Drug Interactions

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Chapter 4 Drug Interactions

Drug interactions are a frequent and preventable cause of drug-related adverse events. Interactions between drugs (drug-drug interactions) are particularly common, and as the number of conditions that can be treated with drug therapy increases, polypharmacy—the use of multiple medications in a single patient—will become commonplace.

Fortunately, not all drug interactions will harm the patient. If this were the case, it would severely limit our ability to prescribe a number of very useful drugs. In the following pages you will note that a number of very commonly prescribed drugs are involved in drug interactions. Understanding the mechanisms behind these interactions will help you develop a strategy for determining which interactions are manageable and which combinations should be avoided altogether.

Mechanisms of Drug Interactions

Just as pharmacology is divided into two fundamental branches—pharmacokinetics and pharmacodynamics—the mechanisms of drug interactions can also be subdivided into these two branches. Note that there is a third type of interaction, a physical (chemical) interaction that may occur outside the body (in vitro). This last type involves direct interactions between drugs and is largely the concern of pharmacists.

Pharmacokinetic Interactions

Pharmacokinetic interactions can be subdivided into those involving absorption, distribution, metabolism, and excretion (ADME).

Absorption

A given drug may directly reduce the absorption of another drug through the following:

image Chelation

image A chelator is an organic chemical that bonds with and removes free metal ions from solutions. Typically, the molecule being chelated will be a divalent cation (e.g., Ca+2, Mg+2, Fe+2).
image There are a few examples of agents that chelate drugs, reducing the absorption of both. The classic example would be tetracycline, which is chelated by calcium. This can inhibit absorption of tetracycline, reducing its antibacterial activity, but perhaps more important, tetracycline can reduce the availability of calcium, which can have dramatic effects on the developing fetus.

image Binding

image Drugs may also bind other drugs, although this is a relatively rare interaction. The classic example would be cholestyramine, a positively charged drug used to lower cholesterol. It lowers cholesterol by binding to negatively charged bile acids in the gut. Consequently, cholestyramine is also capable of binding other negatively charged drugs in the gut.
image Note that cholestyramine is rarely used anymore, having been largely replaced by the statins.

A given drug may also indirectly reduce absorption of another drug, by altering the following:

image Gastric pH

• Some drugs require a very acidic environment for their dissolution. Drugs that increase gastric pH can reduce the absorption of these agents.

image GI motility

• Both drugs and food can alter gastrointestinal (GI) motility, enhancing or inhibiting the absorption of other agents.

image The small intestine, with its large surface area, is a key area for drug absorption. Drugs such as anticholinergics, which reduce GI motility, may reduce the rate of absorption by delaying gastric emptying. Slowing the rate of absorption may have an impact on drugs that we want to work quickly, such as analgesics.

image Transport proteins, such as P-glycoprotein (Pgp) (Figure 4-1)

• Pgp is one member of a superfamily of efflux transporters that are found in several regions of the body, including the GI tract and the blood-brain barrier. Pgp extrudes drug from the cell (i.e., pumps drug out of the cell).
• In the cells lining the GI tract, these efflux pumps will therefore pump some of the drug that was going to be absorbed back into the GI tract, preventing a proportion of drug from being absorbed.
• Pgps have inhibitors and inducers:

image Pgp inhibition leads to retention of Pgp substrates. All things being equal, this would likely lead to increased absorption of the drug.
image Pgp induction leads to an increased number of Pgp pumps, leading to increased extrusion of Pgp substrates. All things being equal, this would likely lead to decreased absorption of the drug.

image

Figure 4-1 P-glycoprotein.

Distribution

Plasma Protein Binding

Recall details of plasma protein binding from the introductory chapter on pharmacokinetics. It is only the unbound portion of a drug that crosses cell membranes and is able to exert a pharmacologic effect.

Drugs compete with one another for binding to plasma proteins. If a given drug, drug A, displaces drug B from its binding site, this will increase the amount of drug B that is unbound and free to exert a pharmacologic effect.

Displacement from plasma proteins plays a minimal role in drug interactions. Aside from the fact that there are few reports of clinically significant interactions of this type, there are a couple of theoretical reasons why we would not expect to see displacement from plasma proteins causing major problems in the clinical setting:

image Free drug is also free to be metabolized and/or excreted from the body.
image Free drug distributes very rapidly into tissue, quickly reducing plasma levels.

Therefore for a clinically significant interaction to occur, the interacting agent must also interfere with the metabolism or excretion of a given drug.

Metabolism

Phase I Reactions

Cytochrome P-450 Enzymes

Cytochrome P-450 (CYP450) enzymes are responsible for phase I (oxidative) metabolism of endogenous or exogenous substrates. See introductory chapter on pharmacokinetics for review.

CYP450 enzymes are categorized according to a number-letter-number system (e.g., CYP3A4). Thus 2C9 and 2C19 are more closely related than are 2C9 and 3A4. There are at least 40 CYP450 enzymes, although only a few are seen commonly, and it is only these that you need to be concerned with. The most common isozymes are 3A4, 2D6, 2C9 and 2C19, and 1A2.

Clinically significant drug interactions arise from either induction or inhibition of these enzymes.

Enzyme Inhibition

Inhibition of a CYP450 enzyme will result in increased levels of a substrate (drug) that is metabolized by that enzyme. Inhibition may be either competitive or allosteric:

image Competitive inhibition (Figure 4-2)

image Two drugs are metabolized by the same enzyme system, and one of the drugs binds more readily to the enzyme, resulting in the inhibition of metabolism of the other drug.
image Example: Erythromycin and atorvastatin are both metabolized by CYP3A4. Erythromycin is also a CYP3A4 inhibitor; therefore it inhibits the metabolism of atorvastatin.
image Allosteric (noncompetitive) inhibition

image A drug inhibits an enzyme that it itself is not metabolized by. This inhibition occurs at an allosteric site (i.e., not at the site where the substrates bind) (Figure 4-3).

image

Figure 4-2 Competitive enzyme inhibition.

image

Figure 4-3 Noncompetitive (allosteric) enzyme inhibition.

Whether the inhibition is competitive or allosteric, if the enzyme is responsible for inactivating the drug in preparation for excretion from the body, then inhibiting this enzyme will lead to increased levels of active drug. All things being equal, this would likely result in increased biologic activity (or toxicity) of the drug.

Prodrugs require metabolic enzymes for transformation to an active (or more active) metabolite. In this case, an enzyme inhibitor would lead to a reduction in levels of active drug, in turn reducing the biologic activity of the drug. Few drugs are prodrugs; however, you should be aware of this twist on enzyme inhibition.

Enzyme Induction

An inducer stimulates increased production of a CYP450 enzyme. This effect can be seen in days but often takes 2 to 3 weeks to be established. An inducer accelerates the metabolism of substrate (drug).

image If the drug is inactivated by that enzyme for the purpose of excretion, an inducer will result in reduced circulating levels of active drug. All things being equal, this will likely result in reduced biologic activity of the drug, perhaps leading to therapeutic failure.
image Most cases of induction are allosteric, although rarely a drug may also induce the enzyme system by which it is metabolized.

Now imagine a scenario in which a patient’s condition has been stable on both a substrate (drug A) and another drug (drug B) that induces the metabolism of drug A.

image What would happen if the patient discontinued drug B?

• This is a classic example of why monitoring should not end once an interacting drug has been discontinued. This is particularly important if the dose of drug A was increased in order to accommodate the effects of the enzyme inducer. If the dose is not adjusted back down, the patient might experience toxicity from the elevated plasma levels.

Note the effect that enzyme induction will have on a prodrug. If its metabolism is accelerated, more prodrug will be activated, leading to an exaggerated effect, or the exact opposite of what would be seen with drugs that are not prodrugs. See Table 4-1 for a list of common substrates, inhibitors, and inducers of CYP450 enzymes.

TABLE 4-1 Common Substrates, Inhibitors, and Inducers of the Most Important CYP450 Drug-Metabolizing Enzymes

image

Phase II Reactions

Details of Phase II reactions are available in the introductory chapter on pharmacokinetics. Phase II reactions are performed by a family of enzymes called uridine 5′-diphosphate glucuronosyltransferases. This enzyme system functions similar to the CYP450 system, with each enzyme having its own substrates, inhibitors, and inducers. The naming system is also the same alphanumeric system (e.g., 2B15).

image The principles of inhibition and induction summarized earlier also apply to phase II reactions.
image However, phase II reactions play a far less important role in drug interactions than the CYP450 enzyme system.

Other Metabolic Interactions

Enterohepatic recirculation involves the recycling of drug between the liver and gut.

Drugs are inactivated by glucuronidation in the liver. These glucuronides are delivered from the liver via the bile into the intestine, where they are hydrolyzed, releasing the active drug. Active drug can then be reabsorbed in a process known as enterohepatic recirculation. This recirculation prolongs the residence of active drug in the body. Drugs that interfere with enterohepatic recirculation will potentially reduce the activity of any drug that undergoes this process (Figure 4-4).

image

Figure 4-4 Enterohepatic recirculation.

Bacteria in the gut play an important role in this hydrolysis of glucuronides. Antibiotics, particularly broad-spectrum antibiotics that kill off these bacteria, can interfere with the process of enterohepatic recirculation. Because the dosage of drugs such as oral contraceptives relies on enterohepatic recirculation to maintain therapeutic levels, an unexpected interruption in this process can lead to therapeutic failure. This is the explanation for the well-known interaction between oral contraceptives and antibiotics.

Monoamine oxidase (MAO) inhibitors (the wine-cheese reaction). MAO breaks down amines such as norepinephrine (NE), dopamine (DA), and serotonin, as well as tyramine. Circulating tyramine releases NE.

Irreversible inhibitors of MAO were once commonly used as antidepressants. When a patient on an MAO inhibitor would ingest foods or beverages rich in tyramine, the patient would often experience a sudden and dangerous increase in blood pressure, sometimes leading to stroke or even death. Tyramine-rich foods tend to be aged, so this phenomenon became known as the wine-cheese reaction.

Excretion

In terms of excretion, we are most concerned with drugs that rely on the kidney for their elimination. As these drugs are not inactivated by the liver, inhibiting their excretion will prolong the residence of active drug in the body, potentially leading to an exaggerated (or prolonged) pharmacologic effect (Figure 4-5).

image

Figure 4-5 Renal mechanisms in drug excretion.

A drug can affect excretion of another drug in various ways:

image Filtration—by altering plasma protein binding
image Secretion—by inhibiting tubular secretion
image By altering reabsorption
image By altering urine pH

Filtration

Drugs that are bound to plasma proteins cannot be filtered (and excreted) by the kidney. Displacement of a drug will therefore facilitate its filtration and subsequent excretion.

As was the case with absorption and plasma protein binding, this plays a very minor role in drug interactions.

Secretion

A few drugs are actively secreted into renal tubules, leading to their excretion in the urine. One drug may inhibit the secretion of another drug, hence reducing its rate of excretion in the urine.

In some cases, this prolongation of effect can be beneficial to the patient. Probenecid is a drug that inhibits the renal tubular secretion of penicillin. By inhibiting the secretion of penicillin, probenecid actually prolongs the residence of penicillin in the body, allowing for longer intervals between doses.

Reabsorption

Reabsorption of one drug may also be enhanced by another. The kidney controls fluid balance by absorbing and excreting ions (for review, see Chapter 25).

Diuretics work by enhancing sodium (Na+) excretion. As compensation for this reduction in fluid volume, your kidney will try to reabsorb Na+. The kidney cannot differentiate between lithium (Li+) and Na+; therefore patients who are taking Li+ and are volume depleted or lacking in Na+ will retain both Na+ and Li+. To make things worse, Li+ is toxic to the kidneys, so patients who retain Li+ are prone to develop renal damage.

Urine pH

The excretion of drugs that are weak acids or weak bases may be affected by other drugs that change urinary pH. This is a toxicologic principle that is useful in overdose situations for eliminating a drug from the system.

Pharmacodynamic Interactions

Pharmacodynamic interactions are based on mechanisms of drugs having either an additive (or synergistic) effect or an antagonistic effect on each other. Unlike pharmacokinetic interactions, these are generally predictable based on an understanding of the mechanism(s) of action of the interacting agents.

Additive or Synergistic Effects

Often, additive pharmacologic interactions may seem obvious but nevertheless still occur as a result of either carelessness (on the part of patient or provider) or simple lack of knowledge.

image For example, Ginkgo biloba is an herbal product commonly used as a “memory enhancer,” and as such it is often taken by elderly patients. Among its many effects, Ginkgo inhibits platelet aggregation. Warfarin is an anticoagulant that is very commonly prescribed in the elderly, and combining the two agents can lead to increased bleeding.
image Another example is the use of alcohol along with other central nervous system (CNS) depressants such as benzodiazepines (e.g., diazepam). This can be a particularly dangerous combination for those who are performing activities that require attention, such as driving.

Antagonistic Effects

Two drugs can oppose each other’s actions. This typically occurs through competition for the same receptor.

image A classic example of two drugs antagonizing the effects of each other is seen when an asthmatic is prescribed salbutamol, a β2 agonist, along with nonselective β-blockers. Propranolol is a β-blocker (see Chapter 11) prescribed for many indications. It works as an antagonist at both β1 and β2 receptors.
image Warfarin is an anticoagulant with a narrow margin of safety. Its anticoagulant effects are based on the fact that it is a vitamin K antagonist. Green leafy vegetables such as broccoli contain vitamin K, and therefore they antagonize the effects of warfarin.

Characteristics of Drug Interactions

When considering drug interactions, it is important to understand that it is not just prescription drugs that interact with one another. The list of potentially interacting agents encompasses anything that can be ingested, whether drug, food, or other.

Drugs

Prescription drugs are the cause of the majority of drug interactions; however, there are some important drugs that are often overlooked when drug interactions are considered.

Nonprescription (Over-the-Counter) Drugs

A common and potentially dangerous assumption is that over-the-counter medications are safer than prescription drugs. Although safety is a consideration when regulatory agencies decide which drugs to approve for over-the-counter sale, there are numerous examples of over-the-counter agents that have the potential to cause harm. In many cases, these harmful effects are caused by drug interactions. Some examples of the more common interacting agents are listed in Table 4-2.

TABLE 4-2 Common Nonprescription Drugs That Are Involved in Drug Interactions

Drug Common uses Mechanism of Interaction
Cimetidine Antacid CYP3A4 inhibitor
Omeprazole Antacid CYP2C19 inhibitor
St. John’s wort Antidepressant
CYP450 inducer
Pgp inducer

Pseudoephedrine Decongestant Additive adrenergic effects Antihistamines (various)
Allergy
Upper respiratory tract infections

Additive anticholinergic effects Ginkgo biloba Memory enhancer Additive antiplatelet effects

Illicit Drugs

Several drugs of abuse have clear potential for pharmacodynamic interactions. These interactions, and particularly pharmacokinetic interactions, have not been well characterized in the literature. For obvious reasons, few prospective studies have been performed assessing drug interactions with agents such as cocaine and cannabis.

Pharmacodynamic interactions generally demonstrate additive effects with either stimulants such as cocaine or depressants such as cannabis. For example, patients who are taking sedative-anxiolytics such as benzodiazepines would expect to encounter additional sedation if they are also taking cannabis.

In addition to the challenges in trying to characterize the nature and extent of interactions between illicit drugs and “conventional” agents is the stigma associated with the use of illegal substances. This almost ensures that, like over-the-counter agents, illicit drugs will continue to lurk in the shadows of a patient’s drug profile, only revealing themselves when a serious problem arises.

Food

Food interactions are typically pharmacokinetic in origin. Most commonly, food can affect the absorption of drugs. The simplest example of this is when food delays gastric emptying, slowing down the passage of drug into the small intestine, the primary site for drug absorption. However, there are some notable pharmacodynamic drug interactions involving food. One of the most important examples of a food-drug interaction involves the anticoagulant warfarin and its interaction with green leafy vegetables, which contain vitamin K.

Alcohol

The role of alcohol in pharmacokinetic interactions changes depending on whether use is chronic or acute. Acutely, ethanol competitively inhibits CYP450 enzymes, whereas chronic use leads to CYP450 induction as the body tries to increase its ability to eliminate ethanol.

Environment

Cigarette smoking induces CYP450 enzymes.

Assessing the Clinical Impact of Drug Interactions

The majority of drug interactions do not result in an absolute contraindication to the concomitant use of the two interacting agents. In fact, the spectrum of drug interactions represents a continuum from those that are actually clinically beneficial to those that may cause great harm, including death, to the patient.

Some considerations when attempting to predict the potential harm from a drug interaction include the following:

1 The toxicity profile of the drug(s) in question

image Margin of safety

• Recall from the introductory pharmacodynamics chapter that the margin of safety is the difference between the therapeutic and toxic doses of a drug. Drugs with a narrow margin of safety more easily reach toxic levels when they accumulate.

image Nature of the toxicity

• Not all toxicities are created equal. The nature of the anticipated toxicity plays a key role in determining the potential clinical impact of a drug interaction, and, accordingly, whether the interaction represents a contraindication.
• For example, the antihistamine terfenadine causes fatal arrhythmias once plasma levels become toxic, and drugs that cause elevation in the plasma levels of terfenadine would be contraindicated for use with terfenadine.

2 Regimen

A drug regimen consists of a dose, frequency, and duration, and each of these factors can contribute to the potential harm incurred from a drug interaction.

image Dose

• There is typically a direct correlation between dose and plasma levels of a given drug. Therefore, the higher the dose of drug used, the more likely that a pharmacokinetic interaction leading to accumulation of that drug will cause a problem.

image Frequency

image As noted earlier, the frequency with which a drug is administered will affect whether an interaction is manageable or not. This is particularly the case with interactions that are acute in nature, such as when two drugs interfere with each other’s absorption. Simply separating the doses of these two drugs so that they do not interact with each other in the stomach can completely negate any interaction.

image Duration

image Not all drugs are taken chronically. A drug interaction between a chronically administered agent and an acutely administered agent can have some distinct issues compared with interactions between two chronically administered agents.
image The advantage of a chronic-acute interaction is that the interaction is short-lived. The classic example is an interaction between a chronic agent and an antibiotic such as erythromycin. Depending on its margin of safety, a temporary interaction such as this might not last long enough to cause enough accumulation to push plasma levels into the toxic range.
image However, the disadvantage of these temporary interactions is that if dose adjustments are required, they also require a readjustment once the interacting agent has been discontinued. This may complicate drug regimens when patients have to undergo multiple, interrupted courses of therapy.

3 The severity of the interaction

Numerous drugs either induce or inhibit metabolizing enzymes; however, not all drug interactions result in dramatic drug accumulation or therapeutic failure. There are a few reasons why not every metabolic drug interaction results in disaster.

image A range of inhibition can occur. There are potent enzyme inhibitors and inducers, and relatively weak ones.
image Drugs may be metabolized by more than one enzyme. The effects of inhibiting one metabolic pathway may be mitigated somewhat by the use of a secondary pathway.
image Genetics likely play an important role. We are just beginning to understand how important a role, but we do know that the severity of the same drug interaction can vary widely among individuals. This is one of the reasons why severe drug interactions are sometimes not detected until a drug has been approved by regulatory agencies for widespread use.

4 How frequently the interaction occurs

image Related to the previous paragraphs, a given drug interaction may be clinically significant in one patient and have seemingly no effect on the next patient.
image Genetics (again) likely plays an important role here.
image Numerous other patient-related factors can also contribute, including other concomitant therapies, as well as the health status of the patient, age, diet, environmental factors, and so on.

Strategies for Mitigating Harm from Drug Interactions

The majority of harm that can occur from drug interactions is preventable; the key is knowledge.

1 Reduce the use of nonessential prescriptions.

image Patients are often prescribed drugs that they do not actually need. Prescribers should always set a therapeutic goal first before prescribing a medication, and consider nonpharmacologic options. For example, when a patient has been diagnosed with hypertension, consider lifestyle options first (diet, exercise) before moving to pharmacologic interventions.

2 Ensure that the patient medication profile is complete, including nonprescription medications.

image Numerous over-the-counter medications, including herbal products, interact with prescription drugs. Many jurisdictions do not officially record these agents in a patient’s medication profile; thus unless the patient is interviewed about the nonprescription medications he or she is taking, these drugs will not be taken into account when drug interactions are assessed.

3 Separate the administration of conflicting drugs.

image In many cases, conflicting drugs can be used by the same patient. One of the strategies for minimizing harm in these patients is to separate doses of the conflicting drugs.

4 When initiating therapy, start at lower doses and increase slowly, as needed.

image The adage “start low and go slow” is based on the very simple principle that the lower the plasma levels of a given drug, the less likely problems are to arise from drug interactions that would increase the levels of that drug. A conservative approach such as this also allows the prescriber to assess whether an interaction is occurring and whether changes need to be made. Initiating therapy with a high dose reduces the margin of safety for that drug.

5 Use the resources around you.

image A list of some common resources is provided in the next section. A key point to remember is that given the large and ever-increasing number of drugs that interact with one another, it is impossible to memorize all of these interactions. Clinicians use resources, typically information technology, to identify interactions and in some cases to provide context around the clinical significance of the interaction.

Resources

The Institute for Safe Medication Practices (ISMP) is an international nonprofit organization that educates the healthcare community and consumers about safe medication practices. The ISMP has several resources that are useful to healthcare providers, including safety newsletters that alert practitioners to recent safety issues arising from medications. Practitioners are also able to report adverse drug reactions that they have observed, using a simple online reporting system. Although the ISMP is not focused on drug interactions, it is a resource for up-to-date information on drug interactions that have significant impact on patient safety.

Other resources include the following:

1 Pharmacists.
2 Texts: Any general pharmacy reference will have information on drug interactions.
3 Computer programs.

The Epocrates drug database for personal digital assistants (PDAs) is free and contains a comprehensive tool for checking interactions: www.epocrates.com.

See the related Chapter 4 Case Studies in Student Consult.

Websites

www.hiv-druginteractions.org

www.ismp.org

www.epocrates.com

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