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Brian T. Hocum, PharmD, CGP, Adjunct Faculty Member, Washington State University College of Pharmacy, Spokane, WA
Elizabeth L. Black, MD, Blue Mountain Family Health, Clarkston, WA
Kevin J. Black, MAT, Clarkston, WA
Stuart J. Beatty, PharmD, BCACP, CDE, Associate Professor of Clinical Pharmacy, The Ohio State University College of Pharmacy, Columbus, OH
To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Farel (CME question reviewer) owns stock in Johnson & Johnson. Dr. Stapczynski (editor) owns stock in Pfizer, Johnson & Johnson, Walgreens Boots Alliance Inc., GlaxoSmithKline, Bristol Myers Squibb, and AxoGen. Dr. Hocum (author) reports he is an employee of United Therapeutics. Dr. Greg Wise (editor) is involved in sales for CNS Vital Signs. Dr. Schneider (editor), Ms. Fessler (nurse planner), Dr. E. Black (author), Kevin Black (author), Dr. Beatty (peer reviewer), Ms. Mark (executive editor), and Ms. Coplin (executive editor) report no financial relationships with companies related to the field of study covered by this CME activity.
Drug-to-drug interactions (DDI) are a concern of increasing significance at all levels of healthcare. This article will provide examples and illustrations to demonstrate the metabolic processes that underlie many of these interactions. An understanding of the fundamental mechanisms of drug metabolism and transport is important for understanding DDI in the emergency setting.
The mechanisms of drug metabolism have an interesting evolutionary history. The metabolic systems that are relied on to transmit drugs through the body were not developed to introduce beneficial substances into the body, but rather to keep harmful substances out. As animal ancestors diverged from plants and began relying on them as a food source, plants developed phytoalexins that could poison and deter the animals that fed on them. Through selective pressures, animals with more robust enzymatic systems that could neutralize those toxins thrived. This back and forth “animal and plant warfare” resulted in diversification of enzymes that now metabolize drugs in the body.1
Medications increasingly are being developed specifically either to avoid or exploit particular metabolic processes to achieve better efficacy or decrease the potential for interaction with other medications that use the same metabolic pathways. These metabolic points of interaction between drugs are the primary focus of this article.
Emergency physicians are well aware that the number of elderly seeking care in the ED is increasing. As patients age and the number of comorbid conditions increases, more medications will be employed to meet multiple treatment goals. Inevitably, this will increase the risk of polypharmacy in these patients.
DDIs represent one of the most significant risks of polypharmacy. As the number of medications involved in a patient’s treatment regimen increases, the likelihood of any two of those medications having an interaction that significantly affects the action of one or both of the medications involved increases dramatically.
Providers with access to electronic medical records (EMRs) and electronic prescribing (ERx) software are becoming increasingly familiar with interaction alerts that are automatically generated by such systems to help anticipate DDIs. Before the widespread adoption of these software tools, healthcare providers were not ideally successful at anticipating or evaluating DDIs on their own. One study showed that a group of physicians was able to recognize or classify such interactions only just over half the time, even with strongly contraindicated medication pairings.2 Clearly, these software tools are a necessary adjunct to successful management of pharmacotherapy. As polypharmacy becomes more endemic, however, these alerts may become so frequent that providers may no longer be able to easily discern which alerts are most likely to dramatically affect the overall safety and efficacy of the medications involved. This is especially important, as alerts generated by these systems do not always represent DDI of sufficient clinical significance to avoid certain medication combinations. A more recent study showed that providers’ understanding of the relative clinical significance of DDI was “generally poor.”3 This further highlights the importance of improving provider understanding of the mechanisms underlying DDI.
Guidance is even less clear in interactions that may affect the potential efficacy of a medication in the patient, but are not clearly contraindicated. Coadministration of a particular pair of medications may adversely affect the effectiveness of one or both of the medications, but not to the point where they are entirely ineffective in achieving desired goals. Alternatively, some drug combinations actually may reinforce the effectiveness of one medication to the point that they can be used at lower doses than are usually necessary to achieve the desired therapeutic results.
An excellent place to begin the discussion of drug interactions is with the absorption of orally administered medications. Before oral medications can reach systemic circulation and their site of action, they must be absorbed. Multiple factors, including gastric pH and motility, gut pathology, and the chemical structure and formulation of the medication itself, can influence this.4 These factors can be manipulated to achieve increased or decreased blood levels of drugs and desired therapeutic outcomes. For example, the presence or absence of food may dramatically influence gastrointestinal (GI) motility.
GI motility is more rapid on an empty stomach.5 When taken on an empty stomach, some medications (like diazepam) reach the small intestine more rapidly, where they are absorbed into the bloodstream (see Table 1). This may result in a faster time to reach the maximum concentration (Cmax) and, thus, maximum effectiveness, compared to taking the same medications with food. The presence of food tends to slow gastric motility. Although this may delay the time it takes for the drug to reach Cmax, the increased time in the gut may allow more time for the medication to enter into solution, which is required for absorption. Thus, the overall exposure to the drug, as measured by the area under the curve (AUC), may be greater. Composition of foods also can alter the absorption of drugs. Foods rich in fat, fiber, or calcium have a significant effect on the absorption of many medications.
Another factor that contributes to drug bioavailability is the acidic environment of the stomach. This harsh environment can destroy drugs before they ever make it to the small intestine for absorption, and some drugs must be specially formulated (e.g., delayed-release omeprazole) to reach the small intestine intact. For further information on food-drug interactions, consider reading article 1 in the provider resource tool kit included at the end of this article.
“First pass” refers to the initial passage of a medication, after absorption from the gut, as it passes through the liver to the bloodstream. First pass concludes when a medication or its metabolites enter systemic circulation and is used as a baseline for determining bioavailability. Bioavailability is defined as the fraction of unchanged drug that reaches systemic circulation or the molecular site of action.4 Once absorbed into the cells of the small intestine (i.e., enterocytes), drugs encounter the body’s next line of defense against xenobiotics, the drug metabolism and transport system. Understanding this system is an important basis for discussing drug interactions. We will be using illustrations to depict a slightly simplified physiology of drug transport and metabolism in the body. This will facilitate a deeper understanding of the mechanism of drug interactions.
As outlined in Figure 1, the drug efflux transporter p-glycoprotein (p-gp) and the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) are highly expressed in enterocytes. These work together as an intestinal “tag team” (Jessica Oesterheld, MD, e-mail communication, December 2014). Drugs are continually absorbed into the enterocyte. P-gp effluxes the drug molecule out of the enterocyte. Inside the cell, drugs encounter CYP3A4 and undergo extensive metabolism. These processes happen over and over during GI transit so that the amount of drug that reaches the portal vein will be significantly decreased if it is a substrate for either of these pathways. See Table 1 for several examples of interactions that take place at this juncture.
For some drugs that have active metabolites, interactions involving inhibition may shift the metabolic ratio such that less of the active metabolite is formed and effectiveness is lost. When the parent molecule is inert relative to the active metabolite, the drug can be classified as a prodrug. Codeine, clopidogrel, and tamoxifen are three examples of prodrugs. Many drugs fall into a category in which there is activity in both the parent and metabolite form.
Competitive Inhibition. This can function in two ways. One molecule (inhibitor) may have a higher affinity for the metabolic enzyme so that it binds more readily to the enzyme, and the interacting medication (drug) is displaced and metabolized less readily. Another way this type of inhibition occurs is that the inhibitor molecule may have a greater concentration at the site of metabolism, saturating it and outcompeting the interacting medication for the metabolic action of the enzyme. This may be a similar function at the transporter level, but this is less well-understood.
Mechanism-based Inhibition. In this type of inhibition, the inhibiting substance (inhibitor) binds irreversibly to the enzyme, rendering the enzyme functionally inert. This removes the potential for the enzyme to metabolize the interacting drug (drug). In theory, the effects of mechanism-based inhibition may last longer. The permanent nature of the alteration of the enzyme requires that more enzyme must be produced by the body to replace the enzyme rendered inert by the inhibiting reaction. The difference between competitive and mechanism-based inhibition may not be clinically significant. The end result is that the medication that is less readily metabolized is more likely to have increased systemic exposure and effect.
Induction. This occurs when a drug signals nuclear receptors of cells to increase expression of a particular drug-metabolizing enzyme. Classic examples of inducers include the enzyme-inducing anticonvulsants phenobarbital, primidone, phenytoin, and carbamazepine. Rifampin is another classic enzyme-inducing drug, and smoking also has significant enzyme-inducing effects. The effects of induction would actually be opposite of the effects seen in Figure 1. Increased transporter and cytochrome activity would ultimately lead to decreased amounts of drug reaching the bloodstream.
Predicting interactions on the basis of inhibition or induction of transporter proteins can be more challenging than those based on enzymatic inhibition or induction.
To adequately understand transporter-based interactions, it is important to have specific knowledge of both the function and location of the transporter proteins involved. For example, inhibition of the effluxing transporter p-gp in the enterocytes (see Figure 1) will result in increased drug available to reach systemic circulation and, therefore, increased drug exposure. Likewise, inhibition of a hepatic influx transporter, such as SLCO1B1 (see the basolateral border of Figure 2), will result in less exposure of the drug to CYPs and, therefore, increased systemic exposure due to decreased metabolism. Also, inhibiting influx transporters OAT1 and OAT3 on the basolateral side of the proximal renal tubule will result in increased drug exposure due to decreased renal elimination (see Figure 3).
In theory, inhibition of p-gp efflux in hepatocytes could actually result in a “trapping” of the drug in the hepatocyte and increased metabolism of the drug, resulting in decreased systemic exposure, rather than the drug entering into the bile and undergoing enterohepatic recirculation. Lastly, inhibition of the efflux transporter p-gp in the blood-brain barrier (BBB) would not be expected to change systemic exposure of a drug to any clinically significant extent, but it may increase the amount of drug that reaches the CNS and, therefore, increase the risk of toxicity. The difference between these potential effects and the effect of p-gp inhibition in the enterocyte illustrates the importance of considering the location of action as well as the affected transporter in anticipating the clinical impact of inhibition or induction on transporter-based interactions.
Once beyond the gut, drugs and their respective metabolites enter the portal vein en route to the liver. Here they are metabolized through the hepatocytes before they either enter back into systemic circulation via the central vein or are cleared via the bile. Drug molecules can enter hepatocytes by transporters, as already discussed, or by other means, such as passive diffusion (see Figure 2). For drugs that rely on transporters, like statins, clinically significant interactions may exist if their influx transporter (SLCO1B1) is inhibited. In this case, the blood levels of the statin may significantly increase. This would increase the risk for adverse effects, such as myalgias and rhabdomyolysis (see Table 3).
Highly expressed as well as highly polymorphic, the various families of cytochrome P450 enzymes (CYPs) are also encountered within the hepatocytes. Although the discussion will focus on these enzymes, it is important to note that many others metabolize drugs during phase I and phase II metabolism. However, CYPs are among the most studied and well understood in terms of clinically significant interactions.
Phase I metabolism is the term used to describe the process of adding or exposing hydrophilic functional groups (functionalization) to drug molecules.1 From a drug interaction standpoint, CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 are the most important, as they are involved in the metabolism of the majority of all hepatically cleared drugs.8 Examples of common drugs and drug classes metabolized by these pathways can be found in Table 2. The types of reactions that cytochromes have with drugs is oxidative in nature. Reactions can result in inactivation or activation of drugs as well as a change in structure that makes the drug molecule more amenable to conjugation via phase II drug-metabolizing enzymes and/or more amenable to elimination. Because so many medications are metabolized by the CYP450s and because these enzymes can dramatically influence the exposure of drugs, this system is highly vulnerable to interactions. One useful example to illustrate the impact of this mechanism is the interaction between dextromethorphan and quinidine.
Dextromethorphan, an opioid analog that is commonly used to treat cough,4 recently was discovered to be an effective medication for pseudobulbar affect, a neurologic disorder that can increase emotional instability.9 Dextromethorphan is also a CYP2D6 and p-gp substrate. To be effective at treating pseudobulbar affect, high concentrations of the drug must pass through the BBB and into the CNS. For most individuals, this is not possible without giving very high doses of dextromethorphan. Coadministration with low-dose quinidine, a potent CYP2D6 inhibitor, boosts systemic exposure of dextromethorphan up to 20-fold (see Table 3). An interesting fact about this interaction is that coadministration with quinidine is not required in individuals who are genetically deficient in the CYP2D6 enzymes (CYP2D6 poor metabolizers). This is because dextromethorphan exposure is sufficiently high in these patients. Exposing them to quinidine, which has its own profile of adverse effects such as QTc prolongation, is unnecessary.10
Other examples of phase I interactions are included in Table 3 and include the use of disulfiram to deter alcoholics from drinking and the use of ethanol or fomepizole to treat methanol and ethylene glycol poisoning (see Table 3).
Another example is treatment of bacterial vaginosis in heavy alcohol drinkers. Metronidazole has resulted in cases of disulfiram-like reactions with alcohol. This is likely due to metronidazole-possessing aldehyde dehydrogenase (ALDH)-inhibiting properties. This increases plasma levels of acetaldehyde and causes unpleasant side effects: flush, vasodilatation, throbbing head and neck pain, respiratory difficulties, vomiting, sweating, and thirst. Although this interaction would probably be less likely with intravaginal administration of metronidazole, there has been a case report of such an interaction.
Phase II metabolism is the term used to describe secondary drug metabolism and is usually conjugative in nature.1 This usually occurs after phase I metabolism, but this is not always the case. It may happen in the same cell or tissue immediately after phase I metabolism. It also may occur after the drug has re-entered systemic circulation and again entered into tissues like the liver for further metabolism.
The most important phase II enzymes from a drug metabolism and interaction standpoint are the uridine 5’- diphosphate glucuronosyltransferases (UGTs). This enzyme family functions via glucuronidation — the addition (or conjugation) of glucuronic acid, which is highly water soluble — to a drug molecule.
Figure 3 can be used to visualize the mechanisms of interactions that occur in phase II metabolism. Lamotrigine is a non-enzyme inducing anticonvulsant that undergoes glucuronidation to inactive metabolites. The known UGTs that metabolize lamotrigine include UGT2B7, UGT1A3, and UGT1A4. Ethinyl estradiol is known to induce glucuronidation and has been shown to result in clinically significant decreases in lamotrigine blood levels (see Table 3). Using Figure 2, one can infer that the induction of UGT metabolism of lamotrigine with ethinyl estradiol could result in increased conversion of lamotrigine to inactive metabolites. This would decrease blood levels of the active drug and, therefore, decrease effectiveness.
Thiopurine methyltransferase (TPMT) is another example of a phase II drug-metabolizing enzyme, although it is unique in that it conjugates drugs with methyl groups (methylation), which is a process that actually decreases water solubility. It is important for the inactivation of thiopurine drugs like azathioprine, 6-mercaptopurine, and 6-thioguanine.
Although the known interactions are fewer in numbers than phase I interactions, their clinical importance should not be overlooked. Article 3 in the provider resource tool kit at the end of this article provides a comprehensive review of the enzymes covered here, as well as others that are involved in drug metabolism. Article 4 provides a specific review on UGTs.
As with CYP metabolism, UGT glucuronidation usually inactivates drugs but there are some glucuronide metabolites that are active or more potent than the original parent molecule. The glucuronide metabolite of morphine, morphine-6-glucuronide, is one example of this.12 Table 4 lists some of the of UGT metabolized drugs, inhibitors, and inducers.
Although this article will not go into a great deal of review on drug distribution, this is also an important concept for understanding drug interactions. As a drug reaches systemic circulation, it will begin to distribute into tissues. As with absorption, distribution of a drug is dependent on a host of factors, such as its blood concentration (a direct result of factors such as dose, bioavailability, and clearance), protein binding, lipophilicity (fat solubility), the patient’s body weight, fat distribution, and renal function.
Interactions involving distribution tend to be more difficult to identify because they don’t necessarily result in a change to the systemic exposure of the drug. One type of distribution-based interaction affects how much of the free drug (i.e., unbound from plasma protein) is available to distribute into tissues and/or bind to a molecular site of action (bound drug is considered unavailable for either of these). The interaction between phenytoin and valproic acid is a classic example that demonstrates this (see Table 5).
Interactions that deal with protein displacement are actually controversial, and some experts claim that any change in unbound free drug by protein displacement would be buffered by redistribution, metabolism, and elimination of the newly freed/unbound drug.13 According to one expert, for a protein displacement interaction to be clinically significant, it must meet the following criteria: the victim drug must be > 90% protein-bound, have a narrow therapeutic index, have a high hepatic extraction ratio, and be administered as an IV formulation.13
Another distribution type of interaction is that between loperamide and quinidine (see Table 5). Loperamide is an antidiarrheal agent with potent mu opioid binding affinity but poor penetration into the central nervous system.4 Under normal circumstances, loperamide is effluxed out of the brain by p-gp and does not have a significant CNS effect. However, when combined with a p-gp inhibitor like quinidine, the loperamide may begin to accumulate in the brain, resulting in adverse effect and toxicity.
As drugs and their respective metabolites circulate, they are eventually eliminated from the body. The primary elimination site for most drugs is the kidneys, but other elimination routes include the hepatobiliary system, the lungs, skin, saliva, and breast milk. Providers commonly adjust for delays in renal elimination by estimating the glomerular filtration rate via use of the creatinine clearance calculation. This estimate is used to dose many drugs, especially antibiotics. However, anticipating dose adjustments for drug interactions that take place at the kidneys may be less familiar to most providers. Even more so than the other sites covered in this article, renal clearance is a complex process and this review only addresses the highlights of this system. For more information on this system, consider reading article 7 in the provider resource tool kit at the end of this article.
During kidney elimination, many drugs will be passively filtered through the glomerulus and eliminated this way. However, many drug/metabolite molecules also undergo renal tubular secretion, which is an extremely important site for drug interactions since this is a predominantly transporter-mediated process.14 Renal tubular secretion happens in the proximal tubule of nephrons and again involves a highly complex network of transporters, some of them energy dependent, that move drugs and other electrolytes in and out of the collecting tubule (urine) and blood. Glucuronidation and sulfation (via sulfotransferases [SULTs]) also occur in the renal proximal tubule. It is believed that the contribution to overall drug metabolism in the kidneys is much less clinically significant compared to that which occurs in the intestine and liver.14
Two of the most well-understood transporters from a drug interaction standpoint are the organic anion transporters OAT1 and OAT3. These transporters work by exchanging intracellular endogenous molecules with extracellular anions.15 Probenecid, used as an antigout agent because of its ability to inhibit reabsorption of uric acid from the collecting tubule, is a classic inhibitor of these transporters. (See Table 6.)
An interaction that could occur in the ED is if oseltamivir is prescribed to a patient taking probenecid for gout. This interaction results in elevated serum levels for oseltamivir (see Figure 4) and increased potential for adverse effects. As with the drug-metabolizing enzymes, by understanding the drug’s route of elimination, providers can avoid harmful interactions and sometimes promote beneficial ones.
As pharmaceutical sciences advance, one certainty is that the constellation of medications that patients may be taking at the time of their ED visit is likely to expand. To further complicate this issue, aging patient populations will only increase the incidence of comorbidities that make polypharmacy a common situation. While software tools can help facilitate the recognition of current or potential DDI in the polypharmacy patient, the software cannot always provide adequate information about managing DDI while still meeting treatment goals.
The best solution to this DDI dilemma is to seek out and capitalize on the expanding knowledge of the fundamental mechanisms of drug metabolism. This understanding can accomplish much more than simply avoiding DDI or mitigating its dangers and effects when it is encountered.
It is important to remember that community resources, especially pharmacists, have more extensive training that can and should be fully utilized to facilitate understanding and management of pharmaceutical therapies, including metabolism-related DDI.
Financial Disclosure: To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Farel (CME question reviewer) owns stock in Johnson & Johnson. Dr. Stapczynski (editor) owns stock in Pfizer, Johnson & Johnson, Walgreens Boots Alliance Inc., GlaxoSmithKline, Bristol Myers Squibb, and AxoGen. Dr. Hocum (author) reports he is an employee of United Therapeutics. Dr. Greg Wise (editor) is involved in sales for CNS Vital Signs. Dr. Schneider (editor), Ms. Fessler (nurse planner), Dr. E. Black (author), Kevin Black (author), Dr. Beatty (peer reviewer), Ms. Mark (executive editor), and Ms. Coplin (executive editor) report no financial relationships with companies related to the field of study covered by this CME activity.