while restricting the passage of compounds with larger molecular weights. As blood flows through the kidney and encounters the glomerulus, much of the fluid portion of the blood is filtered into the lumen, or center, of the nephron. The kidney is exceptionally efficient at what it does. Approximately 125 mL of blood flows through the glomeruli in the kidneys per minute, the glomerular filtration rate (GFR), and it is an important measure of renal function.

Glomerular filtration is the first step toward production of urine containing excreted drug. Filtration preserves plasma proteins while removing free drugs and other waste products from the plasma. The large volume of fluid filtered through the glomerulus is an ideal vehicle for drug removal. As the ultrafiltrate is formed, drugs that are free in the plasma and not bound to plasma proteins or blood cells are filtered. Filtration may be slower for drugs that are large because of the size of the pores through which filtration occurs; very large drugs may not be filtered at all. The pores of the glomerulus contain a fixed negative charge, so filtration may also be affected by drug charge.

Figure 2–12. Diagram of the nephron, the functional unit of the kidney. Blood vessels flowing into the glomerulus provide blood, which is filtered into the lumen, the inner opening of the nephron. As fluid passes along the nephron, transporters can either reabsorb drugs (dark arrow) back into the blood or secrete (light arrow) drugs from blood into the lumen.

The glomerular filtrate in the nephron contains a variety of smaller molecules, including excreted drug and metabolites. As the filtrate moves through the lumen of the nephron, molecules are reabsorbed from the lumen into the blood. The extent to which a drug diffuses back across the nephron to reenter the circulation is one of the factors that determine urinary excretion of drug. The passive diffusion of substances back into the circulation is encouraged by the reabsorption of water that occurs along most of the nephron, creating a concentration gradient promoting reabsorption if the lipid solubility and ionization of the drug are appropriate.

The unionized or uncharged form of the drug will diffuse more readily, and the acidity of urine can influence the ionization and reabsorption of drugs. Acidification of the urine creates a situation that favors the excretion of basic drugs and metabolites, whereas basic urine encourages the excretion of acidic drugs and metabolites. Effects of urine acidity on drug elimination can have important clinical implications. Urine can be made acidic by administration of ammonium chloride and can be made basic by administration of sodium bicarbonate.

Tubular Reabsorption

In addition to reabsorption by passive diffusion, some substances filtered at the glomerulus are reabsorbed by active transport systems located primarily in the proximal tubule of the nephron. Active transport is important for endogenous substances that the body needs to recover from the glomerular filtrate, such as ions, amino acids, and glucose. The active transport systems are located on the luminal cell surface and transport substances into the cell, where they are passively transported into the plasma.

A small number of drugs may be actively reabsorbed. It is more common that drugs acting on tubular secretion do so by inhibiting active transport. Uricosuric agents such as probenecid and sulfinpyrazone inhibit the active reabsorption of uric acid. Substances that are actively reabsorbed can also be actively secreted and drugs may inhibit both processes. For example, low doses of salicylates, such as aspirin, inhibit tubular secretion and decrease total urate excretion, whereas higher doses inhibit tubular reabsorption and result in increased excretion of uric acid.

Tubular Secretion

The nephron also contains active secretory systems that transport drugs from the blood into the lumen of the nephron. There is a transport system that secretes organic anions and a transport system that secretes organic cations. The transporters are present on the plasma side of the tubular cells of the nephron, where they actively pump anions or cations into the cell. The substances then pass into the lumen by passive transport. The secretory capacity of these transporters can be saturated so that less drug is excreted at high drug concentrations. When two drugs are substrates for the same transporter, they compete with one another and decrease the rate at which each is excreted.

Active secretory systems for anions and cations are important because charged anions and cations are often strongly bound to plasma proteins and may not be readily excreted by glomerular filtration. Tubular secretion often contributes to the renal elimination of drugs that have short half-lives. Hydrochlorothiazide, furosemide, penicillin G, and salicylates are among the substrates for the organic anion transport system. The organic cation transport system actively secretes atropine, cimetidine, morphine, and quinine.

Renal Excretion of Drugs

The rate at which a drug is excreted by the kidneys depends on several factors. Renal blood flow influences the GFR, which is how much plasma is filtered per minute by the glomerulus. Filtration in the glomerulus depends on the molecular size, the charge, and the degree of protein binding, each of which influences how much drug passes through the glomerular basement membrane. Tubular acidity will influence the degree of reabsorption. Active reabsorption or active secretion into the urine may also influence excretion rate.

Renal excretion of drugs is typically well characterized. What is variable, however, is the level of renal function in an individual patient receiving a renally excreted medication. It is common to monitor renal function of patients in the clinical setting and to adjust dosages based on renal function and the renal contribution to drug excretion. Renal function is typically assessed from patient serum creatinine along with height, weight, age, and gender.

Biliary Excretion

In addition to metabolizing many drugs, the liver secretes about a liter of bile each day. Drugs can enter the bile and be excreted into the intestinal tract when bile is released to help digest food. Only small amounts of drug enter the bile by diffusion; instead, biliary excretion contributes to removal of some drugs. The biliary system includes three types of active transport. Organic cation and organic anion transporters are similar to those found in the renal tubules. The additional system is the bile acid transport system. Conjugated metabolites of drugs generally have enhanced biliary excretion. Cardiac glycosides, such as digoxin, are an example of drugs secreted into the bile.

Some drugs that are excreted in bile can be reabsorbed in the intestine. This creates a phenomenon called enterohepatic cycling, in which drug is excreted in the bile, absorbed from the intestines, and then excreted in the bile again. Enterohepatic cycling decreases the amount of drug that is actually excreted and extends the time that a drug remains in the body.

Other Sites of Excretion

Drug excretion is not limited to the kidneys and liver. Drugs can diffuse out of the body at various sites, and while these excretion sites are typically not major, they can be important for forensic or clinical reasons.

Pulmonary excretion can occur for any volatile material present in the body. Pulmonary excretion is important for anesthetic gases, such as nitrous oxide. Pulmonary excretion is also important following alcohol consumption. Ethanol distributes throughout the body and is readily excreted each time we breathe. Because the amount of ethanol exhaled in each breath is proportional to blood level, the Breathalyzer can be used to estimate blood levels of ethanol. Pulmonary excretion is also important for volatile ketones, which are produced in diabetic patients who are poorly controlled; the smell of ketones on a patient’s breath can be an important clue that the patient may have diabetes and be at risk for diabetic ketoacidosis.

Substances can be excreted through the skin, although this is often a minor route of elimination. The skin has a large surface area through which excretion can occur; drugs may be incorporated into the hair and can be excreted through the sweat glands. Excretion of drugs into sweat and saliva is of minor importance for most drugs and depends on the diffusion of uncharged drug across the epithelial cells of sweat and salivary glands. Excretion into hair, sweat, and saliva is quantitatively unimportant but can be used to noninvasively detect drugs in the body. Interestingly, some drugs excreted into saliva can produce changes in taste. Excretion into saliva might help explain part of the pharmacological action of certain drugs, such as antibiotic erythromycin, in throat infections.

Drugs can also be excreted into the breast milk of nursing mothers. The concentration in the breast milk depends on drug properties such as lipid solubility and the degree of ionization and on patient properties such as the extent of active secretion into breast milk and the blood level of the drug in the mother. Low-molecular-weight drugs that are unionized can passively diffuse across the epithelial cells of the mammary gland and enter the breast milk. Because breast milk is more acidic than plasma, it tends to accumulate basic drugs.

Infants can be exposed to drugs through breast milk. The risk to the infant from drug exposure in breast milk depends on the amount and type of drug involved and the ability of the infant to metabolize the drug. Breastfeeding is discouraged when there is a potential for drug toxicity in the infant.

SUMMARY

The rational use of drugs is based on a foundation of chemical and physiological principles. Drugs interact with specific sites, called receptors, according to chemical laws; higher concentrations of drug produce more interactions and greater effects. How rapidly a drug is absorbed, distributed, metabolized, and excreted dictates local concentrations of drug that produce effects. The onset and duration of a drug effect reflect the pharmacokinetics of the drug and the properties of the receptor. Sound therapeutic decisions draw upon the unifying foundational principles of pharmacology.

REFERENCES

Burton, L., Lazo, J., & Parker, K. (2005). Goodman & Gilman: The pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill.

Kenakin, T. P. (2005, October). New bull’s-eyes for drugs. Scientific American, 293(4), 50–57.

Rice, P. J. (2014). Understanding drug action: An introduction to pharmacology. Washington, DC: American Pharmacists Association.

CHAPTER 5

ADVERSE DRUG REACTIONS

Connie A. Valdez • Anne E. Morgan • Peter J. Rice

MECHANISTIC CLASSIFICATION OF ADRS

TIME-RELATED CLASSIFICATION OF ADRS

DOSE-RELATED ADRS

SEVERITY OF ADRS

COMMON CAUSES OF ADRS

Drug Interactions

Medical Conditions

DETECTION AND ASSESSMENT OF ADRS

Responding to ADRs and Warnings

Narranjo ADR Probability Scale

ADR REPORTING

SUMMARY

According to the U.S. Food and Drug Administration (FDA), over 2 million serious adverse drug reactions (ADRs) occur annually, resulting in emergency room visits, hospital admissions, and an estimated 100,000 deaths (FDA, 2009). It is estimated that 3% to 6% of all hospital admissions annually are for treatment of ADRs and that 10% to 15% of hospitalized patients experience an ADR (Gomes & Demoly, 2005). The total cost associated with ADRs has been estimated to range from $3.5 to $136 billion per year (Centers for Disease Control and Prevention [CDC], 2012; FDA, 2009;). In order to reduce morbidity and mortality associated with ADRs, it is important for practitioners to understand the causes and mechanisms of ADRs and develop practices to predict and prevent their occurrence.

An ADR is any undesirable or unintended effect following administration of a medical product, whether or not the effect is considered related to the medical product (FDA, 1995, 2009). Although ADRs are common, most are not severe and usually resolve when the drug is discontinued or the dose reduced, or they diminish as the body adjusts to the drug. For example, dry mouth from amitriptyline is a mild reaction that will resolve once the medication has been discontinued; dizziness from lisinopril is generally considered to be a common reaction that can be minimized by reducing the dose; an individual using diphenhydramine will notice that the sedative effects will diminish after about 2 to 3 weeks of consistent use. Unfortunately, some ADRs may be serious and/or persist for a significant duration of time even after the drug is discontinued. For example, isotretinoin can cause birth defects when used before or during pregnancy, and antipsychotics can cause tardive dyskinesia that endures after discontinuation of the medication. Since ADRs manifest in many forms, it is helpful to categorize the reactions based on type, onset, and severity.

MECHANISTIC CLASSIFICATION OF ADRS

There are two basic types of ADRs: pharmacological and idiosyncratic (Aronson & Ferner, 2003; Pirmohamed, Breckenridge, Kitteringham, & Park, 1998). A pharmacological reaction (Table 5-1) is often predictable based on the drug’s mechanism of action and is typically dose-related (Aronson & Ferner, 2003; Edwards & Aronson, 2000; Pirmohamed et al, 1998). Idiosyncratic reactions are unpredictable and may be more likely to result in mortality (Aronson & Ferner; Edwards & Aronson; Pirmohamed et al, 1998).

Pharmacological ADRs are more common and comprise approximately 85% to 90% of reported ADRs (Pirmohamed et al, 1998). These reactions are often an exaggerated physiological response related to the pharmacology of the drug, for example, hypotension from the beta blocker metoprolol, diarrhea from the fat-blocking drug orlistat, and insomnia from the stimulant methylphenidate. These adverse reactions are often managed by withdrawing the medication or reducing the dose. Pharmacological ADRs may also occur based on secondary pharmacology, such as weight gain from the atypical antipsychotic olanzapine, flatulence from the fiber supplement psyllium, or myopathy from the HMG Co-A reductase drug simvastatin. Because there is an interest in reducing adverse effects, preclinical trials are now focusing attention on secondary adverse effects to predict what may occur when the drug is administered to humans.

Table 5–1 Pharmacological Adverse Drug Reactions

85%–90%	Predictable and dose-dependent
10%–15%	Idiosyncratic: unpredictable and not dose-related

Idiosyncratic reactions are concerning because they are unpredictable, often serious, and may result in death (Pirmohamed et al, 1998). Idiosyncratic reactions are mediated by the immune system, receptor abnormalities, drug–drug interactions, abnormalities in drug metabolism, pharmaceutical variations, or unmasking of an abnormal biological system. Most commonly, idiosyncratic reactions are mediated by the immune system when a drug molecule is recognized as a foreign substance (Aronson & Ferner, 2003; Edwards & Aronson, 2000; Pirmohamed et al, 1998).

The hapten hypothesis describes how drugs may cause an immune-mediated hypersensitivity reaction. The hypothesis suggests that drugs are haptens, that is, low-molecular-weight chemicals that can become antigenic when they covalently bind to a carrier molecule, which is usually a protein (Chipinda, Hettick, & Siegel, 2011). Through this mechanism, individual patterns of metabolism may generate reactive metabolites that act as haptens to elicit an immune-mediated reaction. Penicillin is an example of a hapten with a low molecular weight that is able to bind to a protein and result in a Type I hypersensitivity (anaphylaxis) reaction.

Medications that are not haptens are also able to elicit an immune-mediated reaction through a different mechanism identified as the “pharmacologic interaction with immune receptors.” For example, lidocaine, sulfamethoxazole, mepivacaine, celecoxib, carbamazepine, lamotrigine, and ciprofloxacin are chemically inert drugs, unable to covalently bind to proteins. However, these medications are able to “fit” into major histocompatibility complex (a set of surface molecules) and the T-cell receptor sandwich. This elicits a hypersensitivity reaction (Chipinda et al, 2011). Immune-mediated reactions can be further defined as Type I, II, III, or IV hypersensitivity reactions as described in Table 5-2 (Janeway, Travers, Walport, et al, 2001).

Type I immune-mediated reactions (IgE-mediated, immediate-type hypersensitivity) are provoked by reexposure to an antigen. A Type I reaction is an acute hypersensitivity reaction that may be local or systemic, involving the skin, bronchopulmonary system, nasopharnyx tract, eyes, and/or gastrointestinal tract. It is caused by inducing the release of mediators (i.e., histamine, leukotrienes, and prostaglandins) from mast cells, basophils, and recruited inflammatory cells following antigen exposure, which then activates IgE. Although most cases are mild, symptoms may vary from mild to severe (allergic conjunctivitis, rhinitis, bronchospasm, urticaria, atopic dermatitis) and can be life-threatening (angioedema, anaphylactic shock). Symptoms may occur immediately, within minutes, or have a delayed onset where it may take several hours for symptoms to present following exposure to the provoking medication or antigen. For example, acute anaphylaxis may occur following the exposure to antibiotics (penicillin, cephalosporins, sulfonamides), neuromuscular blockers (suxamethonium, alcuronium, vecuronium, pancuronium, atracurium), and some chemotherapeutic agents (carboplatin, oxaliplatin) and monoclonal antibodies (cetuximab, rituximab). Management of Type I reactions usually involves administration of epinephrine, antihistamines, and corticosteroids.

Table 5–2 Immune-Mediated Adverse Drug Reactions

Type I	IgE-mediated, immediate-type hypersensitivityExample: angioedema and anaphylaxis
Type II	Antibody-dependent cytotoxicityExample: heparin-induced thrombocytopenia
Type III	Immune complex hypersensitivityExample: Arthus reaction to tetanus vaccine
Type IV	Cell-mediated or delayed hypersensivityExample: Drug Rash, Eosinophilia and Systemic Syndrome

Type II hypersensitivity reactions (antibody-dependent cytotoxicity) may affect a variety of organs and tissues. In the bloodstream and on the surface of cells, antibodies unite with antigens or haptens and induce destruction of cells and tissues through activation of the complement system or through removal by macrophages. Immune-mediated thrombocytopenia, also called drug-induced immune thrombocytopenia (DITP), is generally caused by medications but may also be caused by foods or herbal products. Most DITP reactions are associated with the formation of drug-dependent antibodies that bind to glycoprotein and cause an antibody–platelet reaction resulting in thrombocytopenia. Examples of medications with a risk of DITP include abciximab, argatroban, beta-lactam antibiotics, carbamazepine, eptifibatide, linezolid, phenytoin, quinine, quinidine, sulfonamide, rifampin, ranitidine, tirofiban, trimethoprim-sulfamethoxazole, valproic acid, and vancomycin (Aster, Curtis, McFarland, & Bougie, 2009; Burgess, Lopez, Gaudry, & Chong, 2000; Dihmess, et al, 2012; Gentilini, Curtis, & Aster, 1998; George et al, 1998; Kaufman et al, 1993; Nguyen, Reese, & George, 2011; Patel et al, 2010; Pedersen-Bjergaard, Andersen, & Hansen, 1996; Pedersen-Bjergaard, Andersen, & Hansen, 1997; Pedersen-Bjergaard, Andersen, & Hansen, 1998; Pereira et al, 2000; ten Berg et al, 2006; Von Drygalski et al, 2007).

DITP can also occur when heparin binds to platelet factor 4 (PF4) proteins resulting in the formation of an antigenic complex where IgG antibodies bind to the platelet. The antibody-coated platelets are viewed by the body as foreign and the body destroys the platelets via complement activation, causing thrombocytopenia. Hemolytic anemia and neutropenia occur by a similar mechanism. Hemolytic anemia occurs when a drug binds to antigens on the surface of red blood cells, resulting in complement activation and cell lysis. Examples of medications that cause hemolytic anemia include cephalosporins (e.g., cefotetan, ceftriaxone), penicillin and penicillin derivatives, NSAIDs, quinidine, quinine, and trimethoprim-sulfamethoxazole. Neutropenia or agranulocytosis can occur when antibodies unite with antigens on the surface of neutrophils. The reaction time generally occurs within minutes to hours following drug administration. Examples of common drugs that cause neutropenia or agranulocytosis include clozapine, antithyroid medications (e.g., methimazole, carbimazole), sulfasalazine, clomipramine, trimethoprim-sulfamethoxazole, ACE inhibitors, and H2 receptor antagonists (Alvir, Lieberman, Safferman, Schwimmer, & Schaaf, 1993; Casato et al, 1995; van der Klauw et al, 1999; Yunis, Lieberman, & Yunis, 1992). Treatment involves anti-inflammatory and immunosuppressive agents.

Type III hypersensitivity reactions (immune complex hypersensitivity) occur when aggregates of antigens and IgG and IgM antibodies create insoluble immune complexes in vessels or the blood that may be deposited in tissues (e.g., joints, kidneys). The reaction generally takes a week or more to occur and may present as serum sickness, drug fever, or vasculitis. The Arthus reaction is a local vasculitis reaction that causes severe pain, swelling, edema, induration, hemorrhage, and possibly necrosis, which can occur following tetanus/diphtheria toxoid (Td) vaccination. The risk of the Arthus reaction from the Td vaccine is elevated when a patient receives vaccination more frequently than every 10 years. The risk of developing more antibody–antigen immune complexes is higher if revaccination occurs when there is a high concentration of circulating tetanus antibodies. This is because the Arthus reaction results from deposition of immune complexes and complement activation. For this reason, it is recommended that individuals who have experienced an Arthus reaction following vaccination with tetanus toxoid do not receive Td more frequently than every 10 years, even if the vaccine is part of a protocol for wound management. The Arthus reaction can also occur with the 23 valent pneumococcal vaccine, and should this occur following the initial dose, revaccination is contraindicated (CDC MMRW, 1997). Other medications and treatments that can cause type III hypersensivity reactions include streptokinase, monoclonal antibodies (e.g., rituximab, infliximab, alemtuzumab, omalizumab, natalizumab), rabies vaccine, antivenom, and other antitoxins. These reactions are treated with antihistamines and anti-inflammatory agents (NSAIDS and corticosteroids).

Type IV hypersensitivity reactions (cell-mediated or delayed-type hypersensitivity) are unlike other hypersensitivity reactions because they are not an antibody-mediated reaction but rather, a cell-mediated response that results in activation and proliferation of T cells. Type IV hypersensitivity reactions are the result of autoimmune and infectious diseases or contact dermatitis. These reactions generally occur within 2 to 3 days but may take days to weeks to occur. Following rechallenge, the reaction may occur within 24 hours.

The reaction may be in the form of contact dermatitis, morbilliform or maculopapular eruptions, Stevens–Johnson syndrome, toxic epidermal necrolysis, or drug-induced hypersensitivity syndrome. Drug-induced hypersensitivity syndrome (DiHS) is a severe reaction that not only causes rash but is frequently associated with fever (38° to 40°C), eosinophilia, and organ failure (i.e., lungs, kidney, liver, heart). DiHS is also known as DRESS (Drug Rash, Eosinophilia and Systemic Symptoms) (Ben m’rad et al, 2009; Cacoub et al, 2011; Peyrière et al, 2006). Examples of drugs that may cause DRESS include abacavir, allopurinol, carbamazepine, dapsone, minocycline, nevirapine, and phenobarbital. Corticosteroids and other immunosuppressive agents are used in treatment.

ADRs have also been categorized as Types A–F. Type A reactions are equivalent to pharmacological reactions, account for 85% to 90% of ADRs, are dose-dependent, and are predictable, whereas Type B reactions are idiosyncratic, account for 10% to 15% of ADRs, are not dose-dependent, and are not predictable (Rawlins, 1981). Adverse reactions have been further stratified by letters C through F. Type C reactions result from chronic medication use, Type D reactions are delayed, Type E reactions are from drug–drug interactions, and Type F reactions result from treatment failures.

TIME-RELATED CLASSIFICATION OF ADRS

One distinguishing feature of drug reactions is the correlation between administration and tissue exposure to onset of the reaction. The World Allergy Organization classifies immunological reactions as immediate or delayed. Symptom presentation that occurs within 1 hour following exposure is classified as an immediate reaction, whereas a delayed reaction occurs more than an hour following exposure (Johansson et al, 2004). Time-related reactions can be further categorized as rapid, first dose, early, intermediate, late, and delayed.

Rapid reactions occur during or immediately following the administration of a medication. These unintended adverse reactions generally occur when medications are administered improperly and are not necessarily related to being the first dose. For example, vancomycin can cause an adverse reaction known as red man syndrome when administered too rapidly (Aronson & Ferner, 2003). Phenytoin can cause can adverse reaction known as purple glove syndrome (blood vessel irritation and inflammation) when administered peripherally (Earnest, Marx, & Drury, 1983). Skin or tissue necrosis secondary to extravasation may occur with administration of chemotherapeutic agents. For example, hand-foot syndrome may occur when extravasation of chemotherapy occurs and damages the surrounding tissues in the hands and feet, causing redness, swelling, burning, blisters, ulcers, peeling skin, and difficulty when walking (Yokomichi et al, 2013). For these reasons, it is important for practitioners to be familiar with the proper administration technique of medications to avoid precipitation of these adverse reactions.

First-dose reactions occur following the first dose of a medication. For example, orthostatic hypotension is a common reaction that occurs following the first dose of doxazosin, which generally does not occur with repeated doses. Cytokine release syndrome can occur following the first dose of orthoclone OKT3. Patient education and monitoring are essential when administering medications that are known to have a first-dose reaction, especially to ensure continued adherence, as the reaction is unlikely to persist.

Early reactions occur early in treatment and generally resolve with continued treatment as the patient develops tolerance. These reactions typically do not require discontinuation of the drug but may simply require patients to adapt to the medications. It is often useful to initiate drugs likely to cause early reactions with low starting doses and sequentially titrate the dose upward to mitigate the severity and duration of side effects. Examples include gastrointestinal upset following the initiation of metformin or selective serotonin reuptake inhibitors. Immune hypersensitivities may occur following the first or subsequent dose. These reactions, however, often do require immediate discontinuation of the drug and possibly further medical attention, such as in the case of anaphylaxis resulting from administration of penicillin or its derivatives.

Intermediate reactions occur following repeated exposure to a medication. Examples include hyperuricemia from furosemide, hemolytic anemia from ceftriaxone, interstitial nephritis from penicillin G, and contact dermatitis from neomycin. Intermediate reactions are difficult to predict but should be monitored. Patients with predisposing factors or increased susceptibility for adverse reactions should be followed vigilantly while on therapy for occurrence of these reactions.

Late reactions occur after prolonged exposure to an offending agent. Examples include osteoporosis or thinning of the skin due to prolonged corticosteroid use or hypogonadism following prolonged use of opioids (Brennan, 2013). It may be possible to symptomatically treat late adverse drug reactions, but most are predictable and occur following repeated exposures. Thus, it is often recommended to remove the offending agent before the reaction is predicted to occur in order to manage this type of adverse effect. Late reactions also include reactions that occur when a dose of a chronic medication is reduced or withdrawn. For example, rapid discontinuation of oxycodone can cause the patient to experience symptoms of withdrawal (i.e., anxiety, insomnia, rhinorrhea, diaphoresis, tremor, vomiting, diarrhea, and/or tachycardia). A patient who takes clonidine or propranolol may experience rebound hypertension following withdrawal of the medication. These types of adverse drug reactions are relatively common and can often be avoided by thoughtful tapering of the drug, as they are a predictable extension of the drug’s therapeutic effect.

Delayed reactions occur at variable time points following drug exposure and can even occur after the discontinuation of a drug. For example, drug-induced tardive dyskinesia may occur following prolonged exposure to antipsychotics or metoclopramide, with symptoms persisting for months to years following discontinuation of the precipitating drug (Tarsy & Baldessarini, 1984). Polyalkylimide implant injection (cosmetic filler) can cause swelling and tender nodules near the injection site as well as other symptoms (fever, arthritis, xerostomia) up to 12 months following the injection.

DOSE-RELATED ADRS

Adverse drug reactions may also be dose-related. This could be from administering an excessive dose or failing to adjust doses properly for age and organ function (i.e., renal insufficiency or liver failure). For example, a person with diabetes may become hypoglycemic after administering an excessive dose of insulin. An individual patient could experience lithium toxicity upon development of acute renal failure with no adjustment of the lithium dose.

SEVERITY OF ADRS

The severity of an adverse drug reaction varies based on the clinical effect and the outcome. The FDA defines serious ADRs as those that result in death, are life-threatening, result in hospitalization (new or prolonged), are disabling or incapacitating, produce congenital abnormality or birth defect, or require an intervention to prevent one of these outcomes. Any ADR that meets FDA criteria should be reported to the FDA MedWatch program (FDA, 2013).

In this chapter, the severity of ADRs will be further categorized as mild, moderate, and severe. Mild adverse events can typically be managed by dose reduction, discontinuation of the drug, or with no intervention if the reaction subsides following development of tolerance by the patient (Aronson & Ferner, 2003; FDA, 2013;). Moderate adverse events often require discontinuation of the drug and minimal medical intervention but typically do not cause permanent harm. An example of a moderate adverse reaction is drug-induced sunburn requiring an analgesic to treat the pain. Severe ADRs may be life-threatening and result in hospitalization, disability, birth defects, or even death and will require intensive medical intervention (FDA, 2013).

COMMON CAUSES OF ADRS

It is important for practitioners to realize that many ADRs are preventable. Approximately one-third result from medication errors and up to one-third from allergic reactions (Budnitz et al, 2006). Practitioners can reduce ADRs by being aware of specific drugs and drug classes that have a high incidence of ADRs. Budnitz and others evaluated ADRs that led to an emergency department visit. One single drug or drug class was the suspected cause in 94% of those cases. The top five drug classes responsible included insulins, opioid-containing analgesics, anticoagulants, amoxicillin-containing medications, and antihistamines or cold remedies. Additionally, the top five drug classes implicated in precipitating hospitalizations following admission to the emergency department included anticoagulants, insulins, opioid-containing analgesics, oral hypoglycemic medications, and antineoplastic agents. In the elderly population, one-third of all ADRs requiring treatment in the emergency department were due to only three medications: warfarin, insulin, and digoxin (Budnitz et al, 2006). In addition to the above medications, practitioners should be aware that antibiotics, sedatives, antipsychotics, and chemotherapeutic agents are also drug classes that have a high rate of ADRs (Bates et al, 1995; Evans, Lloyd, Stoddard, Nebeker, & Samore, 2005; Gurwitz et al, 2005; Woolcott et al, 2009).

One of the most common manifestations of ADRs is in the form of cutaneous skin reactions, ranging from mild skin rashes to life-threatening Stevens–Johnson syndrome. Out of the top 10 drugs linked to skin reactions, the majority are antibiotics. Specifically, the top 10 drugs linked to skin reactions are, in order, amoxicillin, trimethoprim-sulfamethoxazole, ampicillin, iopodate, blood products, cephalosporins, erythromycin, dihydralazine hydrochloride, penicillin G, and cyanocobalamin (vitamin B12) (Roujeau & Stern, 1994).

RISK FACTORS

Multiple patient characteristics can increase an individual’s risk of experiencing an adverse drug reaction (Aronson & Ferner, 2003). Risk factors for ADRs include genetic abnormalities, age, sex, polypharmacy (increasing the risk for drug–drug interactions), and concomitant medical conditions (increasing the chance for drug–disease interactions). Not all drug classes are susceptible to these risks, but an assessment should be made for all patients when starting or stopping medications to determine the relevance.

Genetics

Genetic features that affect the body’s ability to metabolize medications can contribute to pharmacological and idiosyncratic reactions (FDA, 2009; Pirmohamed et al, 1998). Although rare, some people have DNA mutations that predispose them to develop adverse drug reactions. For example, if an individual has an alteration in liver enzyme activity secondary to a gene mutation, the rate at which affected medications are metabolized may be increased or decreased, thus altering the concentration of active, inactive, and potentially toxic drug products in the circulation. If drugs are not metabolized appropriately, patients can accumulate toxic or reactive metabolites, leading to adverse drug reactions, as is the case with acetaminophen. Malignant hyperthermia following administration of general anesthetics is an example of a receptor abnormality (mutations encoding for abnormal RYR1 or DHP receptors), which results in sustained muscle contraction from the unregulated movement of calcium from the sarcoplasmic reticulum into the intracellular space. Genetic factors can also increase the likelihood of a hapten-induced hypersensitivity reaction (Pichler, Naisbitt, & Park, 2011).

A common mediator for these immune responses is variation in the HLA-B alleles. For example, patients who express the HLA-B*5701 allele are at a significantly increased risk of severe T-cell–mediated hypersensitivity reactions to the HIV medication abacavir. Additionally, the Han Chinese, who express HLA-B*1502 or HLA-B*5801 alleles, are at higher risk of hypersensitivity reactions to carbamazepine and allopurinol, respectively. For this reason, it is recommended that all patients receive genetic testing to confirm the presence or absence of the specific HLA-B allele prior to initiation of known high-risk medications (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013; Pichler et al, 2011).

Age

Children and the elderly are at higher risk of experiencing an ADR (Budnitz et al, 2006; Kongkaew, Novce, & Ashcroft, 2008). Children are at higher risk primarily because medication dosages must be tailored to their specific weight or body mass index. Inattention to weight-based dosing may cause harm. The very young may additionally have immature organ function, which further complicates dosing and increases the risk for an ADR (Kaushal et al, 2001).

Predictable underlying concerns in patients over 65 include taking more medications and taking them more often than younger patients. Also, elderly patients have decreased renal and hepatic function, resulting in decreased metabolism and clearance and causing an elevated drug concentration and risk of drug accumulation and toxicity. Patients over the age of 65 required hospitalization for treatment of ADRs 7 times more often than patients under the age of 65 (Budnitz et al, 2006). Hospitalizations in this age group due to ADRs were most commonly a result of unintentional overdoses (Budnitz et al, 2006). More than half of ADRs in hospitalized patients 70 years of age and older are considered to be preventable (Gray, Sager, Lestico, & Jalaluddin, 1998). Therefore, all prescribers working with these populations should take care to minimize polypharmacy, unless clinically necessary, to reduce the risk of drug–drug interactions, confusion between medications, and drug accumulation with insufficient renal and hepatic function. In addition, it has been shown that four out of five ADRs can be prevented by using prescriber computer order entry with clinical decision support and clinical pharmacist consultation in high-risk populations (Kaushal et al, 2001).

Gender

Women have more ADRs than men in part due to differences in body composition (impacting drug distribution, pharmacokinetic properties of medications, and hormonal fluctuation). Furthermore, ADRs may be related to pregnancy and lactation.

Drug Interactions

Similar to genetic differences in metabolism, drug–drug interactions can also affect the rate at which individuals metabolize medications. Some medications bind to certain enzymes in the liver and either speed up (induction) or slow down (inhibition) the rate of metabolism and clearance of drugs that flow through the same enzyme pathway. Both scenarios can cause problems, but most commonly drug inhibition leads to accumulation of drug and higher-than-desired concentrations in the circulation, often leading to ADRs. An additional interaction is the potential for two drugs to compete for metabolism, which increases the concentration of both medications and the risk of side effects.

Most drug interactions can be identified by reviewing patient medication profiles and using a drug interaction checker, such as Micromedex, Online Facts and Comparisons, or Lexicomp. These resources also provide recommendations based on the severity of the interaction. A review of therapy should be performed prior to the initiation of new medications. There is also the potential for foods to interact and affect metabolism. The best example of food–drug interactions is grapefruit reducing the clearance of simvastatin and increasing the risk of myopathy, or herbal products such as St. John’s wort reducing clearance of cyclosporine (Aronson & Ferner, 2003; FDA, 2009).

Some drug–drug interactions can manifest rapidly (within 1 to 2 days). For example, when trimethoprim-sulfamethoxazole is added to warfarin, an anticoagulant, warfarin metabolism is reduced, resulting in an increase in the INR and prothrombin time. Ultimately, this increases the risk of bleeding and should be avoided, if possible, or adjustments should be made in monitoring warfarin frequency and dose. Many interactions, however, may take longer to present. For example, when the antiarrhythmic amiodarone is added to digoxin, amiodarone inhibits the metabolism of digoxin. This interaction can take weeks to months before the full extent of the effect precipitates due to the long half-life of amiodarone. It requires diligence to appropriately adjust the digoxin dose and monitor serum concentrations. Although not all interactions are significant, clinicians should evaluate each interaction and determine clinical importance.

Medical Conditions

Many disease states alter the physiology of the body and affect drug metabolism, increasing the risk of ADRs (FDA, 2009). Liver and renal disease can decrease the metabolism and clearance of medications, resulting in increased serum concentrations. Medications that are extensively cleared from the body through the kidneys have specific dosage adjustments based on creatinine clearance. These recommendations should be followed to prevent drug accumulation. Heart failure decreases liver and kidney perfusion and can reduce metabolism and clearance. Similarly, thyroid dysfunction can alter drug metabolism; decreased thyroid function will reduce metabolic activity and increased function is likely to induce a faster metabolic rate. Additionally, other medical conditions, such as pregnancy, can create temporary changes in physiology that require dose adjustments or avoidance to prevent adverse reactions for the mother and/or child. Practitioners should be aware that medications can also affect various medical conditions. For example, indomethacin can precipitate an exacerbation of heart failure, aggravate gastroesophageal reflux, or worsen renal function in a patient with kidney disease. For these reasons, patients should always be assessed for past medical history and concomitant medical conditions upon initiation and/or changes of drug therapy.

DETECTION AND ASSESSMENT OF ADRS

Drugs or drug combinations suspected of producing adverse reactions will frequently be identified through drug interaction screening by pharmacists. It is important to remember that most (~90%) of identified drug interactions will not have clinical consequences for an individual patient but do represent a warning to monitor an individual patient for a potential problem. A smaller number (perhaps 2%) of identified drug interactions will have profound clinical consequences. The clinical challenge is that individual adverse reactions can present in patients without warning. It is appropriate for prescribers to work closely with pharmacists and other members of the health-care team to identify potential problems and monitor patients closely to optimize patient medications.

It can be difficult to determine causality between a drug and a potential adverse drug reaction. To aid in this distinction, several important elements should be considered. The presence of a temporal relationship between drug exposure and a reaction is often the first clue for causality (Field, Furwitz, Harrold, Rothschild, Debellis, Seger et al, 2004). Some reactions, such as hypersensitivity reactions, occur almost immediately upon administration and can be easily linked to the drug being administered. This is more common with IV medications because they are directly administered into the bloodstream. Pharmacological and hypersensitivity reactions to oral medications are likely to present early but may subside after persistent exposure. Assuming no other changes in medications or health status, adverse reactions that present temporally with administration of a new drug can often be attributed to the drug in question.

Adverse reactions due to drug–drug or drug–disease interactions may be more difficult to discern because the interactions may not follow the timeline for initiation of the offending agent but may be more closely related to changes in disease status or alterations in interacting medications.

Responding to ADRs and Warnings

Many drugs suspected of causing an ADR are promptly discontinued and should be if the offending drug can be safely stopped, if the event is life-threatening or intolerable, if continuing the medication would worsen the patient’s condition, and if there is a reasonable alternative medication. Drugs responsible for an adverse drug reaction may be continued in a patient if the drug is medically necessary and there is no acceptable alternative drug or if the problems are tolerable and reversible. Most adverse reactions that are related to dose and pharmacological effects will respond favorably to dosage adjustment.

If the ADR resolves following discontinuation of the medication, then the adverse event was likely caused by the discontinued medication. The only definitive indicator for causality is the recurrence of an adverse event following readministration of a potential drug offender. As long as no other medication changes are made and no change in the patient’s health status occurs, the reappearance of an ADR following a rechallenge confirms causality.

Table 5–3 Naranjo Adverse Drug Reaction Scoring

Naranjo Adverse Drug Reaction Scoring	Yes	No	Not Known	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0
2. Did the adverse event appear after the suspected drug was administered?	+2	–1	0
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0
4. Did the adverse reaction reappear when the drug was readministered?	+2	–1	0
5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?	–1	+2	0
6. Did the reaction reappear when a placebo was given?	–1	+1	0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	+1	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0
Definite >8Probable 5–8Possible 1–4Doubtful <1	Naranjo Score (Total)

Rechallenge is not a common practice and is generally not appropriate, especially for life-threatening ADRs. Also, patients are often reluctant to retry something that potentially caused an ADR. Therefore, although rechallenge is the gold standard for ADR detection, causality is often presumed based on temporal relationships, patient risk factors, and/or disappearance of the ADR following removal of the drug.

Assessing the causality of an adverse drug reaction involves consideration of several parameters relative to the reaction. Prior history of an ADR to the same or similar medications, literature reports, or a relationship in time between drug administration and the onset and resolution of the ADR support causality by an individual drug. The presence of alternative etiologies or absence of a relationship between dosing and the ADR support alternative explanations for the adverse reaction.

Naranjo ADR Probability Scale

Naranjo et al (1981) developed a framework for assessing the probability that an adverse reaction is related to administration of a particular drug. The Naranjo protocol, based on timing, prior history and reports, rechallenge, alternative causes, dose dependency, and objective evidence, defines the relationship between drug and adverse reaction as definite, probable, possible, or doubtful based on scoring. The Naranjo protocol is shown in Table 5-3.

ADR REPORTING

As drugs progress through preclinical and clinical trials, potential problems are identified based on the drug’s pharmacology, toxicology, and pharmacokinetics. Exposure of patients to drugs during clinical trials identifies many adverse effects and their frequency. By the time a drug reaches the market, however, it may have been studied in only several thousand patients. Because of this, it is likely that adverse events occurring in fewer than 1% of patients are not fully characterized.

Post-marketing surveillance becomes an important safety strategy. FDA post-marketing reporting programs seek to identify problems not identified prior to approval as well as any problems that may arise related to drug labeling or manufacturing. The FDA maintains a computerized database of adverse events for approved drugs and biologicals, the FDA Adverse Event Reporting System (FAERS). MedWatch is the FDA’s safety information and adverse event reporting program that provides health-care professionals with medical product information on prescription and nonprescription drugs, biologics, medical devices, and nutritional products.

As health professionals, we have an obligation to provide data to allow the FDA to monitor medication and vaccine safety. MedWatch allows health-care professionals and consumers to report adverse events and serious problems caused by FDA-regulated products. The Vaccine Adverse Events Reporting System (VAERS) is a separate program used to report adverse events related to vaccinations and like MedWatch allows voluntary reporting on adverse events by both health-care professionals and consumers. The FDA monitors adverse events and can respond with safety announcements, alerts, and/or removal from the market. The FDA publishes alerts in MedWatch (Fig. 5-1) and consumer publications.

Figure 5–1. The FDA MedWatch form provides a mechanism for health professionals to report ADRs. Source: U.S. Food and Drug Administration, www.fda.gov/Safety/MedWatch

To ensure a favorable balance between benefits and risks for certain drugs or biologicals, the FDA requires manufacturers to implement a Risk Evaluation and Mitigation Strategy (REMS). A REMS protocol is composed of various actions (called ETASU: elements to assure safe use), including letters to prescribers; additional patient information; and required patient, prescriber, and/or pharmacy registration and training. REMS are required for many drugs, including those listed in Box 5-1.

BOX 5–1 COMMON DRUGS WITH REMS

• Isotretinoin

• Extended-release and long-acting opioid analgesics

• Rosiglitazone

• Testosterone

• Verenicline

• Metoclopramide

• Mifepristone

• Buprenorphine and naloxone

• Naltrexone

SUMMARY

Adverse drug reactions are an unavoidable reality with pharmacotherapy. Fortunately, many ADRs respond well to dosage adjustment or discontinuation of the offending agent. Strategies such as drug-interaction screening and conscientious monitoring and reporting of adverse responses can identify at-risk patients and help minimize the incidence of ADRs.

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CHAPTER 6

FACTORS THAT FOSTER POSITIVE OUTCOMES

Marylou V. Robinson • Teri Moser Woo

OVERVIEW OF NONADHERENCE

Intentional Versus Nonintentional Nonadherence

ADVERSE DRUG REACTIONS

ASYMPTOMATIC CONDITIONS

CHRONIC CONDITIONS

KNOWLEDGE DEFICIT AND PATIENT PERCEPTION

Keys to Patient Education

Health and Cultural Beliefs

Medical Terminology Literacy

Written Handouts

COGNITIVE IMPAIRMENT AND PSYCHIATRIC ILLNESS

Longer-Acting Drugs

Use of Reinforcements

CAREGIVER’S ROLES

The Pediatric Patient

Caregiver’s Quality of Life

Behavioral Therapy

COMPLEXITY OF DRUG REGIMEN AND POLYPHARMACY

Personalized Drug Schedules

Simplifying the Regimen

FINANCIAL IMPACTS

Cost Versus Complications

Out-of-Pocket Versus Insurance

Family Versus Self

Generic Versus “New and Improved” Brand Name

Public and Private Assistance

COMMUNICATION DIFFICULTIES

Non–English Speakers and Interpreters

Speech and Hearing Issues

COMMUNICATION BETWEEN PROVIDERS

PATIENT’S RESPONSIBILITIES

MEASURING ADHERENCE

Patient Reports

Clinical Outcomes

Pill Counts

Refill Records

Biological and Chemical Markers

Medication Adherence Scales

PREDICTORS OF ADHERENCE

SUMMARY

The goal of health-care providers is to help patients become healthier. When the patient does not or cannot follow recommendations or instructions that lead to this goal, the provider may become frustrated. Multiple clinical studies have revealed that even though providers expect adherence and positive outcomes, in reality these often do not happen. A change of perspective toward patient-centered care and patient participation in setting health-care goals may foster a positive change for adherence and positive outcomes.

Many questions arise when discussing adherence. Why do patients not adhere to instructions about taking their medications? What occurs outside the office setting to sabotage the best of intentions? What is the patient’s responsibility, and what is the provider’s? This chapter discusses the major issues in adherence and ways to foster positive outcomes.

OVERVIEW OF NONADHERENCE

The problem of poor adherence to drug therapy is widespread around the world (Brown & Bussell, 2011). In the United States, it is estimated that less than 50% of patients adhere to their drug regimen (New England Healthcare Institute [NEHI], 2009). Other studies report similar data (Brown & Bussell, 2011; Osterberg & Blaschke, 2005) with chronic disease patients more likely to have spotty adherence (NEHI, 2009). Those at highest risk include patients who have asymptomatic conditions, chronic conditions (Hayes, McCahon, Panahi, Hamre, & Pohlman, 2008; Mahat, Scoloveno, & Donnelly, 2007), cognitive impairment, psychiatric illness, or disorders requiring significant lifestyle changes (e.g., smoking cessation) (Myung, McDonnell, Kazinets, Seo, & Moskowitz, 2009) and those who are on complex regimens with multiple daily dosing and significant adverse reactions (Luthy, Peterson, & Wilkinson, 2008; Sarver & Murphy, 2009). When patients’ interactions with the provider include poor communication (Zagaria, 2008), the risk of nonadherence is even higher. Wheeler, Roberts, and Neiheisel (2014) have synthetized much of the literature on adherence with much research left to be done on the multiple variables associated with whether medications are taken or not.

The health-care provider–patient relationship is not a parent–child relationship; it is one of setting and working toward realistic mutual goals. Providers cannot expect compliance unless patients have participated in realistic goal setting, including validating their belief they can follow the plan and identifying barriers that will impede those goals. Compliance implies an involuntary act of submission and provider-centric decision making. Adherence implies a voluntary act of negotiation and joint acceptance of a treatment regimen. Horne (2004) points out that “typically, over 30% of patients harbor strong concerns” about the need for their medication and the risk involved in taking it. What is more, the patient tends to overestimate the risk. If these issues are not addressed by open communication, surreptitious nonadherence is likely to result. This shift in attitude from compliance to adherence highlights the providers’ essential focus upon their responsibility to educate patients about their diseases and drugs.

Nonadherence to pharmacological regimens can lead to failure to reach the desired treatment goal, which may be very costly. Patients who stop using their drugs have more complications from their disease, which results in total increased cost for themselves and the health-care system. The health-care system itself creates barriers to adherence by limiting access to health care; using restricted formularies; and having prohibitively high drug costs, co-payments, or both. Over $290 billion in unnecessary emergency room and health-care costs related to adherence issues are estimated to occur in the United States every year (NEHI, 2009). Mortality rates double for cardiovascular and diabetic patients who do not follow their treatment plans. Increasing insurance rates and co-pays contribute to this. The Affordable Care Act (ACA) is intended to remove some of these system barriers. Payment reform with an emphasis on quality outcomes is anticipated to also foster more prescriber attention to adherence factors.

Intentional Versus Nonintentional Nonadherence

Taking or not taking medications may be intentional or inadvertent. Unintentional nonadherence can be attributed to forgetfulness (especially if it is a side effect of a drug), dementia, mental health problems, simple procrastination, or an overextended lifestyle. Not perceiving the usefulness of a medication for symptom resolution is one source of intentional nonadherence. Whether people believe the medication is effective, are unaware of the subtlety of its actions, or become frustrated with a “lack of cure” can contribute to whether they take medications as prescribed. Drug cost may also be a factor in intentional nonadherence.

ADVERSE DRUG REACTIONS

Real or perceived adverse reactions directly affect the outcome of a prescribed drug regimen. If a patient reports a prescribed drug is causing a reaction, then the provider should explore alternative options to treating the problem. This response assures patients that the provider is willing to listen and work with them until the right drug or right dosage is prescribed. Patients might think that their skepticism about a drug will be interpreted as lack of confidence in the provider (Horne, 2004). It may be difficult for patients to tell providers that they have a different view of the drug. Encouraging open communication about these concerns and perceptions is important. Communication is discussed further below.

Certain adverse reactions are more likely to produce nonadherence than others. Oddly enough, serious adverse reactions such as severe hypotension or anaphylaxis are not among them. The ones most likely to produce nonadherence are the “irritating” ones that interfere with the patient’s ability to carry out activities of daily living, including what he or she may do for a living. These reactions include headache, dizziness, anorexia, nausea and vomiting, constipation, sexual dysfunction, and diarrhea. Unfortunately, these are also the most common adverse reactions. What is a problematic adverse reaction for one person may not be for another. When looking for potential nonadherence, it is important to look for the adverse reactions that commonly cause nonadherence and talk to patients about them, but it is also important to ask which ones would be a problem for the individual patient and take these into consideration in making a drug choice.

ASYMPTOMATIC CONDITIONS

A variety of disease states are essentially asymptomatic until their later stages. Some of these can be treated with drugs in their early stages to prevent their progression. However, it may be difficult to convince a patient that he or she has a serious disease when there is no overt indication of the disorder except the provider’s word. It is even more problematic when the drugs given to treat this “invisible” disorder produce “disease symptoms” themselves. One of the most common of these asymptomatic disorders is hypertension.

Uncontrolled hypertension contributes to increased risk for cardiovascular disease, including stroke, ischemic heart disease, and heart failure, yet adherence to antihypertensive medications is often poor (Rajpura & Nayak, 2013). Rajpura and Nayak report that 66% of elderly patients with hypertension did not take their medication as prescribed, with the reasons for not taking the medication including the patient’s perception regarding the seriousness of the illness and beliefs or concerns about the medication. Beliefs about the benefits of the medication can outweigh cost as a reason for nonadherence.

Patients may realize through education that control of hypertension is very important to their health but may not adhere to the regimen secondary to the adverse reactions they experience to the drugs given to treat this disease. Antihypertensive drugs that have a rapid onset and short duration of action are not very desirable in long-term therapy secondary to possible large variations in blood pressure. If the patient misses one dose, the antihypertensive effect disappears, creating a possible rebound or adverse reaction. Since many of the drugs used to treat hypertension have these effects, nonadherence (including missed doses) is likely. Selecting a more “forgiving” drug that either does not depend on half-life or has a longer half-life will produce limited effect on the efficacy of the drug if doses are delayed or missed (Osterberg & Blaschke, 2005). Antihypertensives that require several dose titrations (e.g., alpha-adrenergic blockers) can be particularly troublesome (e.g., severe orthostatic hypotension) if the patient misses some doses and then restarts the drug, even if it is not at the full dose.

Erectile dysfunction (ED) is a highly publicized medical problem that may have as its root cause an adverse reaction to medications. Antihypertensives and psychotropic drugs have been implicated as the cause of ED. The provider must explore a change in medication if a patient is experiencing ED, anorgasmia, loss of libido, or other changes in sexual health.

Predicting probable adverse reactions of certain medications provides a basis for making an alternative treatment plan for individuals experiencing side effects. The provider looks at the tolerability profile of each drug and discusses it in selecting drugs for a particular patient. Tolerability is directly linked to patient adherence for both short- and long-term therapy and ultimately to the overall success of treatment.

CHRONIC CONDITIONS

One out of every two Americans has at least one chronic condition (Centers for Disease Control and Prevention [CDC], 2010). Chronic diseases account for three-fourths of the nation’s 1.4 trillion dollars in medical care costs and one-third of the years of potential life lost before age 65 (CDC, 2010). Many variables, such as increased individual risk factors, a lack of health-care resources for the poor and underserved, and environmental conditions that do not support the adoption and sustainability of healthy eating and physical activity impact chronic care onset and medication adherence. These factors may clinically express themselves differently from one person to another. As a result, the prescriber and members of a multidisciplinary health team must use a variety of approaches to positively intervene for persons living with chronic illness.

Ideally, the patient develops a pattern of taking drugs consistent with her or his activities of daily living; for example, taking the white pill before breakfast and the blue one at dinner. Weekends, vacations, visiting family, and unexpected events alter the pattern, leading to missed doses. Discuss methods for remembering how to take medication, such as calendars, phone or watch alarms, or day-of-the week pill organizers to assist patients in managing their medication regimen.

Building support mechanisms and setting up monitoring of drug taking for patients with chronic disease is critical to their adherence to their regimens. Kutzleb and Reiner (2006), for example, found significantly improved symptom control and disease self-management in patients with heart failure who received weekly telephone follow-up by nurse practitioners. Early phone contacts enable the provider to determine if the information shared in the clinic has been clearly understood and is being followed. Similar results were found with Web-based collaborative care for type 2 diabetes patients (Ralston et al, 2009). Such follow-up contacts not only help with adherence but also contribute to building a stronger patient–provider relationship. Factors influencing adherence in chronic illness are summarized in Table 6-1.

KNOWLEDGE DEFICIT AND PATIENT PERCEPTION

Understanding the disease state and the treatment regimen plays a role in adherence. Providing educational material alone, written or oral, cannot ensure that the patient will not have a knowledge deficit regarding the drug regimen or that she or he will be adherent. Today, providers feel pressured into having shorter visits with the patient, but more time spent with a patient is not the only component related to increased patient adherence. The quality of the communication and interaction that occur during that time is most important. Patients report greater adherence to a drug regimen if they feel that their concerns and specific points of knowledge deficit are addressed during the encounter. Post-encounter contacts by the office staff nurse, group visits, and tele-health may all be part of the solution to shorter encounters.

Table 6–1 Factors Contributing to Medication Adherence With Chronic Illness

Understanding treatment regimen	Beliefs in effectiveness
Fitting with current routine	Cultural relevancy (see Chap. 7)
Having the skills to carry out the regimen	The staging of disease and level of wellness
Fear of side effects	The ability to control side effects
Remembering to take the medications	Mental health
Family/caregiver support	Interaction with street drugs
Personal views of health	Trust in provider

Adapted from Frank, L., & Miramontes, H. (1998). Health care provider adherence curriculum. Pittsburgh, PA: AIDS Education and Training Centers Program.

Keys to Patient Education

To be effective, patient education must:

• Be simple and focus on the critical points. What does the patient need to know to take this drug safely?

• Use language that is clear and understandable to the patient. This does not just mean “English versus Spanish,” for example; it means reduced “medicaleze.” It is important not to talk down to people who do understand the medical terms; however, never assume patients do or do not understand terms used. Likewise do not assume that a fellow health-care worker does not have knowledge deficits.

• Be in a form the patient can refer to as needed after the contact with the provider, such as an after-visit summary. Zagaria (2008) found many prepackaged materials are written at the 12th-grade reading level at least. Most patients read medical information at or below the 6th-grade reading level, and some do not read at all and are too embarrassed to tell the provider.

• Be in the order of use or preparation if steps therapy is used.

• Be inclusive of the family and caregivers. Health behaviors are learned and reinforced with the family, so a family-centered approach (Mahat et al, 2007; Tyler & Horner, 2008) that engages and supports parents and children has a better chance of improving adherence.

Patients may understand what you taught but not be able to follow through even when they want to do so.

Health and Cultural Beliefs

Other influences regarding a patient’s knowledge deficit include culturally based health beliefs (see Chapter 7) and the relationship between the patient and the provider (Castro & Ruiz, 2009). Some patients do not want to share in the decision-making process. Their beliefs about health or their cultural beliefs may influence how they perceive their role in their care, and they may believe they need to do what the health-care provider tells them to do. To some others, the idea of having to share the control of taking care of themselves is foreign. Those patients who expect the provider to tell them what to do may perceive that the decision-sharing provider does not know what she or he is doing and may not return to that provider. Conversely, a mismatch can also occur between the patient who wants to be in control and a provider who presents information in an authoritarian manner.

Medical Terminology Literacy

Nearly 9 out of 10 adults have difficulty understanding health information (CDC, 2011). Certain populations are especially at risk for low health literacy. They include adults 65 years of age and older, minority populations, low-income individuals (who may read below the 5th-grade level), and immigrant populations whose English proficiency may be limited (U.S. Department of Health and Human Services, 2010; Zagaria, 2008). Using plain language makes it easier for patients to understand and use health information (CDC, 2012). Avoid using medical jargon and biomedical terminology when explaining disease processes and treatment plans. When in doubt as to whether the patient understood the information, ask the patient to repeat the information back to you in his or her own words. Remember that health literacy is not only about accessing and understanding the information but then being able to apply it to one’s own personal health-care plan (Sakraida & Robinson, 2009).

Resources that may help the provider understand and address health literacy in their practice include the following:

• The Centers for Disease Control and Prevention health literacy Web site. http://www.cdc.gov/healthliteracy/.

• National Patient Safety Foundation. http://www.npsf.org/for-healthcare-professionals/programs/ask-me-3/.

• University of Arizona has a self-learning module for older adults with health literacy problems. http://www.healthlit.fcm.arizona.edu.

Written Handouts

The National Institutes of Health (NIH) has implemented the Clear Communication initiative to focus attention on health education materials that are accessible to specific audiences based on cultural competence and that incorporate plain language (NIH, 2013). Do not give patients written material without taking the time to explain it. Check all patient education materials to make sure they are written in plain language and meet the CDC and NIH recommendations for health education materials. Patient materials such as a drug insert may not be understood by the patient and may make patients anxious as they read how many adverse reactions may occur. The provider and pharmacist must work closely together to provide patients with plain-language information regarding their medication. Having open communication with patients and using plain language can enhance the positive outcomes from the drug regimen. Enhanced, clear communication forms a positive relationship between patient and provider. In an atmosphere of shared values, shared language (Castro & Ruiz, 2009), and mutual respect, adherence and positive patient outcomes occur.

COGNITIVE IMPAIRMENT AND PSYCHIATRIC ILLNESS

Communicating effectively with patients who have cognitive impairments (e.g., Alzheimer’s disease) can be a challenge. Providers need to be able to count on the patient’s ability to understand and remember education presented about the drug if adherence is to occur. Each person with cognitive impairment is unique, having a different constellation of abilities and needs for support in understanding and remembering. Assessing the abilities of each patient is important to maximizing adherence. This may involve working with a caregiver or guardian (see later).

Patients with psychiatric illnesses may have difficulty adhering to their drug regimen. Half of the patients with major depression for whom antidepressants are prescribed will not be taking the drugs 3 months after the initiation of therapy (Osterberg & Blaschke, 2005). Rates of adherence among patients with schizophrenia are between 50% and 60% (Lacro, Dunn, Dolder, Leckbane, & Jeste, 2002; Perkins, 2002), and among those with bipolar disorder, the rates are as low as 35% (Colom, et al, 2000). Three major factors are involved here. (1) Psychiatric illness has a social stigma. (2) The presence of symptoms may result in thoughts and behaviors that do not foster adherence—for example, paranoia, agitation, or depression. Finally, (3) the adverse effects with psychotropics—for example, dizziness, orthostatic hypotension, blurred vision, decreased central processing, and confusion—are effects commonly associated with nonadherence.

Longer-Acting Drugs

As with hypertension, selecting drugs with longer half-lives may reduce the likelihood of drug withdrawal symptoms and the return of illness. For example, fluoxetine (Prozac), a serotonin reuptake inhibitor used to treat depression, has a 2-week duration of action so that missing doses or stopping the drug altogether produces a long taper and gives the provider time to discover the problem and work to correct it. Fluphenazine (Prolixin) is a parenteral antipsychotic that also lasts 2 weeks and is very helpful in patients with schizophrenia. Other drugs are also being developed in depot formulations that are long acting and can be given intramuscularly. These agents combine better efficacy and tolerability with improved adherence.

Use of Reinforcements

Osterberg and Blaschke (2005) suggest the use of reinforcements such as monetary rewards or vouchers, frequent contact with the patient, and personalized reminders. Educational approaches appear to be most effective when combined with behavioral techniques and supportive services, including reinforcements. Regardless of the diagnosis, mental health patients require careful monitoring related to their adherence to drug therapy that may include help from family, friends, and other providers. Other patient groups also greatly benefit from the attention and support.

CAREGIVER’S ROLES

When the patient is a child, an adult with cognitive deficits or disabilities, or a person with mental illness, the patient’s caregiver must be involved in the educational process. The caregiver can provide valuable information regarding the patient’s responses to drugs or difficulties in adhering to the prescribed medication regimen, including adverse reactions. If the provider detects that the caregiver may be having difficulty in adhering to the drug regimen, it is possible that the caregiver may need to be provided one-on-one interventions to help foster positive outcomes for the patient.

The Pediatric Patient

Achieving full adherence in pediatric patients requires the cooperation not only of the child but also of a devoted, persistent, and adherent parent or caregiver (Mahat et al, 2007; Tyler & Horner, 2008). Adolescent patients create even more challenges, given the unique developmental, psychosocial, and lifestyle issues implicit in adolescence. Adherence rates in children and adolescents are similar to those seen in adults, with rates of adherence to drug regimens averaging about 50%. Special interventions for children are discussed in the chapter on pediatric patients (Chapter 51).

Caregiver’s Quality of Life

The caregiver’s quality of life may have a huge impact on the patient’s quality of life. By exploring with the caregiver the psychological, physical, and social impact of giving care, the provider is acknowledging the difficulties the caregiver must face every day. Helping the caregiver find ways to “take a break” for herself or himself and showing concern for the caregiver as well as the patient will foster a positive relationship with the provider. Greater adherence and positive outcomes can be achieved by understanding the impact caregivers have on their patient and providing positive regard for their efforts.

Behavioral Therapy

Behavioral therapy can empower the caregiver to provide appropriate interventions. Discuss situations in which the patient does not cooperate with his or her care, including drug therapy. Help the caregiver to remember the times the patient did cooperate, and try to determine what the characteristics of the situation were that elicited that cooperation. Techniques to elicit cooperation can then become part of the routine care. An interdisciplinary approach is the best intervention for caregivers of patients having a multitude of consulting providers.

COMPLEXITY OF DRUG REGIMEN AND POLYPHARMACY

The number of drugs used to manage multiple complex disease processes increases the possibility of nonadherence, adverse reactions, and the chances of a decreased positive outcome for the patient. Thirty-two million Americans take three or more medications to treat a variety of ailments. Of Medicare-eligible patients, 51% take more than five medications, and more than half of these patients admit they take less medication than prescribed (PhRMA, 2011). Deciding what to do and when to do it can be complex and frustrating for all involved, patient and provider alike.

Collaborative management is an important method of encouraging adherence to a complex health-care regimen. Collaborative management is care that “strengthens and supports self-care in chronic illness while assuring that effective medical, preventive, and health maintenance interventions can take place” (von Korff, 1997, p 1097). The process of collaborative management is both dynamic and continuous. Collaborative management:

1. Begins with dialogue and mutual respect between the patient and the health-care team.

2. Is a starting point for care in chronic illness that includes choosing desirable and obtainable goals that provide direction for care management.

3. Is flexible in nature to enhance care and communication.

4. Does not end with regimen selection but progresses through stages in the direction of improving adherence, optimal health, and survival (Jani Stewart, Nolen, & Tavel, 2002, p 84).

Moreover, von Korff (1997, p 1098) further outlines the essential elements of health care central to such collaborative management. These essential elements are the following:

1. Collaborative definition of problems.

2. Targeting, goal setting, and planning.

3. Creating a continuum of self-management training and support services.

4. Active and sustained follow-up.

These four elements provide a unique manner for addressing not only medication adherence issues but also chronic illness care in general. For example, patients and providers may define problems differently. Patients may focus on functionality, subjective complaints, and lifestyle choices; providers may focus on disease prevention, medication therapy, nonadherence to recommendations, and risk factors related to prognosis. It is imperative that patients and providers have a mutual understanding of problems and understand one another’s points of view (von Korff, 1997).

Personalized Drug Schedules

Education for the patient, written and oral, regarding the importance of following a daily schedule is the gold standard. Helping patients set up a personalized drug schedule devised only for them is one possible solution. Working with nursing staff at the clinic, a matrix of activities of daily living can be devised into which drug schedules can fit. Because the schedule is specific to that individual patient’s life, it is easier for the patient and/or caregiver to follow and to remember.

Smartphones are used by 7 of 10 U.S. adults for symptom tracking or health-care monitoring (Pew Research Center, 2013). These high-tech “diaries” involve the patient in their own care and help provide an individualized method of refining medication plans.

Simplifying the Regimen

Multiple studies have been done relating adherence to the number of times a drug must be taken each day and the total number of drugs being taken daily. One study of diabetics (Morris, Brennan, MacDonald, & Donnan, 2000) found that for each increase in daily dosing frequency, there was a 22% decrease in adherence. Likewise, liver transplant patients were more adherent to once-daily dosing of the immunosuppressant tacrolimus than twice-daily dosing (Eberlin, 2013). A systematic review of 38 hypertension drug adherence trials involving 15,519 patients (Schroeder, Fahey, & Ebrahim, 2004) found that simplification of dosing regimens improved adherence between 8% and 19.6%. A literature review of 76 publications by Claxton, Cramer, and Pierce (2001) showed that adherence to once-daily dosing was 79%, twice a day was 69%, three times a day was 65%, and four times a day was 51%. The data on short-term use of antibiotics for respiratory infections are even more impressive, with nearly 100% adherence for once-daily dosing. When given an antibiotic dosing schedule of twice daily, at least one-third of patients missed one or more doses. As the number of doses increased, so did the nonadherence (Carlson, Stool, & Stutman, 2005). The ideal drug, it appears, would be taken once daily.

The combination of several medications into one tablet, a poly pill, helps adherence even in the population that is not mentally challenged (Thom, 2013). A meta-analysis of studies regarding the use of fixed-dose combination medications available for hypertension, tuberculosis, and HIV found a 24% to 26% decrease in noncompliance when combination medications are prescribed (Bangalore, Kamalakkannan, Parker, & Messerli, 2007). Consideration of whether the increased cost of fixed-dose combination medication is offset by better disease management due to increased adherence is part of the decision-making process when prescribing.

Sensory or Mobility Challenges

Patients need to be able to read the label and open pill bottles to easily self-administer medications. Large-print labels can increase safety for those with visual impairment. Easy-open lids and pillboxes increase ease of administration when a person has arthritis or impaired coordination or mobility. Prescribers need to anticipate sensory or mobility problems that affect self-administration of medications.

Cues as Reminders

There are multiple methods that can be employed to provide cues to remember to take medications. Some patients use a simple visual cue, such as putting their morning medication near the coffee pot to remind themselves to take their medication when they make the coffee. Pill containers can be purchased with compartments from once-daily to multiple times/day dosing and from weekly to monthly schedules. These containers not only serve as cues to take a drug but also help to monitor when a drug is or is not taken. Daily calendars with sections for each hour of the day can be marked with the name of the drug to be taken. Monthly calendars are sometimes needed for drugs not taken on a daily basis. Electronic technologies include reminders through mobile phones, personal digital assistants, and pillboxes with paging systems. Elders appear to profit the most from having multiple cues (Boron et al, 2013). A Cochrane review of the use of mobile phone messaging in the self-management of chronic disease demonstrated increased medication compliance (de Jongh, et al, 2012). For pediatric patients, stickers, which can be applied to a reminder board or chart, are also helpful. Keeping antihypertensive medications with the home blood pressure cuff may foster both medication adherence as well as self-monitoring of medication effect.

Scheduling Visits for Medication Follow-Up

Patients who miss appointments are often those who need the most help in improving their ability to adhere to a drug regimen. Such patients often benefit from clinical scheduling that matches their drug regimen. If a drug is prescribed for 2 weeks, the next appointment should be on the day after the drug should be completed. For chronic illness, clinic scheduling around the time for any laboratory work or doing physical assessments such as blood pressure can also include consideration for the time to fill the prescriptions. Matching the timing of refill intervals with appointment schedules is also patient-centered.

One-stop-shopping for medical care and prescription refills is a potential adherence strategy. Larger clinics with on-site pharmacies or even pharmacy-based convenience care clinics may provide the bonus of overcoming barriers to filling and refilling medications. Worksites with primary care clinics have nearly 10% better adherence rates (Sherman, et al, 2009).

FINANCIAL IMPACTS

Pharmacological interventions may be costly. Cost can have an impact on the ability and willingness of the patient to adhere to drug regimens. Even if the patient has access to financial assistance (e.g., Medicaid, insurance coverage for drugs), this does not ensure that the patient will view drugs as a primary financial need. Basic needs (e.g., food, housing) may take precedence over drugs in planning a monthly budget. This is especially true for older adults, who are frequently on fixed incomes and yet are the highest users of prescription and over-the-counter drugs. Over 50% of Medicare patients do not keep to their therapeutic regimens (Gould & Mitty, 2010).

Cost Versus Complications

Sipkoff (2005) reported a 3-year study that measured the medical effect of nonadherence on 8,000 people with chronic conditions, including hypertension, diabetes, and depression. Researchers found that study subjects who said they cut back on their prescriptions because of cost were 75% more likely to have suffered a significant decline in their overall health, and 50% were more likely to have had a heart attack, stroke, or chest pain episode than those who filled their prescriptions.

For newly diagnosed patients with chronic illnesses, high cost-sharing—that is, having a large co-payment for each prescription or having to pay up to a certain dollar amount before insurance pays the rest—has been shown to delay the initiation and continuation of drug therapy. A study of patients with hypertension found that 54.8% of the patients delayed initiating therapy when cost-sharing was doubled (Solomon, Goldman, Joyce, & Escarce, 2009).

Out-of-Pocket Versus Insurance

Having insurance that partially covers the cost of medications does not in itself guarantee appropriate utilization of this benefit. From a sample of 27,057 patients with type 2 diabetes, Dor and Encinosa (2004) estimated that the business cost saved by increasing a drug co-payment by as little as $6 would also increase the cost of diabetic complications related to increased nonadherence by $360 million per year, far exceeding the business savings of $31.2 million incurred by the co-payment increase (Lozada, 2005).

An increasing number of patients are either uninsured or underinsured. The hope is that the ACA will assist with this issue. Frustratingly, though, the Veteran’s Administration has found that cheap or even free medication refills do not always produce adherence to treatment regimens. Mail-order pharmacy prescription refills are typically cheaper than monthly pickups at local pharmacy windows. Use of mail-order supplies had a higher adherence rate than those from retail agencies (Iyengar et al, 2013).

Family Versus Self

Patients who have several family members to support may view taking drugs for themselves as somehow being selfish. The child who has a chronic disease also affects the financial stability of the family, which may cause resentment from parents or siblings.

Generic Versus “New and Improved” Brand Name

Many patients see new drugs advertised on TV and the provider hears about them from the drug representative: “This new drug is so much better than the old one” or “This brand-name drug is so much better than a generic.” There are times when a new drug has characteristics that make it better than anything else on the market, and generic drugs that are not bioequivalent may not be as effective as a brand-name drug. However, choosing a new or nongeneric formulation that is very expensive requires careful consideration. A brand-name drug may cost hundreds of times as much as the generic. Providers need to consider cost before prescribing a drug, even if the patient or the insurance provider appears to be able to cover the cost.

Public and Private Assistance

The issue of public assistance is certainly a complex and difficult one. Being aware of possible public programs available to assist financially is only a part of the whole picture. The provider also has to have knowledge of the patient and whether that patient will accept public assistance. Public assistance may not be an alternative if the patient or family views it as a social or cultural stigma that is unacceptable.

Prescribers should keep contact information on hand for large pharmaceutical companies that offer coupon reductions and home-delivery options. Many companies have need-based programs that result in no-cost medications for patients in temporary or even permanent financial crisis. During times of disaster, larger pharmacy chains provide rapid refills and low-cost substitutes for medications lost during floods, fires, and wind storms.

COMMUNICATION DIFFICULTIES

Finding common terminology is not the only communication difficulty. There are also speech, hearing, and language barriers. Communication barriers can create safety concerns, as well as frustration for the provider and patient.

Non–English Speakers and Interpreters

Language barriers may create difficulty in adhering to a drug regimen. Federal law requires that clinics provide an interpreter if the primary language is different from the provider’s. Clinics are able to contact interpreters for a number of different languages via interpreter services or phone interpretation. The difficulty that arises is whether the interpreter is repeating exactly what the provider is saying and, in return, whether the interpreter is saying exactly what the patient is saying.

Professional certified medical interpreters are preferable. A patient may not want to share certain information with the family member who is the interpreter, and the family interpreter may not wish to give the provider certain information about the patient. Cultural norms play a major role here. When a professional interpreter is not accessible, every effort must be made to find a reliable interpreter. The provider can be held liable for poor outcomes if a lay interpreter is used and incorrect information is given to the patient.

Speech and Hearing Issues

Patients with hearing or speech difficulties should not be automatically classified as individuals who will have adherence problems. Patients with hearing difficulties may have learned to compensate by reading lips. If this is the case, the provider must stand directly in front of the patient and speak clearly, looking directly at the patient’s face. Presbycusis (hearing loss due to age) is commonly associated with decreased ability to hear higher-pitched tones, often those within the range of the human voice. Speaking in low tones or finding a provider with a lower voice may improve the patient’s ability to understand. Written instructions are necessary to ensure accurate information is conveyed to the patient.

Patients with speech difficulties include those who are deaf and those who have had strokes or laryngectomies that reduce their ability to produce speech. Sometimes, these patients have learned coping mechanisms or had speech therapy to enable them to communicate. The provider must discover what tools the patient uses/needs to communicate and use these to the patient’s advantage. An interpreter should be provided for patients who use American Sign Language. Patients using speech-enhancing devices usually bring such items with them. In any case, special attention should be paid to ensure that these patients communicate effectively with the provider, and vice versa.

COMMUNICATION BETWEEN PROVIDERS

It can be challenging to coordinate health care for a patient who sees several different providers. Open lines of communication are a must between the patient and his or her provider(s) and among health-care providers. If a patient sees a specialist for whatever reason, ask the patient to request that the records of each visit be sent to the coordinating primary care provider. However, the patient or the specialist’s staff does not always follow through on this request. A congenial call by the primary care provider will do much to secure these reports; coordinate care, regimens, and appointments; let patients know the provider thinks they are important; and let the specialists know who the primary care provider is, thus also enhancing the visibility and credibility of primary care practice.

Patients who see several health-care providers or who do not consistently have the same provider experience greater problems in adhering to treatment therapy. Encouraging repeat visits to the same provider increases communication and knowledge between the patient and the provider.

PATIENT’S RESPONSIBILITIES

Providers are responsible for determining the best plan of care for a patient and for working with the patient to actualize that plan of care. However, the plan of care should be mutually arrived at with the patient, and the patient carries some of the responsibility for its actualization. Not taking a drug, not taking it as prescribed, or premature discontinuance of a drug are common forms of nonadherence. Failure to fill or refill the prescription is another form of nonadherence. All of these are within the control and responsibility of the patient. Chronic illnesses create some of the greatest problems for the patient who has to adhere to ongoing therapy. Time, finances, and a desire to be perceived as healthy appear to have the greatest impact on compliance.

Self-monitoring has been shown to have positive effects on outcomes of drug regimens. For the patient with asthma, self-monitoring of peak expiratory flow rates can improve disease awareness and predict asthma flare-ups (see Chapter 31). Patients demonstrated better adherence after the first follow-up visits but gradually tapered off unless the importance of using the drugs was reiterated in follow-up visits. This technique can be utilized with other chronic diseases (e.g., diabetes, chronic obstructive pulmonary disease, cardiac disease, hypertension, depression) by reviewing whatever device is utilized for home management. Sarver and Murphy (2009) stress the importance of patient-centered versus disease-centered management strategies that include comprehensive patient and caregiver education and “solid partnerships between healthcare providers and patients.”

Do not assume that the patient with a history of homelessness or substance abuse will not follow a treatment plan or that the well-educated, affluent patient will. The provider must find out if the patient actually wants to take the drug and is committed to adhering to a drug regimen. Patients have the responsibility to try to adhere to pharmacotherapeutics, but it is also the provider’s responsibility to attempt to discover the barriers that are impeding a positive outcome.

MEASURING ADHERENCE

Adherence can rarely be measured by only one method. Methods that may be used include patient reports, clinical outcomes, pill counts, refill records, biological and chemical markers, and medication adherence tools.

Patient Reports

Patient reports are the easiest monitoring tool, but caution must be used when determining if the patient is actually pseudocompliant, telling the provider what the provider wants to hear rather than revealing the reality of nonadherence. Patients do not want to be scolded or chastised when nonadherence is discovered. Asking the “why” behind not taking meds helps to understand previously unknown or new barriers to adherence. Have the patient keep a drug diary to help him or her answer the following questions honestly:

• Did you fill your prescription?

• How often have you taken your drug in the past [number of days or weeks]?

• Have you missed any scheduled times to take the drug? If so, what was the reason? The answer to this question may give the provider insight into ways to improve adherence by removing barriers to it.

• Are there things we could do together to help you take your drugs?

Clinical Outcomes

In most cases, there is a clear clinical outcome being attempted by the use of drugs. Did the drug actually lower blood pressure or blood glucose? Did the patient have fewer asthma attacks or trips to the emergency room? Graphs or flow charts demonstrate the trajectory of outcomes and can be very convincing. If the clinical outcome was not met, adherence may be part of the problem, but remember, it is rarely the whole answer.

Pill Counts

Pill counts can be helpful in determining if the correct number of pills was taken between visits. Some new technologies dispense only one pill at a time, thereby reducing the risk that the patient may pour out pills to avoid being “caught.” This type of dispensing can also be tied to reminders to take the pills. Bubble packs are cheap pill-counting methods that do not require fancy technology. If the patient has a caregiver, the caregiver can do the pill counts.

Refill Records

Records of refills can be monitored in the electronic health record or can be obtained from the pharmacy if the patient uses only one pharmacy to refill his or her prescriptions. Having clinic staff monitor whether refills are ordered as expected during the check in process can alert the provider to potential issues of adherence. Completing medication reconciliation as part of each patient encounter will uncover drugs not currently in use or duplication of prescriptions and may bring to light conflicting prescriptions from other providers.

Biological and Chemical Markers

Biological and chemical markers usually are laboratory tests or other diagnostic markers. Serum drug levels are mostly limited to measuring recent activity. Other biomarkers, such as Hb A1c, may be used to determine if a patient is taking the medication and whether the medication is effective.

Medication Adherence Scales

There are several medication adherence scales in the literature. None is considered the gold standard. The reader is directed to the literature for several scales currently in use. A review of four common scales is a good starting point (Lavsa, Holzworth, & Ansani, 2011). The fastest to administer is the Medication Adherence Questionnaire (MAQ, also known as the Morisky 4), which is presented in Box 6-1. Because there are few questions and it is very easy to score, it is a popular tool to try to get to the source of adherence issues, including adverse drug effect and memory issues. The psychometrics include a reliability coefficient of α = 0.61 (Lavsa, 2011). The addition of measuring self-efficacy is found in the Self-Efficacy for Appropriate Medication Use Scale (SEAMS), which has an alpha value of 0.89. Both the MAQ and the SEAMS have been validated in low-literacy populations.

PREDICTORS OF ADHERENCE

There is no end to the variety of factors that impact medication adherence. Wheeler, Roberts. and Neiheisel (2014) propose a model identifying predictors of medication adherence, which includes social, disease, financial, and health system factors that may influence medication adherence. There are additional elements that may influence adherence, including personal elements such as self-efficacy or health beliefs, and biomedical influences such as functional impact of the disease. While multiple elements influence adherence, each individual patient has unique elements that more greatly influence adherence at different points of time (Fig. 6-1). The elements that influence adherence may be grouped into spheres of influence with elements of potential positive and/or negative contribution within those spheres. Determining which factors are impacting adherence at any point in time requires the advanced practice prescriber to conduct a complete nursing database concerning the elements that are playing into the current picture of adherence. These influences are not static; the elements are constantly in motion, with the importance of particular spheres of influence or several elements coming and going in duration and degree of impact on adherence to the therapeutic regimen. Every sphere plays a role in every patient’s choices, abilities, and capabilities for self-care. A particular sphere or factor that may have played a key role previously can become more or less powerful in its influence. When previously reliable prescription adherence changes, the prescriber in tandem with the patient must return to the database to determine what new spheres and elements of influence might be at work.

BOX 6–1 MORISKY SIMPLIFIED SELF-REPORT MEASURE OF ADHERENCE

Scoring: 0 = High Adherence; 1–2 Medium Adherence; 3–4 Low Adherence

1. Do you ever forget to take your medicine?

2. Are you careless at times about taking your medicine?

3. When you feel better do you sometimes stop taking your medicine?

4. Sometimes if you feel worse when you take your medication, do you stop taking it?

Adapted from Jani, A. A., Stewart, A., Nolen, R. D., & Tavel, L. (2002). Medication adherence and patient education. Florida AIDS Education & Training Center. In HIV/AIDS primary care guide (p 87). Gainesville, FL: University of Florida Press.

Providers are encouraged to consider social factors and financial and health system factors when planning treatments in concert with patients. Planning must go beyond the disease factors that direct selection of therapeutic agents based on standard severity and degree of complexity of physiological effects. In concordance with the patient, the prescriber must weigh the pros and cons of different options, regimen complexity, and any concurrent medication or lifestyle challenges that may impact the patient’s ability to adhere to the regimen. The relationship between prescriber and patient can make the difference in whether adherence is achieved or the issues previously discussed overshadow the plan and result in poor adherence. Predicting potential issues and exploring methods to overcome any objections are critical to promoting adherence.

SUMMARY

Patient education, enhanced communication between patient and provider and between providers, and consideration of multiple complicating social factors all contribute to fostering adherence and positive outcomes. Identifying patients at risk for nonadherence or those who actually are nonadherent, determining the cause of the nonadherence, facilitating the removal of the cause or barriers to adherence, and developing partnerships with patients to produce adherence and positive clinical outcomes are important roles for the prescribing provider. Table 6-2 provides a summary of adherence factors.

Figure 6–1. Five spheres of influence and multiple factors that impact adherence and self-management. Robinson, M. (2015). Derived from Wheeler, K. J., Roberts, M. E., & Neiheisel, M. B. (2014). Medication adherence part two: Predictors of nonadherence and adherence. Journal of the American Association of Nurse Practitioners, 26(4), 225–232.

Table 6–2 Factors Influencing Adherence

General Health Status	Medical History, Nutritional Assessment, and Comorbidities
Life goals	To understand deeper issues such as• what gives meaning to a patient’s life• the context of illness and treatment on a patient’s life• the patient’s definition of quality of life• a patient’s attitudes and motivations based on one’s self-perception
Medication history	Past experience, current regimens, and side effects from all medications
Comorbidities	Psychiatric, substance use, and medical illnesses
Social stability	Housing status, food resources, transportation needs, financial status, and insurance status
Employment status	Type of job, constraints, and disclosure issues
Health beliefs & cultural background	Language and perceptions toward illness and chronic illness, diagnosis, prognosis, role of medications, understanding of consequences of medication nonadherence, and spiritual/religious orientation in reference to one’s life and health goals
Family & social support	Identification of personalized medication facilitator and network of social support
Educational background	Educational level, literacy level, baseline knowledge regarding specific chronic illness, medications, and importance of adherence

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CHAPTER 10 HERBAL THERAPY AND NUTRITIONAL SUPPLEMENTS

Fujio McPherson

OVERVIEW OF HERBAL MEDICINE

DEFINITIONS

Western Herbal Medicine

Traditional Chinese Medicine

Ayurvedic Medicine

HERBAL SAFETY

Evidence Grading

Matrix for Evidence Grading

Challenges to Using an Evidence-Based Method

COMMON HERBS

Western Herbs

Traditional Chinese Herbs

Ayurvedic Herbs

Herbs for Common Disorders

HERBAL PREPARATIONS

CONSIDERATIONS FOR THE APN PRESCRIBER

SUGGESTED READING

Western Herbs

Chinese Medicine

Ayurvedic Medicine

General Recommendations

Phytomedicine, defined as “the practice of using plants or plant parts to achieve a therapeutic cure” (Fetrow & Avila, 1999), is the oldest known form of medicine. Originally, plants were considered only for their nutritional value. However, from experience in plant production and awareness of plant behavior, noting the influence of climate and environmental changes on planting outcomes and the effects of specific plants in creating or removing various symptoms in the body, humans began to use plants as medicine.

In many cultures, herbal traditions are a part of a history that began well before the scientific dissection of plant cellular components. It is impossible to determine precisely when humans first discovered the medicinal use of any given plant, but through time and observation every culture developed a pharmacopoeia of herbal remedies. The Egyptians were widely respected for their use and recording of herbal remedies, many of which are still used today, including opium, cannabis, myrrh, frankincense, and fennel. The Greek and Roman use of herbs was based on the principles of the four humors that derived from the Indian and Chinese cultures. One of the oldest forms of herbal medicine was their use in altering states of consciousness in the shamanic traditions of South American and many of the Native American cultures. The Greeks also used hallucinogenic herbs, such as opiates, to heighten the healing powers within the body while the patient lay in an altered state of consciousness in Asclepian healing temples.

Today, the use of herbal medicine in the United States has grown significantly since the early 1990s. As determined by the 2007 National Health Interview Survey, 55.1 million adults in the United States had used herbs or supplements in the past 12 months, up from 50.6 million in the 2002 survey (Wu, Wang, & Kennedy, 2011). And up to 2.9 million children aged 4 to 17 years had used herbs or dietary supplements in the previous 12 months (Wu, Wang, & Kennedy, 2013). As mainstream medicine diverged from a predominantly plant-based pharmacopoeia to a synthesized, chemically based pharmacopoeia that is accompanied by a myriad of harmful side effects, a belief that herbal medicines are safer and have less harmful side effects has evolved to such a degree that many patients often abandon their use of synthetic medication for over-the-counter herbal substitutes. With limited regulation by the U.S. Food and Drug Administration (FDA), herbal formulas and products, which are classified as food sources, have become widely available.

Thus, allopathic providers are now faced with the challenge of drug and herbal interactions as well as by working with strong patient belief systems that can compromise management of the patient’s condition. Providers need to consider the impact herbs may have on their medical and pharmaceutical management. In many cases, herbal therapy has proven to be very effective at either enhancing medical management of a disease and/or reducing the need for stronger pharmaceutical management, in some cases successfully replacing more harmful pharmaceutical drugs without the harmful side effects while achieving the same efficacy. For example, the root bark of Hibiscus syriacushas been used for many years in Asia as an antipyretic, antihelminthic, and antifungal agent. The results of a 2008 study indicated the herb had a significant and dose-dependent antiproliferative effect on lung cancer cells in vitro and in vivo (Cheng, Lee, Harn, Huang, & Chang, 2008).

Yet there are also many studies that identify potentially harmful effects of herbal therapy. Buettner, Mukamal, Gardiner, & Davis (2009) found lead levels to be 10% higher among women who used St. John’s wort, Ayurvedic herbs, and some traditional Chinese herbs. Coenzyme Q10, a supplement commonly used to improve memory and cardiovascular function, was found to reduce the effectiveness of warfarin, and evidence is still inconclusive regarding its effect in reducing cardiovascular conditions like exercise-induced angina. When taken in doses higher than 3,000 mg per day for a prolonged period of time, CoQ10 can cause elevated liver enzymes.

Many studies support the argument that further research or regulation of herbal therapy is needed, but they also make clear that the safety and efficacious use of herbs in the treatment of specific disorders cannot be truly evaluated without considering the theories and principles of the traditional medicines of which they are a part. It is common knowledge that every pharmaceutical prescription has side effects that range from mild to life-threatening, so excluding the use of an herb solely due to its side effects is not only misguided but fails to consider the difference between herbal side effects and pharmaceutical side effects. For example, in Chinese medicine, an herb may be used for its cooling effect, and so the side effect that would indicate the herb is working properly would be the patient’s display of symptoms of cold versus heat and a side effect of loose stools (which is an indication of cold) would actually be a positive sign rather than a negative side effect, as it would be considered by any Western research criteria. Most traditional herbal theories do not use scientific criteria in determining the use of an herb, and so allopathic medical practice does not recognize the theories and long traditions on which trained herbalists base their diagnoses and prescriptions of specific herbs and herbal formulas.

By definition, herbal therapy encompasses any plant source, which means that it also includes food. When the plant or a constituent of the plant is identified as a specific treatment for a disease or symptom, it is often referred to as an herb. And the designation of an herb as a medicine is based on how it is used. Herbs have long been considered one of the safest medicines to take and, like foods, can be classified by their effects on the body—mild, strong, or toxic. However, as mentioned, it is more important to understand the theory behind the herb before one can understand how it is used in the treatment of a disease. This includes understanding the various methods by which herbal preparations are prepared and manufactured. So it is imperative that nurse practitioners and other allopathic providers understand not only the name, ingredients, and source of a particular herb but also the various theories used in herbal medicine, or they should consult with clinicians who are trained in herbal medicine to better care for the patient who chooses to use herbal remedies.

This chapter serves as an introduction to phytomedicine. Because this is a relatively new area of study for Western health practitioners, the chapter includes definitions of terms and descriptions of the various principles involved in prescribing and using herbal medicines in North America. The purpose here is not to train readers to be herbalists but rather to introduce them to some of the major herbal theories used in the prescription of herbs, that is, the chapter is an introduction rather than a prescriptive resource.

OVERVIEW OF HERBAL MEDICINE

To understand the concept and theories of herbal medicine, it is important to examine the many herbal traditions practiced in the world today. For the purpose of this particular text, three traditions will be examined: Western herbal medicine, Ayurvedic herbal medicine, and traditional Chinese herbal medicine. Yet the reader is encouraged to explore other traditions of herbal medicine also, among them Unani medicine, homeopathic medicine, Native American traditional medicine, and shamanic herbal medicine.

DEFINITIONS

Medicinally an herb is any plant part or whole plant used for its therapeutic value. Yet many of the world’s herbal traditions are not limited to plants only; mineral and animal substances are included as well. Herbal medicine is the art and science of using herbs for promoting health and preventing and treating illness. It has a written history that is more than 5,000 years old. Although the use of herbs in America has been overshadowed by dependence on modern medications in the last 100 years, 75% of the world’s population relies primarily on traditional healing practices and the use of herbal medicine.

Pharmacognosy is the branch of pharmacology that uses the chemicals from plants, molds, fungi, insects, and marine animals for their medicinal value. Today, most pharmaceutical drugs are single chemical entities from plant sources that have been highly refined, purified, and synthesized into a single active component of the plant. Many of the drugs used in allopathic medicine were derived from plants in this way, including digitalis from foxglove, ephedrine from Ephedra, and ergotamine from Claviceps purpurea. In 1987, about 85% of modern drugs were originally derived from plants. However, only about 15% of all drugs are derived from plants today owing to advancements in synthetic reproduction and purification of plant constituents. In contrast, herbal medicines are prepared only from living or dried plants and contain hundreds to thousands of interrelated compounds, creating a type of synergy between its many constituents that science is now considering as the reason for the safety, effectiveness, and lower incidence of side effects of herbs (American Herbal Guild [AHG], 2006).

Western Herbal Medicine

The beginning of science-based herbal medicine can be traced back to the European Renaissance, when political independence from the Church and advances in science contributed greatly to the study of medicine. William Turner (1510–1568), regarded as “the father of British botany,” was the first to scientifically study plants. John Gerrard (1545–1612), a surgeon and the author or Gerard’s Herbal, studied over 1,000 plants and recorded his observations of their behavior and uses. But one of the most interesting scientists of this era was Nicolas Culpepper (1616–1654), who studied the relationship of herbs to astrology. Although he was ostracized by his peers at the time for his theories, his understanding of herbs from an energetic perspective influenced by factors other than the physical components of nutrients was very similar to the Eastern interpretation of plant-based medicine. Yet he fared much better than his female counterparts outside of the scientific community who used herbal medicine to heal. These female healers, branded as witches, were hunted down during the Inquisition, which effectively suppressed and eliminated this form of medicine and succeeded in denigrating the efforts of lay healers. Another pioneer in herbal medicine was Johann Wolfgang Von Goethe (1749–1832), a German herbalist who stated that the chemical mixture of the plant was the “open secret” to its effectiveness. Despite these setbacks, many of these early discoveries have survived and continue to be practiced today.

In Western herbology, herbs are primarily classified according to their therapeutic properties and the constituents of the plant. For example, the categories of diuretics, diaphoretics, and tonics allow Western herbalists to group herbs with similar qualities and then use them accordingly. This system is primarily based on the chemical constituents of the plant and remains the basis of Western pharmacology as well some of the herbal therapies used by many naturopathic physicians and other herbalists who base their practice on scientific examination of the plant.

What makes this form of herbal therapy different from Western pharmacology is that it is based on constituents taken from the plant instead of the synthetic modification commonly found in prescription drugs. One example is bromelain, a sulfhydryl proteolytic enzyme that is found in pineapple juice and in the pineapple stem. Bromelain activates the proteolytic activity at sites of inflammation and is commercially used as a natural anti-inflammatory agent (Pizzorno & Murray, 2006). Therefore, an herbal option to reduce inflammation can be bromelain or pineapple. Another example is the rhizome ginger commonly used in cooking. Ginger is considered a tonic, and one identified constituent of ginger root (Zingiber officinale) is the sesquiterpenes, which have significant antirhinoviral activity that is used to combat colds (Mills & Bone, 2000). Products made from ginger (e.g., teas, candy, lozenges) are used in the treatment of cold symptoms.

It is common to see the same plant being used in several different herbal theories, and although the principle actions are the same, the differences lie in how the plant is used and which parts. One example is cinnamon. Cinnamon (C. zeylanicum) is often referred to as “true cinnamon” or Ceylon cinnamon. However, a commercially related species known as cassia (C. aromaticum), or Saigon cinnamon (C. loureiroi), and C. burmannii are also labeled as cinnamon. True cinnamon (Ceylon cinnamon) comes from the thin inner bark; is finer, less dense, and more crumbly in texture; and is considered to be less strong than cassia. Cassia is derived from the entire bark layer, so it is thicker and has a much stronger, harsher flavor than cinnamon. This distinction is important because of a moderately toxic component called coumarin, which can cause liver and kidney damage in the high concentration that is found in higher doses of cassia compared to Ceylon cinnamon, in which the levels of coumarin are negligible.

Often used for its oil, cinnamon contains primarily cinnamic aldehyde but also has ethyl cinnamate, eugenol (found in the leaves), beta-carvophyllene, linalool, and methyl chavicol; it is used to cure colds and treat diarrhea and problems of the digestive system. It has been reported to be effective in the treatment of type 2 diabetes mellitus (Khan et al, 2003). In traditional Chinese medicine, cinnamon (Gui Zhi) is used to treat colds but is defined by its ability to release excess wind-cold conditions, warm and open channels and collaterals, and warm yang and is identified as being contraindicated in patients with yin deficiency or those having blood disorders because it stimulates blood circulation (Chen & Chen, 2001).

Traditional Chinese Medicine

The origins of traditional Chinese herbal medicine (TCM) are difficult to date; however, one of the oldest surviving texts that form the basis of TCM is the Huangdi Neijing, “The Inner Canon of Huangdi or Yellow Emperor’s Inner Canon,” first referenced in the Book of Han, in 111 CE. The Huangdi Neijing is composed of two texts, each with 81 chapters or treatises, and is primarily a written record of questions and answers between the mythical Huangdi (Yellow Emperor) and six of his ministers. The first text, the Suwen, covers the theoretical foundation of Chinese medicine and its diagnostic methods, and the second text, the Spiritual Pivot, discusses acupuncture therapy. The second important text in Chinese herbal medicine is the Shang Hang Lun, “Treatise on the Treatment of Acute Diseases Caused by Cold,” written by Zhang Zhong-Jing (142–220 CE). The Shang Hang Lun describes the six stages of acute disease as an approach to the diagnosis and treatment of acute illness and is comprised of classical herbal formulas that can be used to treat them. Today, formulas contained in the Shang Hang Lun, such as Ge-Gen Tang, Shao Yao Gan Cao Tang, and Xiao Qing Long Tang, are still commonly used among TCM practitioners.

The Huangdi Neijing not only departed from the shamanic beliefs of the past but elaborated on the concepts of Daoist theory on which TCM is based. The Dao concept is that man is a microcosm of a larger macrocosm and to stay healthy or “in balance” there must be an intimate respect and understanding for the laws of nature and how those laws apply to man. Health or balance by definition results when there is a free flow of energy (qi). When qi is abundant and flowing freely, the body is able to heal itself and the patient will feel a balance of the mind, body, and spirit. Just as in nature, when there is enough water, nutrients, and sunlight, the plant will flourish and grow. Of course, knowing how to determine an imbalance (diagnosis before the presence of disease) or knowing the source of a disease resulting from an imbalance and how to prevent the progression of the imbalance, support self-healing, and treat the disease is the principle science of TCM.

There are a number of theories about how to interpret changes of balance in the human body, mind, and spirit. How TCM is practiced based on one or more of these theories often depends on the training of the practitioner and what the practitioner feels best suits the patient’s condition. By understanding the basic principles of these TCM theories—yin and yang; the five elements; and the influence of environmental factors (wind, damp, hot and cold, dry, and wet)—along with the effects of diet, lifestyle, age, and emotions, a specific TCM diagnosis regarding the cause of imbalance can be determined and herbal therapy along with other treatment modalities like acupuncture, diet, counseling, movement, massage, and so on can be used to bring the body back into balance, promote self-healing, and treat diseases.

If there is one feature that distinguishes Western medicine from traditional Chinese medicine, it is the paradigm from which they view man and the role of plants. Instead of relying on science to identify the nature of disease and health, the Chinese look at nature from a Daoist perspective, paying attention to cycles of growth, the characteristics of the plant (according to taste and expression), the underlying condition of the individual consuming the herb, and most importantly the constitution of the individual.

In TCM, the herbs that represent energy (qi) are classified in a number of ways: by their amount of energy, quality, seasons in which they are at maximum strength, tastes, directions, and actions on the body (e.g., moving blood, reducing dampness or heat, breaking up stagnation, etc.). Traditionally, herbal formulas also include animal organs and minerals for the same reasons. Using these principles, TCM practitioners use herbs to influence the imbalances unique to the patient. This symbiotic relationship is one of the most important aspects of TCM herbal medicine. Customizing the herbal formula and its properties to address the individual deficiencies or excesses assumes a more holistic approach to healing and the role of herbs in the treatment of diseases. For example, in TCM menopause is often considered a time of yin deficiency, so herbs that are yin in nature and that clear heat arising from deficient yin, such as mountain peony bark (mu dan pi) and phellodendron bark (huang bai), or formulas that contain each, are often recommended (Liu & Tseng, 2003). In doing so, TCM recognizes that if these herbs were applied inappropriately, for example, giving a yin herb to a yin excess patient, the herb could potentially make the condition worse even though the underlying condition is menopause. As mentioned, it is important to remember that TCM does not often restrict treatment to a single herbal therapy as does Western herbal medicine; it recognizes the principles of the Dao and concepts of change, so herbal therapy and formulas will often be changed within short intervals of time.

Although the focus of this chapter is herbal therapy, it is also important to remember that TCM places as much value on the power of food as it does on herbs in healing and never excludes food or herbs from the other aspects of TCM, which include the practice of acupuncture, energy movements (tai chi), massage (tui nai), and balance.

Ayurvedic Medicine

Ayurvedic medicine was developed in ancient India; it is defined as the study of life: ayur means “life” and veda means “to study.” It is considered the oldest form of medicine in the world and is based on original texts derived from Vedic scriptures that date from 1500 BCE to 1200 BCE. Ayurvedic medicine eventually spread from India and influenced a number of cultures in the Far East, including TCM, Japanese acupuncture, Unani medicine, and the humoral medicine practiced by Hippocrates.

Although many of the teachings originate from knowledge that was handed down through generations of healers, many believe Ayurveda knowledge to be of divine origin received from the meditation of sages. Similar to TCM, Ayurvedic medicine encompasses a myriad of therapies based on the constitution of the individual and nature of the particular disease. But the use of herbal medicine is somewhat broader in that it is used in a number of different mediums and in delivery systems beyond the oral route. As well as being taken orally, herbs are used in body massage oils, in food preparation, and in aromatherapy, although the choice of therapy is still based on the individual and is linked to the patient’s constitution and level of imbalance.

In Ayurvedic herbology, herbal therapy is interchangeable with food and spices, which are viewed as a sequence of herbal therapies that range from mild (food) to moderate (spices) to strong (herb). And their use depends on a person’s constitution, classified according to a tridosha theory and the nature of the disease. In the tridosha system, all entities of matter, including people and plants, contain three doshas: vata (air/ether), which corresponds to the nervous system and movement; pitta (fire/water), representing transformation, circulation, warmth, and digestion; and kapha (water/earth), representing nourishment, solidity, and the formative aspects of tissue, fluid, and bone (Tiwari, 1995a).

Although all three doshas exist together, often plants and people are classified by the one that is most dominant in them, referred to as the person’s “Prakruti,” and specific to them as an individual. Treatment is then based on balancing the specific constitutional type for a particular patient, since each dosha is aggravated or pacified by certain therapies, herbs, and foods. So in Ayurvedic medicine (similar to TCM) herbal therapy actually begins with the use of food and spices that are consumed on a daily basis to maintain the balance of a given doshic constitution.

An example of this theory would be treating a person with a vata constitution and a vata disorder. Vata, meaning “wind,” conceptually is made up of the elements of ether and air. Ether (space) affects the ability of air to gain momentum; if unrestricted, air can gain momentum and become forceful, so when balanced, a vata-type person will have free movement and flow (e.g., breathing will be strong, movement of the muscle and bones easy and light, movement of blood smooth, movement of thought and emotions easy, movement of the colon unimpeded). If unbalanced in either an excess or deficient condition, the person will experience either an excessive movement (e.g., manic behavior, diarrhea, nervousness) or deficient movement (e.g., constipation, depression, asthma). Therefore, the goal of therapy would be to counter the excess or deficiency first with food and spice and then support it with specific herbal therapy.

One Ayurvedic principle similar to the one used in homeopathic medicine is that “like increases like.” Consequently, substances of similar doshas will increase those qualities in the body. A person experiencing an excess vata imbalance tends to be intolerant of dry or bitter substances (which are considered vata in nature); therefore, treatment would consist of avoiding foods that are dry and bitter and incorporating food like honey and rose hips and herbs like calamus or marshmallow root in the diet (Tiwari, 1995b). Similar to TCM, Ayurvedic treatment of imbalances within the tridoshic theory is not limited to herbal therapy alone. It also includes the five purification therapies (panchakarma), diet, aromatherapy, massage (abyanga), meditation, daily routine (dinacarya), and the practice of yoga.

It is important to remember that in most traditional cultures throughout the world herbal therapy is applied according to the energetic effects on the body and not on the individual constituents found in the plant. This in part recognizes the synergistic effects of the plant as being more important than the individual components. The conceptual model upon which clinical decisions and herbal recommendations are made is remarkably different from that of Western allopathic medicine. In the West, herbal medicines are often viewed strictly in terms of their actions, disregarding the energetic composition of the herb or the person consuming it. In the short term, this practice may result in a positive effect, but in the long and/or short term, it can often lead to poor or harmful effects. Therefore, it is important for Western clinicians who have an interest in herbal medicine or have patients who are taking herbal medicine to be aware of the different systems used to classify herbs and to recognize the importance of consulting with providers trained in a particular system. By doing so, practitioners can employ herbs efficiently and avoid the improper use of these therapies, which can either result in no effect or create an opposite and undesired effect.

HERBAL SAFETY

Today there are national standards and certification requirements for practitioners of TCM and naturopathic medicine (ND) for licensure to prescribe herbal therapy; however, state requirements may vary. In addition, herbal certification programs are now available, and guidelines for safe herbal practice have been established by the American Herbal Guild (AHG). The AHG is a nonprofit, educational organization founded in 1989 to represent the goals and voices of herbalists. It is the only peer-review organization in the United States for professional herbalists specializing in the medicinal use of plants. Herbalists from any tradition with sufficient education and clinical experience who demonstrate advanced knowledge in the medicinal use of plants and who pass the AHG credentialing process (a careful review by a multidisciplinary admissions board) receive professional status and the title Registered Herbalist, AHG. The AHG has also developed a code of ethics, continuing education programs, and specific standards for professional members as well as curriculum guidelines for herbal educational programs. The AHG Educational Guidelines recommend a curriculum with a minimum of 1,600 hours of total study, 400 of which should be in actual clinical work (AHG, 2006).

When considering herbal medicines it is important to understand that the development and preparation of medicines from plant and animal products can involve wide variations, based on the conditions of growth, harvesting, processing, storing, and shipping. Plants grown in the wild may be quite different from the same plants grown agriculturally. Methods of harvesting and weather variations in nature inevitably are different from those under controlled environments. In addition, variations in how plants are processed based on the drying and sterilizing techniques that are used have an effect on the potency of the herb. If products are not stored carefully, the inherent quality of the herb may be further compromised and it may be less effective.

In the United States, pharmaceuticals must meet a strict standard established by the FDA not only in the research and development stages but also in processing to maintain consistent standards of quality. Herbs, however, are regarded as food sources and do not come under the drug and pharmaceutical standards established by the FDA. However, many herbal manufacturers, particularly those in the United States, have adopted the FDA Good Manufacturing Practice (GMP) criteria for manufacturing, packing, and handling human food in the preparation of herbal medicines.

The GMP establishes federal guidelines for plant management, disease control, harvesting, storage, and distribution of foods, and herb manufacturers that meet these standards are authorized to display the GMP label on their products. Herbal products also provide supplement facts, active ingredients, and serving recommendations. The Dietary Supplement Health and Education Act (DSHEA) also requires dietary supplements (among which herbs are included) to carry this statement on the label: “This product has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.” These measures have been taken to ensure the safety of herbal products and should be reviewed with each patient and practitioner who recommends or reviews a patient’s use of herbs.

Evidence Grading

In an effort to evaluate herbal therapy, several systems have been developed to provide clinicians with methods for understanding the mechanism, use, and potential harmful effects of herbal therapy using an evidence-based system.

Natural Standard (www.naturalstandard.com) is a complementary medicine grading system founded by clinicians and researchers from more than 100 academic institutions. It is designed to provide clinicians with the latest scientific data and expert opinion on complementary therapies, including herbal therapies, and is based on the Jadad scoring system of study quality (Jadad et al, 1996). A Jadad score of 0 to 5 is assigned, with 5 being the highest-quality study. In addition, a “magnitude of benefit” score is given to evaluate how strongly a study is able to show the benefit of a therapy. Natural Standard determines magnitude of benefit by subtracting the mean of the treatment group from the mean of the placebo group.

Taking into account the Jadad score, the magnitude of benefit, and other factors, Natural Standard grades the treatment. Grades reflect “the level of available scientific evidence in support of the efficacy of a given therapy for the specific indication.” Treatments are also graded based on “evidence of harm.” The Natural Standard’s evidence rating scale is graded on a scale from A to F. A grade of “A” indicates that there is strong scientific evidence of the benefit of the therapy, whereas an “F” suggests that there is strong negative scientific evidence.

Healthnotes’ The Natural Pharmacy (2006) was designed as a reference for both practitioners and consumers. It evaluates the current state of the evidence in regard to herbs and nutritional supplements. This text is a culmination of the research contained in 25,000 articles in more than 600 peer-reviewed journals. In addition, chapters are contributed by a team of medical doctors, pharmacists, naturopaths, and chiropractors—all of whom have been in clinical practice. New editions of this manual are updated continually with the latest evidence-based information and recommendations. The Natural Pharmacy (2006) is notable for providing evidence that is based almost solely on human studies, as well as on information that specifically addresses contraindications to any herb or supplement. In addition, each recommendation is based on evidence derived from clinical, double-blind, meta-analyses or traditional empirical studies.

The Rakel Evidence Versus Harm Scale (Rakel, 2007) utilizes the Strength of Recommendation Taxonomy (SORT) (Ebell, Siwek, & Weiss, 2004) to rate the scientific evidence of a variety of integrated medicine treatments. The scale evaluates the strength of the evidence along with the evidence of potential harm. The evidence of benefit is graded from A to C, with “A” indicating that the evidence is “based on consistent, good quality, patient-oriented evidence.” On the other hand, the potential harm of a therapy is graded from 1 (little or no risk of harm) to 3 (potential to result in death or permanent disability). An A rating represents that evidence is culled from systematic reviews or meta-analyses. It also incorporates Cochrane reviews of high-quality, randomized controlled trials that resulted in clear recommendations.

Cochrane Database of Systematic Reviews (Cochrane Collaboration, n.d.) was created to help health-care providers keep up with and evaluate relevant scientific evidence. The Cochrane Collaboration produces reviews of evidence and creates a database of health-care interventions. The quality of the studies included in a review is evaluated using specific, predefined criteria. Most Cochrane reviews are based on randomized controlled trials and are statistically summarized into meta-analyses, showing a more thorough validation of clinical effect. Cochrane is considered one of the best sources of reliable evidence for and against specific treatments for specific conditions.

The German Federal Institute for Drugs and Medical Devices Commission E is a federal organization formed in 1978 to determine the efficacy and safety of herbs and supplements sold in Germany (National Institutes of Health, National Cancer Institute, n.d.). The commission is a multidisciplinary team of scientists, physicians, pharmacists, and herbal medicine experts who together review and analyze available data and form clinical recommendations based on the current evidence. To date, more than 300 herbs have been included in the recommendations and have been approved for clinical use in Germany.

Recommendations are published as monographs for each herb. Monographs include all pertinent botanical data, an explanation of mechanism (pharmacodynamic and pharmacokinetic action), and a complete therapeutic index (indications, contraindications, side effects, drug interactions, dosing, and duration). Additionally, the monographs include traditional uses, unapproved uses, and a summary of evidence. Commission E monographs are considered authoritative by experts in the field and have been reviewed for completeness and accuracy by the American Botanical Council (American Botanical Council [ABC], 2009).

The ABC is a nonprofit educational and research organization dedicated to the science of herbal medicine (American Botanical Council, 2009). It looks at evidence from both modern scientific and traditional perspectives. The ABC is comprised of an advisory council of experts and is affiliated with several natural medicine health science institutions and organizations. It maintains comprehensive databases; publishes a peer-reviewed journal (Herbalgram); and provides commentary, additions, and, in some cases, editor’s notes for correction on all Commission E monographs. Although specific herbal indications by Commission E are not based on a true evidence-graded system, the ABC considers them as having strong supportive evidence for inclusion within the context of Herbalgram.

Hypertension

CPM Therapy	Natural Standard	Healthnotes	Rakel	WHO	Commission- E
Acupuncture	Grade C			Category 1 (Essential & Primary HTN)
Diet/Exercise	Grade B (Qi gong/yoga)		A1
Mind-Body	Grade B		B1
CoQ10	Grade B	3 Star	B2
Fish oil (mixed EPA/DHA)	Grade A	3 Star	A2		Approved component
Calcium	Grade B	2 Star
Magnesium		2 Star
Garlic	Grade C	2 Star			Approved
Hawthorn (Crataegus spp.)	Grade D	1 Star	B1		Approved
Cochrane Summary:• Review of calcium demonstrated positive effects but reviewers concluded data was insufficient due to poor study design and lack of heterogeneity between trials, leading to bias.• Garlic review for peripheral arterial occlusion was inconclusive. No statistical significance in walking distances was seen.

*Tables not inclusive.

Clinical Implications for Practice: Hypertension

Herb/Supplement	Indications	Contraindications	Dose	Rakel Harm Scale
CoQ10	HTN	None	90–150 mg/qd	2
Fish oil (mixed EPA/DHA)	HTN	Coagulation (bleeding) disorders	3 g/qd	2
Calcium	HTN	Hypercalcemia, constipation, kidney stones, prostate cancer	800–1,500 mg/qd
Magnesium	HTN	Caution in renal insufficiency	250–350 mg/qd
Garlic	Hyperlipidemia	AllergyCaution with warfarin (WHO)	1–3 g/qd
Hawthorn (Crataegus spp.)	Cardiac insufficiency/heart failure	Allergy	Varies with form: tincture 35% ETOH 406 mL/TID Tea: 5–10 g/TID	1

*Dosing recommendation compiled from Healthnotes, Natural Standards, ABC Clinical recommendations, and Bastyr University clinical monographs.

The two evaluation systems that may be the most valuable to the primary care provider are Natural Standards and Rakel, since they provide a broad approach to recommended interventions for a given condition. Healthnotes, however, provides the most comprehensive data on individual supplements and serves as an expert source for clinical investigation of an herbal product. The Cochrane Database contains high-quality data reviews but is clinically the least useful for complementary and alternative medicine (CAM) evaluation because of its specificity in regard to what is reviewed.

Matrix for Evidence Grading

The following is a simple chart for comparing the various evidence-grading criteria for the treatment of several disorders.

Evidence supports the inclusion of mixed fish oil, CoQ enzyme 10, and probably calcium in the treatment of both essential and primary hypertension. Clinical consideration should also be given to incorporation of both acupuncture and mind–body techniques in addition to diet modification and exercise. Due to the broad systemic effects and safety profile of these interventions, supplemental therapy should be used to help control hypertension, prevent progression to advanced stages, and potentially decrease poly-pharmacy use.

Hyperlipidemia

CAM Therapy	Natural Standard	Healthnotes	Rakel	WHO	Commission- E
Acupuncture				Category 2
Diet/Exercise	Grade B (Yoga)		A1
Mind-Body	Grade C
Plant sterols	Grade A	3 Star	A2
Psyllium	Grade A	2 Star	A2		Approved as fiber for constipation and diarrhea
Fish oil (mixed EPA/DHA)	Grade A	3 Star	A2		Approved component
B vitamins	Grade A	3 Star (Niacin, B3)	A2
Guggul (Commifora mukul)	Grade C	3 Star			Not approved
Fenugreek (Trigonella foenum-graecum)	Grade C	2 Star			Approved as appetite stimulator and digestive aid
Red yeast rice (Monascus purpureus)	Grade A	2 Star
Garlic	Grade B	2 Star			Approved
Cochrane Summary:• Omega-3 (fish oils) have strong evidence for lowering triglycerides and VLDL• No conclusive data on dietary intervention for familial hyperlipidemia• Plant sterol review currently pending• Garlic protocol currently pending

*Tables not inclusive: Commission E approval is specific per condition unless otherwise noted.

Clinical Implications for Practice: Hyperlipidemia

Herb/Supplement	Indications	Contraindications	Dose	Rakel Harm Scale
Plant sterols	Hyperlipidemia	None(Caution in estrogen receptor + neoplasms)	2–3 g/qd	2
Psyllium	Hyperlipidemia	Caution in IBS	10–30 g/qd
Fish oil (mixed EPA/DHA)	HyperlipidemiaHTN	Coagulation (bleeding) disorders	3 g/qd	2
Niacin (B3)	HyperlipidemiaDepression	Active liver disease, active ulcer or arterial bleeding	1 g/tid	2
Guggul (Commifora mukul)	Hyperlipidemia	Allergy, coagulation (bleeding) disorders and pregnancy/lactation	25 mg/bid (standardized extract guggulsterone)
Fenugreek (Trigonella foenum-graecum)	Poor digestion Hyperlipidemia Diabetes I & II	Early pregnancy, hyperchlorhydia/GERD, and active peptic ulcer	Tincture: 30% ETOH, 3–5mL/tid
Red yeast rice (Monascus purpureus)	Hyperlipidemia	Pregnancy and lactation	1200 mg/bid
Garlic	Hyperlipidemia	AllergyCaution with warfarin (WHO)	1–3 g/qd

*Dosing recommendation compiled from Healthnotes, Natural Standards, ABC Clinical recommendations, and Bastyr University clinical monographs.

There is strong evidence for diet and lifestyle modifications, combined with appropriate supplementation, for treating high cholesterol. Psyllium husk as fiber and mixed EPA/DHA fish oil should be considered as standard treatment due to the impact on both cholesterol and blood pressure. Niacin (B3) is available in prescription form. Red yeast rice, garlic, and guggul can be considered as adjuncts, as these herbs also impact blood glucose levels and hematological clotting parameters. The cholesterol-lowering properties of red yeast rice are largely due to fungal metabolites known as monacolins, one of which, monacolin K, is identical to lovastatin and has been found to be effective at lowering cholesterol with minimal side effects (Becker, Gordon, Halbert, & French, 2009). However, guggul has been associated with elevated liver function tests and acute hepatitis (Grieco, Miele, Pompili, & Biolato, 2009). Therefore, the practitioner should still screen patients for liver abnormalities prior to starting these herbs and monitor them during therapy. Although the risks are lower, product uniformity, purity, labeling, and safety cannot be guaranteed, and it is the responsibility of the provider to solicit information from a particular company regarding their production process to ensure patient safety.

Challenges to Using an Evidenced-Based Model

Although evidenced-based medicine (EBM) is currently considered the “gold standard” of care for practice, using blind randomized controlled trials (RCTs) that are based on a statistical analysis to validate and determine efficacy of a particular medication or medical procedure may not be the most effective way to evaluate a holistic approach to care, particularly when it is deemed the only acceptable basis for health care. The value and role of the doctor is undermined, the psychological and social aspects of medicine are neglected, and sole reliance on EBM presents the danger of creating a utilitarian orthodoxy (Williams & Garner, 2002).

There are three factors that become problematic when evaluating CAM therapies, particularly herbal therapy. The first is that the Western scientific method applied to drug-based or pharmaceutical research is designed to measure single chemical components in relation to outcome. This model is used in the evaluation of Western herbs, but it does not reflect the philosophy and treatment parameters used in Ayurvedic or traditional Chinese medicine, which use the whole plant and consider only its nature and effect at reducing or enhancing the body’s balance. Second, definitions used in CAM pose a unique problem for EBM researchers. The scientific method cannot be used to measure things that have yet to be physically defined by Western science. The concepts of qi or prana, representing universal energy or life force, are one example, but other concepts, such as yin and yang, vatta, kapha, and pita, also illustrate the complexity of analyzing concepts that do not have equivocal biomedical definitions. And the third challenge is that outcomes in traditional Chinese medicine and Ayurvedic medicine are determined largely by empirical, rather than experimental, diagnostic measures. Changes in a person’s tongue coat and pulse or a change in symptoms often are enough to satisfy clinical management and evaluate the efficacy of an herbal formula.

Diabetes mellitus type 2 can serve as an example of the fundamental differences between these systems in disease diagnostic and treatment criteria. In biomedicine, diabetes is seen as a specific set of characteristics and laboratory markers. A fasting blood glucose of less than 126 mg/dL on more than one occasion would validate a diagnosis of this disease (Joslin Diabetes Center, 2007). In Oriental medicine, diabetes is comprised of seven possible patterns, none of which would be called “diabetes” and each of which would have a different parameter for the selection of an herbal treatment (Flaws & Lake, 2005).

In traditional CAM modalities, herbs are prescribed based on the phenotypical manifestation of the disease and the constitutional expression of the patient. This is in direct opposition to the drug model of herbal prescription currently being used in biomedicine. This model is based solely on the pharmacological understanding that relies, “perhaps erroneously, on a preference for empirical evidence gained from controlled clinical trials regardless of the underlying theory of disease and healing” (Tonelli & Callahan, 2001). The drug-based model of herbal medicine is a reductionist view, and it purposely ignores thousands of years of observational and empirical evidence that has been validated within many traditional medical models.

In a review of 19 randomized controlled trials that utilized ginseng, the authors found no mention or consideration of the traditional patterns used in TCM to determine appropriateness of herb selection (Yan, Engle, He, Jiao, & Gu, 2009). Ginseng, specifically Panax ginseng, or Ren Shen, is an herb traditionally used to support specific symptom manifestations of “qi deficiency,” which is characterized by symptoms like fatigue, gas or bloating and loose stools, weakness, cold, sweating, bleeding, and prolapsed organs (Kaptchuk, 2000). In addition, several of the 19 trials utilized a different species of ginseng, which traditionally have different properties and applications. Analyzing the results as if looking through the lens of Oriental medicine theory, the reviewer found that positive results of ginseng were seen only in the conditions that corresponded to the traditional Chinese concept of qi deficiency. This demonstrated that biomedical evidence-based research, directed by traditional theory, may have a totally different outcome. Research that can employ these concepts can both improve study design and help validate traditional theory within a biomedical context.

Another challenge in herbal therapy is the use of polyherbal formulations common to traditional medical systems. Using the same type of analysis as just mentioned for a single herb, the criteria for evaluating a polyherbal formula would have to take into account numerous factors based on the traditional medicine model. Thus, patients who just want to take an herbal formula for a particular problem without the assistance of a trained herbalist are faced with the ongoing dilemma of deciding what herbal remedy(ies) are best suited for them.

COMMON HERBS

Today it is possible to find a health section with a variety of herbal remedies in most grocery or supplement stores in communities throughout the United States. These remedies are available without prescription or any particular guidance except what the consumer may gather from the label or other sources that may or may not be reliable. Therefore, it is very important that nurse practitioners, nurses, and other health professionals be aware of herbal therapy and be able to distinguish how they are to be used. For the purposes of this chapter, herbal therapy for a particular disease state will be discussed in three primary categories: Western, traditional Chinese medicine (TCM), and Ayurvedic medicine, along with the criteria for dispensing.

There are several other medicinal practices that use herbs to heal, for example, homeopathic herbal therapy, Bach Flower remedies, and Unani medicine. However, the purpose here is not to teach any particular style of herbal medicine but rather to use examples from TCM and Ayurvedic medicine to illustrate the differences in how herbal therapy is used and to encourage practitioners interested in using or recommending these herbs to understand the differences in order to refer to or consult with an herbalist, naturopath, TCM, or Ayurvedic practitioner whenever herbal therapy is considered. This section is not meant as a recommendation for prescribing to clients but rather as a guideline and reference.

Western Herbs

The most common symptoms for which people use herbs are anxiety, difficulty in sleeping, depression or dysphoria, and forgetfulness and confusion. Like pharmaceutical drugs, some herbs may be beneficial for multiple symptoms.

Anxiety

Kava (ava, awa, kava-kava, kawa, kew, tonga) comes from the dried root of Piper methysticum, a member of the black pepper family. This shrub is native to the Pacific Islands and is commonly used by Hawaiians as a celebratory drink, just as alcohol is used in the West. But unlike alcohol, kava does not stimulate aggression and is not associated with hangovers. It is prepared as a drink from the pulverized root but also comes in tablet, capsule, and extract forms. This herb has been studied in human subjects and appears to have more than one active component that produces its effects. One component acts as a local anesthetic when chewed and produces intense muscle relaxation. It appears to act on the limbic system to suppress emotional excitability and produce mild euphoria without affecting memory or cognition. In therapeutic drug trials, kava seems to act on the gamma-amino butyric acid (GABA) receptor, like the benzodiazepines, and like the benzodiazepines, kava can reduce seizure activity and be used for sedation. Dose varies, depending on the form and the amount of active components retained in the preparation; studies indicate that 70 to 240 mg daily is the adult dose. Pharmacokinetics data are unavailable for kava, but users seem to prefer divided doses, usually 3 times a day. Unlike the benzodiazepines, it does not seem to produce dependence, but the studies are very limited.

When used short-term, kava seems to produce few adverse reactions, although these might include decreased motor reflexes, diminished judgment, and visual disturbances. Chronic use may decrease platelet count and cause dry, flaky skin; reddened eyes; shortness of breath; pulmonary hypertension; and weight loss. Because it seems to act like the benzodiazepines, it may potentiate alcohol, other sedatives, and GABA-nergic drugs such as phenobarbital and benzodiazepines. At higher doses, kava seems to block dopamine receptors and therefore to improve psychotic levels of anxiety as well as interact with antipsychotic drugs. It should not be used in pregnancy or when breastfeeding because its safety is uncertain during pregnancy (Volz, 1997). The FDA has issued a warning regarding the use of kava supplements leading to severe liver damage and the National Institute of Health National Center for Complementary and Alternative (NCCAM) suspended all NCCAM-funded studies of kava after the FDA warning (nccam.nih.gov/health/kava).

Mugwort (felon herb, wild wormwood, St. John’s plant) comes from the root of the Artemisia vulgaris plant. It should not be confused with St. John’s wort, which comes from a different plant. The name may have derived from the fact that it was commonly used to flavor beer before the use of hops. It is available as dried leaves and roots, fluid extract, tincture, or as a tea infusion, but only the root is used for its active constituents, which are believed to be from its volatile oil and acrid resin and tannins. It is a very versatile herb but its medicinal use lies more in its value as a nervine and emmenagogue (hastening menstrual flow when combined with pennyroyal and southernwood). When taken for anxiety and sedation, the usual dose is 5 mL of tincture 30 minutes before bedtime, although there are few studies that support this use. It does have an anticholinergic effect, observed in animal studies. In a recent study of mugwort, elements of alkaloids, coumarins, flavonoids, saponins, sterols, tannins, and terpenes were found with concentration-dependent (0.3 to 10 mg/mL) relaxation of spontaneous jejunum contractions, and a combination of anticholinergic and Ca(2+) antagonist mechanisms were found supporting its use in hyperactive gut and airway disorders, such as abdominal colic, diarrhea, and asthma (Khan & Gilani, 2009). This accounts for its use in the treatment of gastrointestinal problems and menstrual cramps.

One of the unique uses of mugwort comes from TCM, where it is applied topically and burned to treat pain and tonify deficient conditions. It is also used extensively in Japanese acupuncture as well as TCM, comes in several different forms, and is employed in a variety of ways (e.g., as a stick, directly on the skin, or by using a medium—holder, box, ginger—to hold it over acupuncture points or pain locations with or without needles). Adverse reactions to mugwort when taken internally include anaphylaxis and induction of premature birth or miscarriage or contact dermatitis if used topically. It should not be used during pregnancy or breastfeeding or by people who have clotting abnormalities or allergies to hazelnuts. Because there are no controlled studies on mugwort, no therapeutic claims can be made.

Passionflower (Passiflora, passion vines) has been used by many cultures as an herbal remedy for the treatment of anxiety. However, there are over 500 species of this flowering plant, which makes clinical trials inconsistent because they use different species. Two of the most common species used today are P. incamata (maypop), commonly used in Native American cultures, and P. edulis (passion fruit), used extensively in Central and South America. Despite the different species, passionflower is generally considered safe but it can cause drowsiness, dizziness, and confusion in some patients. As a dried herb, passionflower is generally well tolerated at 2 g, 3 to 4 times a day, and as an infusion of 2 g in 150 cc water 3 to 4 times a day. The tincture ratio is 1:5 (g/mL).

Insomnia

In addition to mugwort, melatonin, valerian, passionflower, and chamomile are used for sedation. Melatonin and valerian are discussed here. Melatonin is not an herb but a hormone produced by the pineal gland. Because it is a hormone, exogenous consumption over extended periods of time may act as negative feedback and suppress normally secreted melatonin. Melatonin is produced when serotonin is broken down in the pineal gland with the help of two enzymes: arylakylamine-N-acetyl transferase (AA-NAT) and hydroxyindole-O-methyl transerase (HIOMT). It is the AA-NAT that seems to be the rhythm enzyme, because when it is elevated, melatonin is elevated. Unfortunately, AA-NAT is rapidly destroyed and the production of melatonin is reduced by light.

Under physiological conditions, melatonin is released during the fourth stage of sleep along with prolactin and growth hormone. It is used to induce sleep via the same GABA-nergic mechanism as benzodiazepine sedatives and is widely used to prevent and treat jet lag. A single study identified the utility of melatonin in elderly people to help induce and maintain sleep, probably because the elderly usually have some degree of melatonin deficiency under normal circumstances. Used long-term, it can increase prolactin secretion, which can decrease luteinizing hormone, progesterone, and estradiol levels. Long-term use can also reset the sleep-wake cycle and contribute to disturbed sleep cycling.

Melatonin is available in tablets, capsules, extended-release capsules, and liquid forms. For difficulty in getting to sleep, 1 to 5 mg taken at bedtime is the usual dosage, but it should not be used more than three nights a week. In the elderly, the dosage is usually 1 to 2 mg taken 2 hours before bedtime. To prevent jet lag melatonin (2 mg to 5 mg) is taken at the target destination bedtime (10 PM to midnight) for 3 days prior to departure and for three days’ post-travel (Morgenthaller et al., 2007). Adverse reactions include altered sleep patterns, confusion, headache, tachycardia, and hypothermia. Melatonin potentiates benzodiazepines. It also potentiates succinylcholine, thereby increasing the blocking action, which can be dangerous. Its content of active drug may vary widely in commercial melatonin, making it difficult to determine correct dosages (Brzezinski, 1997; Fetrow & Avila, 1999).

Valerian (all-heal, amantilla, setewale capon’s tail, herba benedicta) is derived from the roots of Valeriana officinalis. It seems to inhibit uptake and increase presynaptic release of GABA; however, it is not readily absorbed, is highly unstable, and readily decomposes. Therefore, availability of the active drug is minimal when it is taken orally. German Commission E suggests valerian root for anxiety, restlessness, and difficulty in getting to sleep. Because of the instability, dosages are difficult to determine, especially among different brands. Usually 400 to 900 mg of extract at bedtime or 1 teaspoon of dried herb in tea several times a day is useful in inducing sleep. Commercial valerian tea at bedtime acts more as a relaxant and permits the person to fall asleep spontaneously. Valerian has no adverse reactions when used at the recommended level; however, overdosage at 2.5 g or more can cause cardiac disturbance, excitability, headache, insomnia, and nausea. It can potentiate alcohol and other CNS depressants if taken in large amounts. Because clinical trial studies are limited, it should not be used by pregnant or breastfeeding women, children, or patients with impaired liver function.

Depression

The popular media have touted the benefits of St. John’s wort for depression, contributing to its great popularity. Kava, mugwort, and DHEA have also been used to treat mild depression. Because kava and mugwort have already been discussed, St. John’s wort and DHEA are covered here.

St. John’s wort is obtained from the tops and flowers of the Hypericum perforatum plant, which is common all over Europe, Asia, and the United States. The exact mechanism of action is still unknown but assumed to be related to inhibition of serotonin presynaptic uptake. Early studies showed inhibition of monamine oxidase (MAO) type A and minimally type B; however, this was later attributed to contaminants. In studies to determine effective dosages, St. John’s wort was effective at blocking serotonin reuptake at much higher doses than could be achieved. St. John’s wort also seems to act on the benzodiazepine receptor of GABA, inhibit norepinephrine reuptake, and block acetylcholine, as well as inhibit stress-induced corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), and cortisol and increase nighttime release of melatonin. Some reports have also indicated antiviral activity, including retroviruses (Chavez, 1997). With such a wide range of receptor activity, it is not surprising that it is used to treat depression, enuresis, gastritis, hypothyroidism, insomnia, kidney disorders, scabies, hemorrhoids, wounds, HIV infection, and Kaposi’s sarcoma.

Most commonly, St. John’s wort is used to relieve mild to moderate depression, less than would meet the criteria for a major depressive episode, or dysthymia. Therefore, it seems most effective for those who have sadness and lesser degrees of depression. When used for clinically diagnosed depression, St. John’s wort is relatively ineffective and may dishearten or demoralize the person who is trying to avoid using more potent antidepressants. For standardized, commercially prepared St. John’s wort, the usual dosage is 300 mg taken 3 times daily; because of the delayed neuroreceptor response, it may take 4 to 6 weeks to determine effectiveness. When St. John’s wort is used as a tea, it requires 2 to 4 g of tea steeped in 1 to 2 cups of boiling water for 10 minutes and taken daily to be effective within 4 to 6 weeks.

There are a few adverse reactions, attributable to the anticholinergic blockade, including constipation, dry mouth, dizziness, gastrointestinal (GI) upset, restlessness, and insomnia. St. John’s wort interacts with MAO inhibitors (MAOIs), tricyclic antidepressants, and serotonin reuptake inhibitors (SRIs) to cause serotonin syndrome. St. John’s wort may decrease digoxin, phenytoin, and cyclosporine levels leading to therapeutic failure. Wafarin’s effectiveness may be decreased. St. John’s wort may lead to loss of virologic response and possible resistance to indinavir and other protease inhibitors. St. John’s wort should be stopped 2 weeks prior to the beginning of treatment with the chemotherapy agent irinotecan and is contraindicated during therapy. St. John’s wort reduces the effectiveness of oral contraceptives, increasing the risk of unintended pregnancy. Because there are inadequate studies available, St. John’s wort should not be taken by children or pregnant or breastfeeding women. The primary care provider who determines that the patient meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) criteria for depression might advise the client to consider taking another kind of antidepressant if there are minimal results in 3 to 4 weeks.

Dehydroepiandrosterone (DHEA) is a steroid precursor found in plants from the yam family and is secreted by primate adrenal glands. Physiologically, DHEA is converted into androgens and estrogens (depending on the person’s gender) and may raise the blood level of a precursor of the human growth hormone. There are many benefits attributed to DHEA, including immune enhancement and prevention of osteoporosis as well as antineoplastic, antiaging, and antidepressant benefits. Because few studies on humans are available, exact pharmacokinetics and pharmacodynamics are not known, but it does not seem to be readily absorbed through the GI tract. Similarly, it is difficult to determine dosage for the particular effect that is desired. At present, 50 mg daily is commonly used for depression, but serum levels should be checked, with an expected level of 3,600 ng/mL for men and 3,000 ng/mL for women. When used for depression, DHEA may have a 4-week lag time before an effect on depression is seen (Wolkowitz, 1997).

Because DHEA is a hormone-like drug, it may give negative feedback to the adrenal glands, thereby reducing production of endogenous hormones. Adverse reactions to be expected with an androsteroid include aggressiveness, hirsutism, insomnia, and irritability. Patients with hormone-sensitive cancers should be discouraged from using DHEA, as should pregnant and breastfeeding women. DHEA is likely to interact with other hormone therapy, such as estrogen replacement therapy. DHEA may be used by athletes to increase muscle mass, but it is a banned substance in college athletes by the National Collegiate Athletic Association (NCAA).

Confusion and Forgetfulness

Confusion and forgetfulness, along with other cognitive impairments, are often seen in dementia, depending on the root cause of the dementia. Additionally, people who are concerned about benign forgetfulness take herbs both to improve their cognitive abilities and to prevent memory problems. Common herbs used include ginkgo, ginseng, chaparral, and galanthamine. Ginseng and ginkgo, which are often taken together or combined in a single preparation, are used here as exemplars.

Ginseng (American ginseng, Asian ginseng, Chinese ginseng, five-fingers, Japanese ginseng, Jintsam, Korean ginseng, ninjin, seng and sang, schinsent) is from the Panax quinquefolius plant, especially the root. Asian ginseng should not be confused with Siberian ginseng, which seems to bind with estrogen receptors. Asian ginseng is usually dried or cured and is highly valued; American ginseng undergoes less processing and is not as widely sought.

Several compounds are biologically active, producing different effects. The mechanisms of action are not understood, but ginseng is said to have differing effects depending on the active component involved: anticonvulsant, analgesic, and antipsychotic effects; CNS-stimulating, anti-fatigue, hypertensive, and stress ulcer exacerbation; improvement of cardiac function; depression of cardiac function; antiarrhythmic activity; reduction of cholesterol and triglycerides; decrease in platelet adhesiveness; impaired coagulation; and increased fibrinolysis. The presumed focus of action is in the adrenal gland, although there are claims in popular literature that ginseng decreases thymus gland activity. Consequently, it is used as a sedative, aphrodisiac, antidepressant, hypnotic, and diuretic. It is also used to improve stress resistance, stamina, work efficiency, concentration, mental performance, and general feelings of well-being. Some studies found it decreased fasting blood sugar and hemoglobin to such a degree that some diabetics no longer needed insulin.

Ginseng comes in capsules, tea bags, and extract, and in some places ginseng root can be bought in bulk, such as in Asian markets. In processed form, however, it is difficult to standardize. Used for illness, it is usually taken at 0.5 to 2 g a day of dry root or 200 to 600 mg of extract daily in divided doses. For dementia in frail elderly people, it is usually taken at 0.4 to 0.8 g of dry root daily. There seems to be a lag time in achieving maximum effectiveness—up to 90 days to see full results. It seems to have minimal and mild adverse reactions, including dizziness, drowsiness, headache, and insomnia, although chest pain, diarrhea, hypertension, impotence, nervousness, agitation, palpitations, nausea, and vomiting have also been reported. It may potentiate insulin and oral hypoglycemics, and it interacts with MAOIs to cause headaches, tremors, and mania. There are more studies of ginseng than of other herbs to identify its effectiveness, yet the pharmacodynamics are elusive. The German Commission E considers ginseng to be an effective drug (Sorensen & Sonne, 1996; Wesnes et al, 1997).

Ginkgo (Ginkgo biloba) is an extract from the leaves of the ginkgo tree, with the toxic ginkgolic acid removed. It is available in many forms, including tablets, capsules, sublingual sprays, and even in juices and foods. It is believed to stimulate prostaglandin synthesis and thereby cause vasodilatation, increasing tissue perfusion and cerebral blood flow. Ginkgo has been used for centuries in Asian countries to improve mental alertness, and today is used in the treatment of cerebrovascular disease and peripheral vascular disease. Additionally, it is popularly taken to improve thinking ability, concentration, and memory.

Dosage for confusion and dementia symptoms is 120 to 240 mg daily in two or three divided doses. For vascular disease, 120 to 320 mg daily has been used, but there is a 4- to 6-week lag time before maximum effect is obtained. Adverse reactions include diarrhea, headache, nausea, vomiting, bruising, excessive bleeding, and seizures in overdose. Trying to use ginkgo leaves to make a home remedy is potentially dangerous because of the ginkgolic acid and the difficulty of determining the quantity of active ingredients. Because it reduces platelet-activating factor and erythrocyte aggregation, it should not be taken with anticoagulants or antiplatelet medications. The German Commission E approved ginkgo for the treatment of dementia and peripheral arterial occlusive disease (Fetrow & Avila, 1999).

Gastrointestinal Problems

Probably the most common use of home remedies is for GI upset, such as constipation, diarrhea, indigestion, and nausea. Because the underlying causes of these complaints are also common, the herbal medications used for them overlap. The herbs most often used for constipation are also incorporated into commercial OTC medications: cascara, castor bean, and senna.

Cascara sagrada is dried bark from the Rhamnus purshiana tree (found primarily in the Pacific Northwest and from Canada to California) that has been dried and aged for at least 1 year and up to 3 years. Cascara acts by increasing the smooth muscle tone of the large intestine and thus peristalsis. The FDA has approved cascara as a safe and effective laxative to be sold OTC. It is available in an extract or extract capsules. Although it is very safe, it may produce such adverse reactions as abdominal cramping, diarrhea, fluid and electrolyte imbalance, steatorrhea, vomiting, and vitamin and mineral deficiencies in long-term use. Cascara can be used in pregnancy but should not be used by breastfeeding women because it is excreted in milk and may cause serious diarrhea in the infant. Because a person can become dependent on cascara, it should be limited to short-term use.

Senna comes from the leaves and pods of the Cassia shrub. It is the active ingredient in OTC medications such as Senokot, Senokot-S, and Senolax and comes in capsules, tablets, and syrup. Dried senna leaves can also be made into a tea by adding 100 g of leaves to a liter of boiling water and steeping for 10 minutes. Sliced ginger or crushed coriander leaves make the tea more palatable. When senna enters the intestinal tract, bacteria convert it into a biologically active agent. Senna increases peristaltic action in the lower bowel. The usual adult dosage is about 340 mg taken at bedtime or 0.5 to 1 dram of syrup. Adverse reactions are similar to those of cascara: abdominal cramping, diarrhea, hypokalemia, and clubbing of the fingers with chronic use. Calcium channel blockers or indomethacin blocks the diarrheal effects. It is excreted in breast milk and should not be taken by breastfeeding woman. A patient with irritable bowel, hemorrhoids, GI inflammatory conditions, or prolapsed rectum should not use senna. Like cascara, it can be overused and create a laxative dependency.

Indigestion and heartburn plague Americans, as evidenced by the large amounts of medications sold to treat dyspepsia. In addition to antacids, common household herbs can be used effectively and safely. Caraway oil distilled from dried seeds of the Carum carvi herb or caraway water made from soaking 1 oz of crushed caraway seeds in a pint of cold water for 6 hours can be used for indigestion, flatulence, constipation, and menstrual cramps. Because of its mild action, it can be given to infants for colic. The usual dosage for adults is 1 to 4 drops of oil in a teaspoon of sweetened water; and for infants 1 to 3 tsp of caraway water. The only adverse reactions reported are diarrhea and mucous membrane irritation.

Licorice root has also been used for gastric irritation and dyspepsia. Licorice comes from the dried root of the Glycyrrhiza glabra shrub and is available in capsules, tablets, liquid extracts, chewing gum, tea, and candy. Studies indicate that glycyrrhetic acid is the active element that potentiates endogenous steroids and stimulates gastric mucus synthesis. It is a soothing and mild expectorant, mild laxative, and antispasmodic. Additionally, licorice has antiarrhythmic effects, lowers cholesterol and triglyceride levels, and may cause immunosuppression. The usual dose is 200 to 600 mg tablets taken daily for 4 to 6 weeks or licorice tea simmered for 5 minutes and taken 3 times a day after eating. Reported adverse reactions include mineralocorticoid effects of headache, lethargy, sodium and water retention, hypokalemia, and hypertension, as well as, in overdose, muscle weakness, heart failure, and cardiac arrest.

Licorice interacts with many medications: antihypertensives, diuretics, corticosteroids, digoxin, loratadine, procainamide, quinidine, and spironolactone. A patient who is taking licorice regularly should be warned against excessive and chronic use, especially when it is combined with diuretics. Licorice candy does not actually contain the herb but rather licorice flavoring, usually from anise oil.

Papaya enzymes, available in tablets and chewable tablets, are frequently used to prevent or treat common heartburn, although it is not effective with gastroesophageal reflux. Papaya is a proteolytic enzyme in the leaves, seeds, pulp, and latex of the Carica papaya tree. The clinical trials with humans have mostly focused on treating inflammation from trauma and surgery. It also has been used effectively as a debriding agent and for intradisk injections in patients with herniated disks. The dosage for inflammation is 10 mg 4 times a day for 1 week. Dosage for dyspepsia is variable and not standardized, but usually 4 to 5 tablets are taken immediately after eating. Adverse reactions are uncommon and limited to dermatitis, hypersensitivity, decreased heart rate and CNS activity, and perforation of the esophagus with excessive ingestion. No drug interactions have been reported. There have been no studies with pregnant and breastfeeding women, so it is safest to avoid use during pregnancy and breastfeeding.

Pain

Joint pain, soft tissue pain, and headache are frequent problems that people often treat with herbal and home remedies. There is little overlap in medications to treat each of these kinds of pain. Two products currently in health food stores are glucosamine and chondroitin, both of which are not herbal.

Glucosamine has been widely used for its anti-inflammatory and cartilage repair ability and is supported by in-vitro studies in the management of osteoarthritis. Glucosamine is thought to stimulate cartilage production and enhance rebuilding of damaged cartilage and has been demonstrated to provide relief of pain and rapid restoration of mobility and range of motion. There are two forms of glucosamine currently being sold as an herbal supplement: glucosamine sulfate (GS) and glucosamine HCL (GH). Both contain similar or equal concentrations of glucosamine, but GS has more salt content and GH has slightly higher concentrations of glucosamine. Although the effects are similar, glucosamine sulfate has been used in the majority of clinical trials; glucosamine HCL is often combined with other materials like chondroitin or MSM.

Glucosamine is a naturally occurring component found in shellfish; however, most of what is sold in the United States is synthetically made. It is sold under such names as Arth-X Plus, Glucosamine Mega, Joint Factors, and Nutri-Joint, in capsules or tablets in a range of dosages, so the upper limit advised is 1.5 g per day and the source an organic natural product. It has very few side effects and there is only rare occurrence of symptoms like constipation, diarrhea, drowsiness, headache, heartburn, nausea, and rash. There have been no drug interactions reported. Frequently, glucosamine is combined with chondroitin for greater efficacy.

Chondroitin is extracted from the cartilage of animals, often cows and pigs. It seems to stimulate chondrocyte metabolism and synthesis of collagen, improving the formation of cartilage. Other studies identified stimulation of hyaluronic acid in synovial cells in patients with rheumatic disease, resulting in increased viscosity and amount of synovial fluid. When it was used for up to 4 months, patients used much less pain medication and were doing weight-bearing exercises comfortably. Often combined with glucosamine, the dosage depends on the patient’s weight: for patients under 120 lb, the recommended dosage is 1,000 mg of glucosamine and 800 mg of chondroitin; for patients 120 to 200 lb, the dosage is 1,500 mg of glucosamine and 1,200 mg of chondroitin. Used alone, the usual dose is 800 to 1,200 mg daily, taken in either divided doses or a single dose. Adverse reactions include dyspepsia, headache, motor restlessness, euphoria, nausea, and risk of internal bleeding. Chondroitin may potentiate anticoagulants. Because there have been no studies with pregnant or breastfeeding women, chondroitin should not be used by this population.

Tumeric (curcumin) is a rhizome from the ginger family, commonly used as a spice in Indian curry. It has been used for 2,000 years to treat conditions of inflammation, particularly in the gastrointestinal system. However, today turmeric is being used extensively for the treatment of chronic pain. Tumeric in food is considered safe but may come in many forms, most commonly as a standardized powder in which the recommended doses range from 400 to 600 mg, 3 times a day. Tumeric is often combined with bromelain or piper longum (black pepper) to increase its absorption from the GI tract. However, caution is advised when tumeric is combined with these agents due to their potential secondary risk of gastritis and increased absorption of other medications.

Wintergreen oil and liniments have been deemed effective in relieving pain from muscle strains, inflamed muscles, ligaments, and joints. Usually the oil is a combination of oil extracted from the leaves and bark of Gaultheria procumbens and methyl salicylate. Although there have been no studies of the efficacy of wintergreen, it is assumed to act through counterirritation, which masks pain, or through the analgesic and anti-inflammatory effects of the salicylate. The 10% wintergreen oil is applied to the skin no more often than 3 to 4 times a day. Overgenerous application can result in salicylate poisoning from absorption into the bloodstream. People who are allergic to aspirin or who are taking oral anticoagulants should not use it.

Feverfew is an interesting herb used most often to treat headache and migraines. It has also been used for toothache, joint pain, asthma, stomachache, menstrual problems, and threatening miscarriage. Feverfew (bachelors’ button, featherfoil, Santa Maria, midsummer daisy) is extracted from the leaves of the feverfew plant, Chrysanthemum parthenium. The assumed mechanism of action is the inhibition of serotonin release from platelets. It is available in capsules, liquid, tablets, and dried leaves for tea. The feverfew research showed a decrease in the number, duration, and severity of migraines in a double-blind crossover study (Murphy, Hepinstall, & Mitchell, 1988). The average daily dose for the treatment of migraines was 543 mcg of parthenolide (the active component of feverfew); for migraine prevention, the dose was 25 mg daily of freeze-dried leaf extract. The most common adverse reactions were mouth ulcerations, hypersensitivity, and a withdrawal syndrome characterized by moderate to severe pain and joint and muscle stiffness.

Traditional Chinese Herbs

It is important to remember that traditional Chinese medicine does not isolate herbal medicine as the single remedy for any disorder but rather includes it as a part of four distinct methods of treatment that include herbal therapy, acupuncture, manipulative therapies (tui na), food, and exercise (qi-gong and tai chi). The application of herbs specifically is based on the nature and capabilities of the herb and the energies, flavors, movement, and meridian the herb affects.

The four energies in herbal medicine are cold, hot, warm, and cool. The concept was derived from years of empirical research and observation of the direct effect of taking the herb over time. If the herb is effective in the treatment of a heat condition per se, it is classified as having a cooling energy. In the most basic sense herbs can be divided into yin (cooling) and yang (heating) energies. But since temperature can be a matter of interpretation, many TCM practitioners will refer to the herbal energy as extremely warm or slightly warm and extremely cold or slightly cold.

The five flavors refer to the effect the herb has on a person’s sense of taste and are classified as pungent (or acrid), sweet, sour, bitter, and salty. Not only do the five flavors describe taste, they also exhibit properties that are medically useful. Pungent herbs can disperse and promote the flow of energy; sour herbs can constrict and obstruct; sweet herbs can slow down, tone up, and harmonize; bitter herbs can harden, dry up, and cause diarrhea; and salty herbs can soften up and promote downward movement. Often a question arises about things that are tasteless. Tasteless is still considered a flavor and tends to be classified with sweet; it can help disperse dampness and promote urination.

The four movements of herbs are upward, downward, floating, and sinking. Pushing upward means that the herb has the capacity of lifting that which can no longer be supported, for example, prolapsed organs like the uterus or rectum. Pushing downward means the herb is capable of suppressing a rebellious symptom, for example, hiccups or a cough. Floating means the herb is capable of dispersing outward, as in inducing perspiration or a purging action. And sinking means the herb is capable of promoting diarrhea and directing excess energy down. Often the movement of an herb is a combination. Herbs that push upward and those that can float have the common function of moving upward and outward, by inducing perspiration and vomiting and elevating the yang energy. While the herbs that can push downward and those that can sink have the common function of moving downward and inward and relieving symptoms like vomiting or excess perspiration or diarrhea.

Meridian routes refer to the meridians the herb can enter and move through (or pathways of energy identified in TCM that correspond to the 12 organ systems). This is important to know because two herbs with the same energy and flavor can display two different actions because their meridian routes are different (e.g., two heating herbs may have different actions—one may be better for cold lung conditions while the other may work better for cold spleen conditions).

All Chinese herbs or herbal formulas have a number of common actions, but the actions are expressed differently than in Western medication. A Western medication will be classified as an antihistamine because it blocks the effects of histamine, but a Chinese herb will be classified by its action to clear heat, stop wind, or reduce fire. And a formula will have multiple actions that are designed specifically for the patient’s condition; for example, one herb will clear lung heat, the other may transform phlegm, and another cool blood. In this way, the formula can be changed as the patient’s symptoms change. This is one argument against the prolific use of standardized formulas.

In most cases, a syndrome will have more than one symptom and cannot be treated with a single herb. Thus, the primary method of herbal therapy used in TCM is the herbal formula. Although many practitioners will use their own formulas to treat patients, most will use established classic formulas with one or two modifications. The general format for herbal formulas is the use of three or more specific herbs. The primary herb that treats the major symptom is called the king herb; the second herb, called the subject herb, will reinforce the action of the king herb as well as treat the concurrent symptoms. Then there are herbs that are added to control undesirable effects of the first two, called the assistant herb; and the fourth herb, called the servant herb, may be one that can direct the formula to the affected region and harmonize the herbs in the formula.

There are three common ways to taking TCM formulas. A decoction is considered the best method, although it is often not practical for many patients. Decoctions are made from raw herbs that are placed in a pot of water and cooked/boiled for an average of 20 minutes. The benefit of a decoction is that it is readily absorbed, takes effect more quickly, and can produce the best therapeutic effect. The second method of taking herbs is in the form of powders or granules, which can be dissolved in water. The quantity will depend on a patient’s weight. The disadvantage of a powder is similar to that of most powdered drinks: they are difficult to dissolve completely and absorption is slower. The third and most common method of taking herbs is by tablet, normally prepared by a manufacturer. The advantage of tablets is the ease of taking the medication and convenience, but they have slow absorption rates, cannot be adjusted, and their quality depends on the manufacturing process.

In general, there are three rules for taking Chinese herbal formulas. The first is timing. To get the most effect from an herbal formula it is very important to know when and how to take the herb. Some herbs are better absorbed with food while others without. In addition, in accordance with TCM theory, there are certain times of the day when the energy of a certain organ system is higher. Depending on the action of the herb, and the organ condition, taking the herb during these times will improve the effect the herb has on the organ. The second rule is that temperature should be considered, depending on the condition being treated. If treating a cold condition, the temperature of the herbal formula should be hot; and if treating a heat condition, the herb may best be taken cold. The last rule is to refrain from taking herbal formulas with tea. Tea can obstruct the movement of the herb and reduce its effect. Tea is also cold in nature and can interfere with warming herbs. And third, tea contains caffeine and can excite the nervous system, cancelling the effect of calming herbs.

CLINICAL PEARL

TCM diagnosis

Although this text does not cover TCM diagnosis or an explanation of the disorder mentioned (e.g., spleen deficiency, heart fire, etc.), the general purpose of including the differential diagnosis is to demonstrate how diverse TCM diagnosis is and how it applies to the choice of herbal medicine prescribed. Please refer to TCM textbooks to further understand TCM diagnosis.

Depending on the source, according to TCM insomnia can be caused by several conditions; heart–spleen deficiency, heart–kidney disconnect, heart–gallbladder deficiency, phlegm fire, or just indigestion from eating too late in the evening. To illustrate the rationale behind the selection of an herbal formula and how each ingredient can be modified (added or removed) depending on the patient’s clinical presentation, one of these differential diagnoses (heart–spleen deficiency) is presented here.

In TCM, insomnia is often associated with the heart because it is considered to be the place where the mind (shen) resides. And disturbances of the shen often result in the symptom of insomnia. Symptoms of a heart–spleen deficiency include sleeplessness and waking often, abdominal swelling, watery thin stools, low appetite, fatigue, impotence, night sweats, and palpitations. The treatment principle is to tone the heart and spleen and calm the mind.

Herbal Formula for Insomnia

Gui-Pi-Tang (restore the spleen decoction) is used for spleen qi deficiency with heart blood and yin deficiency, to tonify qi and blood, and to nourish the heart and strengthen the spleen. Therefore, the indications for its use are similar to those for heart–spleen deficiency: fatigue, palpitations, insomnia, poor sleep or dream-disturbed sleep, night sweats, but also anxiety, phobias, poor appetite, sallow complexion, poor memory, withdrawal, and early periods with loss of excess blood, continuous spotting, blood in the stool, and metrorrhagia.

Gui Pi Tang Ingredients

• Bai Zhu (Rhizoma atractylodis macrocephalae): 5 to 10 g; properties: aromatic, slightly acrid, nontoxic, sweet and warm; supplements the spleen and qi; dries dampness; enters the spleen and stomach channels; used in the treatment of indigestion and stomach disorders.

• Dang gui (Angelica sinensis): 12 g; properties: warm, bitter, sweet, slightly pungent; supports the liver and spleen; used as a tonic for female deficiencies and to enrich blood, promote circulation, stimulate appetite, improve muscle tone, stimulate the immune system, and moisturize dryness.

• Fu-shen (Poria cocos, a mushroom): 12 g; properties: sweet taste; used to calm the liver and heart and quiet the spirit; enters the heart, spleen, and lung channel; used for palpitations, fearfulness, and bad memory due to a frightful experience; considered a superb yin tonic.

• Gan cao (Radix glycyrrhizae or licorice root): 6 g; properties: sweet, neutral; tonifies the spleen and strengthens the qi, improving symptoms like fatigue, lack of appetite, loose stools, and shortness of breath; enters all 12 primary channels but particularly the lung, heart, spleen, and stomach; used to lessen the harsh and toxic nature of other herbs and protect the middle jiao (the primary source of digestion) and enhance the overall effects of a formula; often used with honey to treat drug poisoning or Xing Ren (Semen armeniacaae amarum) for lead poisoning.

• Huang qi (Radix astragali membranacei or astragalus): 20 g; properties: sweet, slightly warm; enters the lung and spleen channels; tonifies qi and blood; used to treat symptoms of spleen deficiency, can raise yang, tonify the wei qi (protective qi), treat spontaneous sweating, promote urination, and expel pus.

• Long yan rou (Arillus euphoriae longanae or flesh of the longan fruit, translated as “dragon eye flesh”): 15 g; properties: sweet and warm; enters the heart and spleen channel; actions are primarily to tonify the blood.

• Suan zao ren (Ziziphus jujuba, commonly called sour jujube seed): 10 to 18 g or 1.5 to 3 g in powder at bedtime; properties: the temperature and taste are neutral, sweet, and sour; supports several channels (gallbladder, heart, liver, spleen) and nourishes heart yin and blood, calms the spirit, and inhibits sweating; used to treat insomnia, irritability, dream-disturbed sleep due to yin and blood deficiency, as well as wind-damp bi syndrome, and wind-heat skin rashes/and itching and also given as a nourishing sedative.

• Yuan Zhi (Radix polygalae tenuifoliae or Chinese senega root): 6 g; properties: bitter, spicy, slightly warm; enters the heart, lung, and liver channels; used to nourish the heart and calm the shen.

The following are some of the single herbs that can be added to the formula:

• Bai zi ren (Biota orientalis, commonly called arbor vitae seed): 10 to 18 g every day; properties: the temperature and taste are neutral and sweet; supports several channels (heart, kidney, large intestine, and spleen) and is therefore used to nourish the heart, calm the spirit, as well as moisten the intestine and unblock the bowels; indications for its use include the treatment of insomnia/irritability/palpitations/anxiety/and forgetfulness due to heart blood deficiency; also used to treat constipation due to yin and blood deficiency and night sweats due to yin deficiency.

• Yin Tonic Herbs

• Bai he (commonly called lily bulb): 10 to 30 g daily; properties: the temperature and taste are cold, bitter, and sweet; supports heart and lung channel; used to moisten the lung, clear heat, calm spirit, heart, and stop cough; often used to treat menopause and also to treat dry cough and sore throat, insomnia, restlessness, and irritability and also used to treat qi and yin deficiency after a febrile disease.

• Bai mu er (common name is fruiting body of tremella): 3 to 10 g of herb, soaked for 1 to 2 hours in soup until it is soft; properties: the temperature is neutral, sweet, and bland; supports the lung and stomach channel; used to tonify the lung and stomach, nourish yin, and generate fluids and also used to treat dry cough from lung heat and night sweats.

The herbal therapy above is just one example of the several differential diagnoses for the causes of insomnia according to the theories of TCM. It demonstrates the complexity of TCM herbal medicine and the diversity of choices and considerations available to the TCM herbal practitioner when choosing an herb or herbal formula specifically suited for the patient and the disease. The complexity of diagnosis is one of the reasons there is a long-standing debate among practitioners of TCM regarding the value of the standardized TCM formulas that are commonly found on the market today and the use of granules and raw herbs. Yet consumer behavior may ultimately determine the outcome of this debate because, as mentioned, raw herbs are difficult to prepare and to take because of the taste and consumers are more apt to take a pill than a preparation.

Ayurvedic Herbs

Ayurvedic herbology is based on the tridoshic theory that there exist six basic tastes (sweet, sour, salty, pungent, astringent, and bitter). When used correctly, these tastes (which are associated with all plants, herbs, and food) can be used to balance or counter an excess or deficient condition. Therefore, the first and basic principle in Ayurvedic medicine is the use of food, spices, and herbs not only to maintain good health but also to prevent and treat diseases. In general, sweet, sour, and salty tastes reduce vata, and bitter, pungent, and astringent tastes enhance it. Astringent, bitter, and sweet tastes reduce pitta; sour, salty, and pungent tastes enhance it. Bitter, pungent, and astringent foods reduce kapha; sweet, salty, and sour tastes enhance it. Based on these concepts, food, spices, and herbs with these specific effects are used to balance disharmonies in vata, pitta, and kapha conditions according to an excess or deficient condition.

For example, Ayurvedic medicine considers women to possess a greater amount of vata-type characteristics (tendency to be cold, dry, and light), which increase with age (old age is considered to be vata-dominant). Therefore, foods, spices, and herbs emphasizing sweet, sour, and salty tastes are often prescribed. However, taking into consideration the uniqueness in all of us, Ayurveda also recognizes that, as different as our body types are, so too are our nutritional requirements. For example, if you are a thin-framed, always-cold person with dry skin, you are considered to have a vata constitution and should eat a vata-balanced diet as a lifetime program. However, if you start to retain water, feel sluggish, and have excess mucus, you are demonstrating kapha imbalance and should avoid a sweet, sour, and salty diet to achieve balance.

Although tridoshic theory is the primary method used by Ayurvedic practitioners to individualize herbal therapy, they commonly use herbs and herbal formulas that target specific disorders when recommending commercial Ayurvedic herbs and herbal formulas.

In Ayurvedic theory, most digestive disorders are a result of poor digestive “Agni” fire, which is responsible for absorbing nutrients in food, destroying pathogens, and converting food to be acceptable to our digestive systems. If Agni fire is weak, the body will not be able to perform these functions and food can become a negative pathogen for the body, creating toxins and undermining the immune system.

Herbs that enhance Agni fire are generally pungent, sour, or salty (e.g., black pepper, cayenne, or ginger). However, recommendations should be based on the condition of the Agni fire: if it is too high, herbs like aloe, barberry, and gentian are more appropriate; and if variable, spices like ginger, cumin, or rock salt are recommended. Generally, sustaining digestive fire is done with mild herbs (e.g., cardamom, turmeric, coriander, and fennel).

Ayurvedic formulas include the following:

Triphala is a blend of herbs or three fruits: amla (Emblica officinalis), bibitaki (Terminalia belerica), and haritaki (Terminalia chebula). The fruits are dried, powdered, and mixed together and given as a general tonic and detoxifier. Triphala is taken every day to help balance all three doshas: each herb balances one of the three doshas—amla controls pitta, bibitaki controls kapha, and harataki controls vata. Triphala has traditionally been used to treat gastrointestinal disorder and restore bowel health. Most research has been done in animal trials; however, a 2007 study to evaluate the inhibitory activities of triphala against common bacterial isolates from HIV-infected patients supported an antibacterial activity by triphala against the bacterial isolates (Srikumar et al, 2007).

Trikatu mean “three herbs”: ginger (Zingiber officinale), black pepper (Piper nigrum), and Indian long pepper (Piper longum). Used for its bitter taste, it is intended to rejuvenate the digestive fire as well as the respiratory tract.

In Ayurvedic theory, disorders that include symptoms of low energy, fatigue, lack of sexual motivation, anxiety, and impotence are often caused by vata (air) conditions. Therefore, tonification therapy will include an anti-vata diet, including foods like dairy products, ghee (clarified butter), nuts, okra, and meat. However, tonics like shatavari, chyavanprash, and aswagandha are commonly prescribed as well.

Shatavari root (Asparagus racemosus, “hundred husbands”) is the main Ayurvedic tonic for women, with a role similar to that of the Chinese tonic dong quai. But it can also be used by men, having a similar role as ginseng, to treat impotence. Shatavari is a woody climber that has leaves that are like pine needles and white flowers with small spikes. It belongs to the Liliaceae family. By taste it is sweet, bitter, and cooling in nature; it is used as a nutritive and calming agent, to regulate menstrual flow, and to boost hormonal triggers, making it valuable in treating menopausal complaints such as vaginal atrophy and to increase female sexuality. Research on shatavari has found it to have multiple influences on the body, acting as an adaptogen, antitussive, antioxidant, antibacterial, immune-modulator, digestive, cyto-protective, galactogogue, anti-oxytocic (preventing the stimulation of involuntary muscles of the uterus), antispasmodic, antidiarrheal, and sexual tonic (Thomsen, 2002).

Amla fruit (Emblica officinalis, Indian gooseberry) is a small, very sour fruit that is the most widely used in Ayurveda as a general rejuvenative herb. This fruit is particularly high in vitamin C, with 20 to 30 times the amount found in oranges. The vitamin C in amla is also heat stable, surviving the cooling and drying process, making it an extremely powerful antioxidant. Amla is the principle ingredient in a jelly called Chyavanprash that has been used for over a thousand years to help rejuvenate the body and fortify the mind.

Aswagandha (Withania somnifera or “Indian ginseng”) has been used for hundreds of years for its ability to restore vitality and strength. In Sanskrit the word means “the smell of a horse” and the herb has traditionally been used as a male tonic. Classified as an adaptogen, ashwagandha contains steroidal lactones, alkaloids, choline, fatty acids, amino acids, and a variety of sugars.

Herbs for Common Disorders

Table 10-1 presents additional information on herbal medicines for common health problems. Although many other herbs may be used for these disorders, the ones listed have all been studied in human trials. Others that are not listed in the table are in use but have been reported on only in case or anecdotal reports.

Table 10–1 Selective Herbal Agents Used for Common Conditions

Condition	Treatment
Candida	GarlicBerberine-containing herbs: Oregon grape, goldenseal, scutellaria, gentian, grapefruit seed extractGinseng, astragalus, red clover, dandelion root, burdock root, asafetida, cumin
Constipation	Psyllium seeds, fennel, fenugreek, olive oil, cannabis seedsFor constipation due to heat: turmeric, gentian, dandelion, Oregon grape, yellow dockAyurvedic herb: triphala or rhubarb
Diarrhea	Blackberry root, raspberry leaf, agrimony, bayberry bark, oak bark, yarrowSpleen qi tonics: ginseng, Codonopsis, white atractylodes, and DioscoreaCinnamon, ginger, or cardamom
PainHeadaches	Chinese herbs: Ligusticum (chuan xiong) or Chinese lovageFeverfew, chamomile, willow barkWestern herbs: angelicaBupleurum, Artemisia annua (Sweet Annie)Menstrual headaches:, black cohosh, dandelion, chrysanthemum, and feverfew or the formula of dang gui, cooked rehmannia, white peony, and Ligusticum
Arthritis	Borage, capsicum, chondroitin, evening primrose oil, ginger glucosamine, turmeric
Insomnia	Chamomile, skullcap, valerian, or kava kava, passionflower, hops, ashwagandha to calm the nervous system, St. John’s wort, lemon balm, schisandra, jujube dates
Benign prostatic hypertrophy	Nettle, pumpkin seed, saw palmetto
Menorrhagia	Shepherd’s purse tincture, 3 to 6 drops every 2 h or a combination of cattail pollen, agrimony, mugwort, yarrow, shepherd’s purse, raspberry, and blackberry leavesBuilding blood with iron floradix or blackstrap molasses, along with Chinese herbs dang qui, lycii, cooked rehmannia, and white peony
Dysmenorrhea	Combination of equal parts of vitex, wild yam, block cohosh, dang qui, sassafras, and licorice with ½ part ginger
Urinary tract infections	Cornsilk tea, parsley, dandelion, horsetail, cranberry, and for extreme burning, use goldenseal, gentian, gardenia

Source: Adapted from Tierra, L. (2003). Healing with the herbs of life. Berkeley, CA: Crossing Press; Fetrow, C. W., & Avila, J. R. (1999). Professional’s handbook of complementary and alternative medicines. Springhouse, PA: Springhouse.

HERBAL PREPARATIONS

Although understanding the use of herbs is important, proper preparation ensures their maximum effect. The following is a summary of several of the most common preparations and their proper use.

Bolus refers to a suppository inserted into the rectum. Common herbs used in this way are astringents such as white oak bark, bayberry bark; demulcents such as comfrey root or slippery elm; and antibiotics such as garlic, echinacea, chaparral, and golden seal.

Compress/fomentation are two terms that refer to the same treatment of applying herbs externally to the body. Especially effective for herbs that are too strong to take internally but that can be absorbed slowly in small amounts, compresses are used to treat many superficial ailments like swelling and pain and to stimulate circulation of blood or lymph in the area where the compress is applied.

Liniments are warming herbal extracts rubbed into the skin and are commonly used to relieve sore or strained muscles and treat conditions like arthritis or itchy skin.

Oils are concentrated extracts used for massaging the body. There are two types of oil preparations: soothing emollients that use herbs like calendula flower, lavender, lemon balm; and warming and stimulating oils that use herbs like ginger, peppermint, and eucalyptus. Oils are usually infused with a particular herb chosen with consideration of the moistening capacity of the oil: nondrying oils include jojoba, cocoa butter, and avocado; semidrying oils include safflower and sunflower; drying oils include soybean and linseed (flax).

Capsules or pills are one of the most popular preparations used in herbal therapy today because they are convenient and mimic Western medicine. They are entirely made up of herbs; however, capsules are generally twice more concentrated than pills.

Poultices and plasters are a topical application of herbs that have been powdered, crushed, or mashed and are usually applied moist, either hot or warm, and left on an area of the body for 12 to 20 hours. Caution must be taken to avoid skin reactions and burns.

Smoking mixtures are used for smoking herbs, like datura leaf for the treatment of asthma. Smoking of herbs should be done only occasionally, and patients should be warned about the risk of lung disease, as with any smoking habit.

Teas are the most well-known method of taking herbs. Although tea is generally considered a beverage, it can have the strongest medicinal effect of any preparation, making it suitable for the most serious illnesses. To be effective, the proportion of herbs to water must be greater than usual.

Tinctures are an alcoholic or vinegar extract of herbs. Their advantage is that they have a long shelf-life when stored in a cool, dry place, whereas dried herbs begin to lose potency after the first year. Tinctures tend to make herbs energetically “hotter,” which affects the circulatory system. Consideration must be given to other chemical constituents found in alcohol, such as glycosides and sugars.

CONSIDERATIONS FOR THE APRN PRESCRIBER

There are many reasons people use herbal remedies instead of conventional medicines. Sometimes these reasons may not be consistent with those of Western medicine or supported by evidence-based studies; however, we have to respect the consumers’ right to choose and acknowledge that consumers are using herbs at an ever-growing rate. Therefore, APNs and other health-care providers should be prepared to educate the patient about the many different concepts and herbal traditions and help guide them to the appropriate resource. In addition, providers need to educate themselves about the herbs that are commonly used by their patients and be aware of the growing amount of research being conducted to evaluate interactions with herbal therapy and allopathic medicines.

Because a product is natural does not mean it is risk-free. In the late 1980s, a particular brand of L-tryptophan tablets resulted in several cases of fatal eosinophilia myalgia, and from 1993 to 1997, several hundred cases of serious adverse effects were documented from ephedra in diet and weight-loss supplements. Yet some herbal preparations have been accepted and found to be relatively safe when used in combination with Western medication, such as astragalus and dong quai for the treatment of infections and menopause.

When consumers and nonherbalists speak either positively or negatively about any given herb, what they seriously fail to acknowledge is the many different herbal traditions and those practitioners who are either certified in herbal therapy or trained in a given medical discipline that has a history of using herbal therapy but that does not fall within the definitions of Western medicine. Often, it is a failure to evaluate a specific herbal theory or or to consult a practitioner of herbal medicine that leads to many of the adverse effects cited in clinical research and by consumers.

BOX 10–1 WEB-BASED RESOURCES FOR HERBS AND ALTERNATIVE THERAPIES

• American Botanical Council, http://www.herbalgram.org

• American Herbalist Guild, http://www.americanherbalistsguild.com

• Biofeedback Certification Institute of America, http://www.bcia.org

• National Center for Complementary and Alternative Medicine, http://nccam.nih.gov

• Natural Standard: The Authority on Integrative Medicine, http://www.naturalstandard.com/

• Cochrane Database of Systematic Reviews, http://www.cochran.org

BOX 10–2 HERBAL RESOURCES

East West School of Herbology

P.O. Box 275

Ben Lomond, CA 95005

1-800-717-5010

herbcourse@planetherbs.com or www.planetherbs.com

Sponsor of planetary herbal formulas that supplies Western, Eastern, and Ayurvedic herbs.

Herb Pharm

Box 116

Williams, OR 97544

1-800-348-4372

Specializing in herbal tinctures.

www.herb-pharm.com

Spring Wind Herb Company

2325 4th Street #6

Berkeley, CA 94710

Good source for Chinese herbs.

Banyan Botanical

6705 Eagle Rock Ave, NE

Albuquerque, NM 87113

1-800-953-6424

www.banyanbotanicals.com

Good source for Ayurvedic herbs.

Mountain Rose Herbs

P.O. Box 50220

Eugene, OR 97405

1-800-879-3337

www.mountainroseherbs.com

Large selection of bulk organic herbs, spices, teas, essential oils, and bulk ingredients.

The Tao of Tea

3430 SE Belmont Street

Portland OR 97214

1-503-736-0198

www.taooftea.com

Good selection of herbal teas.

Health-care professionals need to keep an open mind to all the possible ways of treating health problems, and that ultimately may require the inclusion or consideration of medical systems that are not commonly practiced in Western culture. Primary care providers may need to explore the resources that are available to the public at large, critique the information, and assist the patient in finding practitioners of non-Western–based treatments that can meet their needs. However, professionals must also recognize their scope of practice and not venture into prescribing or recommending without adequate knowledge and training in other areas of therapy.

Medication	OTC Products
Antihistamines: diphenhydramine, chlorpheniramine, brompheniramine, dexbropheniramine, clemastine, cyproheptadine, doxylamine, pyrilamine (maleate)	Allergy medicationsCold medicationsSleep aidsMenstrual cramp medicationsMotion sickness medications
Antimotility agents (loperamide)	Antidiarrheals
Antitussives (dextromethorphan)	Cough and cold medications
H2 antagonists (ranitidine, famotidine, nazatidine)	H2 antagonist/heartburn medications
NSAIDS (naproxen, ibuprofen)	NSAID analgesics
Alcohol	Cough and cold medicationsExpectorantsMultivitamins with or without iron (liquid)Antihistamines (liquid forms)Motion sickness medications (liquid)

REVIEW OF BASIC PRINCIPLES OF PHARMACOLOGY

CHAPTER 10

HERBAL THERAPY AND NUTRITIONAL SUPPLEMENTS

OVERVIEW OF HERBAL MEDICINE

DEFINITIONS

Western Herbal Medicine

Traditional Chinese Medicine

Ayurvedic Medicine

HERBAL SAFETY

Evidence Grading

Matrix for Evidence Grading

Challenges to Using an Evidenced-Based Model

COMMON HERBS

Western Herbs

Anxiety

Insomnia

Depression

Confusion and Forgetfulness

Gastrointestinal Problems

Pain

Traditional Chinese Herbs

Herbal Formula for Insomnia

Gui Pi Tang Ingredients

Ayurvedic Herbs

Herbs for Common Disorders

HERBAL PREPARATIONS

CONSIDERATIONS FOR THE APRN PRESCRIBER

BOX 10–1 WEB-BASED RESOURCES FOR HERBS AND ALTERNATIVE THERAPIES

BOX 10–2 HERBAL RESOURCES

SUGGESTED READING

Western Herbs

Chinese Medicine

Ayurvedic Medicine

General Recommendations

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