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INTRODUCTION

Medications that have been shown to be effective for some patients often fail to work for others.¹ When medications do work, they may be harmful to a subset of patients.¹ Human variability regarding the safety and effectiveness of medications is a major challenge in both drug development and current clinical practice. Differences in genetics, age, and gender are among several variables that influence individual responses to medications.¹ Additionally, a drug’s intended effect may be altered by coadministered medications, underlying disease states, and food.¹ While these interactions are multifold and complex, they further underscore the importance of pharmacy technicians filling prescriptions carefully and accurately at all times. Therefore, pharmacy technicians should have an enhanced understanding of factors that influence the way a drug acts in the body because they are often prompted with patient safety alerts during the order entry process.

FOOD-DRUG INTERACTIONS

Food can alter the bioavailability of drugs by various means. Bioavailability is defined as the rate and extent to which the active ingredient of a drug is absorbed and becomes available at its site of action.² For instance, food can alter gastric emptying, change gastrointestinal (GI) pH, physically or chemically interact with a dosage form or a drug substance, alter intestinal motility, enhance drug solubility, and influence distribution and excretion of selected medications.³ These aforementioned mechanisms affect the bioavailability of drugs and are commonly referred to as pharmacokinetic (what the body does to a drug) and pharmacodynamic (what a drug does to the body) interactions.

Pharmacodynamic food-drug interactions occur when foods act at the same receptor site(s) as a drug, resulting in additive, synergistic, or antagonistic effects at the desired biological target.⁴ For instance, the liver requires vitamin K to make clotting proteins. Warfarin, one of the most commonly used oral anticoagulants worldwide, interferes with vitamin K-dependent enzymes in the liver that are essential in the production of clotting proteins. This warfarin-related interference prolongs the time it takes for a clot to form, thus protecting patients from developing clots.⁴ However, when patients sporadically ingest foods with a high content of vitamin K, such as kale, spinach, and collards, warfarin’s protective effects are diminished because these foods replenish the necessary supply of vitamin K to make clotting proteins. Yet when patients maintain a consistent intake of vitamin K in their diet, the dose of warfarin can be adjusted to maintain appropriate levels of drug to protect patients from clotting disorders or stroke. This warfarin-vitamin K pharmacodynamic interaction is referred to as antagonism.⁴

A different type of food-drug interaction occurs when a person who takes lithium consumes a diet that fluctuates in sodium. Lithium, which is a naturally occurring mineral and carries an electrical charge similar to sodium, is commonly used to treat bipolar disorder.⁵ Elevated lithium blood-concentration levels can result in neurotoxicity, and lithium levels that are too low can worsen mood.⁶ The blood concentration of lithium is predominantly regulated by the kidneys because this is the site where water and electrolytes (including sodium) are excreted or reabsorbed back into the body’s cells.⁶ Importantly, the movement of sodium affects lithium.⁶ Therefore, once lithium reaches a therapeutic level in the blood, it can be altered by small changes in sodium intake—less sodium may cause lithium levels to rise while more sodium may cause lithium levels to fall.⁷ As a result, it is very important for patients who take lithium to maintain a consistent level of sodium in their diet to avoid these fluctuations. This is an example of a pharmacokinetic food-drug interaction because the body either eliminates or retains lithium. Some medications should be taken with food and others on an empty stomach. The medication guide or patient package insert will have this information.

Orally administered drugs and food-drug interactions

The majority of drugs are taken by the oral route of administration. As a result, this route has several documented food-drug interactions. However, in order to more effectively understand these interactions, it is important to recognize how drugs work in the body. For drugs that are taken orally, there are the following 4 basic phases of drug action⁸: (1) the drug is broken down into a useable form in the GI tract and, subsequently, in the liver (ie, hepatic system); (2) the drug enters systemic circulation and is transported to its site of action; (3) the body responds to the drug; and (4) the drug is excreted from the body either by the kidney, liver, or both. Importantly, not all drugs are exposed to the GI-hepatic mechanisms that are involved in drug absorption and metabolism, which play a unique role in reducing the bioavailability of certain medications. For instance, drugs that are administered intravenously are able to bypass these mechanisms, which is commonly referred to as avoiding the first pass effect. For drugs with a significant first pass effect, a substantial portion of the original dose is removed or inactivated before it enters systemic circulation.⁸

Food can cause physiological changes in the GI tract in a way that affects a drug’s transit time, the rate at which it dissolves, and the amount that enters systemic circulation.³ Food effects are usually greatest when a drug is administered soon after a meal, and meals that are high in total calories and fat content are more likely to affect bioavailability.³ For instance, to assess the impact of food on orally administered drug products during clinical development, guidance from the US Food and Drug Administration (FDA) recommends that test meals include 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.⁹ Further, the results from food-effect studies are typically reported in the clinical pharmacology section of the product package insert (PPI), which shape the recommendations that appear in the dosage and administration section of the PPI (eg, take only on an empty stomach).³ The following includes example language that could appear in the clinical pharmacology section of a package insert³:

A food-effect study involving the administration of [the drug product] to healthy volunteers under fasting conditions and with a high-fat meal indicated that the maximum concentration and patient exposure to drug increased 61% and 53%, respectively. This increase in drug exposure can be clinically significant. As a result, [the drug] should be taken only on an empty stomach, 1 hour before or 2 hours after a meal.

For some medications, the influence of a high-fat meal is considerable. One study that found that absorption of the breast cancer drug lapatinib (Tykerb) was increased by 325% with fatty food and by 167% with low-fat food compared with taking the medicine on an empty stomach. ⁹ Conversely, the absorption of alendronate is nearly reduced to zero when taken within 2 hours after a meal is ingested.¹⁰ For these reasons, it is important to provide patients with clear and correct instructions regarding the administration of their medications. In addition, affixing key auxiliary labeling to prescription products may remind patients about the most effective means to take their medications, considering 36% of adult Americans have levels of health literacy below what is required to understand typical medication information.¹¹

Grapefruit juice and drug metabolism

The cytochrome P-450 (CYP450) enzyme family is responsible for the metabolism of many drugs that are used in clinical practice. Specifically, cytochrome P450-3A4 (CYP3A4) enzymes, which are located in the liver and GI tract, affect the bioavailability of a substantial number of prescription and nonprescription drugs.¹² One of the more significant food-drug interactions concerning CYP3A4 involves grapefruit juice (GFJ) and certain orally administered drugs. Notably, research suggests the oral route of administration is the only route affected by GFJ, considering medications that bypass CYP3A4 enzymes in the GI tract (eg, medications given intravenously) are usually spared.¹³ The GFJ-CYP3A4 interaction occurs through the following mechanism: GFJ binds to and inhibits the ability of intestinal CYP3A4 enzymes to metabolize or breakdown medications, resulting in prolonged bioavailability.¹² In fact, nearly one-half of an individual’s CYP3A4 enzymes may be inactivated within 4 hours after drinking an 8 ounce glass of GFJ, and this affect can last up to 72 hours.^12,13 Therefore, separating drug administration times and GFJ consumption is not a plausible recommendation. The GFJ-CYP3A4 interaction is particularly important with narrow therapeutic index (NTI) drugs, such as cyclosporine, because small increases in their blood concentrations may lead to serious adverse events. Cyclosporine, a powerful immunosuppressant that is used extensively to prevent rejection of transplanted organs, is considered a NTI drug because it meets the following criteria¹⁴: (1) there is less than a 2-fold difference between the median lethal and median effective dose; or (2) there is less than a 2-fold difference between the minimum toxic and minimum effective concentrations in the blood; and (3) safe and effective use of the drug requires careful titration and patient monitoring. In clinical studies, GFJ has increased the bioavailability of cyclosporine by more than 60%, which is significant because cyclosporine has many side effects, including kidney impairment, hypertension, and neurotoxicity.¹³ Accordingly, patients who take cyclosporine, as well as other NTI drugs that interact with GFJ, must be informed about this serious food-drug interaction. Thus, auxiliary labels in these specific circumstances become very important. See Table 1 for a list of commonly used medications to avoid using with GFJ.

A resource that may be useful in reviewing common food-drug interactions is available from the National Consumer’s League and FDA: https://www.fda.gov/downloads/Drugs/.../.../UCM229033.pdf.

DRUG-DISEASE INTERACTIONS

Individuals with certain underlying conditions may react differently to some drugs. For instance, beta blocker eye drops are routinely prescribed to treat glaucoma because they lower pressure in the eye, slowing the clinical progression of disease. However, patients who have both glaucoma and asthma should avoid the use of beta-blocker eye drops because these agents carry the potential to make breathing more difficult.¹⁵ Although the ophthalmic route of administration is designed to keep active drug localized in the eye, a small amount of drug can still be absorbed into the bloodstream, which could lead to an adverse event. For example, consider the following: 1 drop of timolol 0.5% ophthalmic solution administered to each eye is equivalent to approximately 10 mg of orally administered timolol.¹⁵ If a patient is unaware of the importance of applying pressure to the puncta (the opening of the tear duct at the inner corner of the eye) for at least 2 minutes after the application of ophthalmic timolol, an asthma exacerbation could arise as a result of its systemic absorption. Because pharmacy technicians are often the first and last individuals that patients see when picking up over-the-counter (OTC) and prescription medications, a baseline understanding of the appropriate methods to self-administer eye drops, gels, and ointments will help them identify patients who could benefit from one-on-one counseling with a pharmacist, ultimately improving patient care.

Moreover, altered drug responses may occur when organs involved with absorption, distribution, metabolism, and excretion are compromised—most notably the kidneys and liver as they actively contribute to the breakdown and elimination of most drugs. In patients with existing liver impairment, certain drugs may place them at risk for potentially serious adverse events. For example, there are 2 phases of hemostasis—primary and secondary—and together they function to stop bleeding. Primary hemostasis occurs when platelets are recruited to an affected site in the body to establish a platelet plug (ie, the beginning of a clot).¹⁶ Aspirin and other antiplatelet drugs disrupt this primary phase, which is why they are effective in preventing cardiovascular events. Importantly, acetaminophen does not disrupt the primary phase of clot formation. Secondary hemostasis is slightly delayed and takes place after the liver releases clotting factors into the blood stream, which function to further strengthen the developing clot.¹⁶ However, the rate at which clotting factors are released is weakened during liver impairment, which delays the body’s ability to arrest bleeding.¹⁷ As a result, when a patient with poor liver function develops a fever, it is not the best standard of practice to recommend aspirin (or ibuprofen) to treat the fever because both phases of hemostasis would then be delayed, further increasing a patient’s risk of bleeding.¹⁷ Thus, most patients with compromised liver function are still administered acetaminophen, although the prescribed doses are typically much lower than those used in patients with normal liver function.¹⁸ This is an example of how a medication (in this case aspirin) might negatively affect a patient with an underlying disease or condition.

One of the major roles of the kidneys is the elimination of waste products, minerals, and drugs.¹⁸ When the kidneys are not functioning properly, the body can become exposed to very high concentrations of these substances, which can lead to patient harm. Therefore, careful patient assessment before prescribing medications is required.¹⁸ To further highlight the importance of patient assessment in relation to drug dosing, consider the hospital use of aminoglycosides. In the hospital setting, intravenous or intramuscularly administered aminoglycoside antibiotics (eg, gentamicin, tobramycin) are often prescribed to prevent or treat illness in neonates, children, and adults. However, aminoglycosides are eliminated almost exclusively by the kidneys, which usually takes place over a period of days, depending on each individual’s underlying kidney function.¹⁸ If not monitored appropriately, aminoglycosides carry the potential to cause significant patient harm, including kidney and hearing damage. In fact, even when cautiously administered, treatment for more than 7 consecutive days has been troublesome for some patients.¹⁸ Although declining kidney function is not an absolute contraindication to aminoglycoside therapy, a reduced dosage or an expanded dosing interval must be recommended in these circumstances to avoid accumulation of excessive amounts of drug in the body.¹⁸ If these adjustments are not made, a patient’s hearing and kidney function could become further compromised. Notably, kidney function is routinely monitored by measuring the amount of creatinine, a byproduct of muscle metabolism, in the blood. As kidney function deteriorates, its ability to eliminate waste products, including creatinine, decreases.¹⁸ A rising serum creatinine level is one indicator that an individual’s kidney function is impaired.¹⁸

DRUG-DRUG INTERACTIONS

The intended effect of a medication can be altered by drug-drug interactions, which can be additive, synergistic, or antagonistic.¹⁹ While many drug interactions can harm patients, some are intentional and lead to a desired clinical or pharmacological response.¹⁹ One of the more common types of drug-drug interactions occurs when a drug affects the way another is metabolized or broken down in the body. This interaction usually involves the CYP450 enzyme system in the liver and GI tract (similar to grapefruit juice interactions mentioned previously).²⁰ Drugs that interact with the CYP450 system are generally referred to as substrates, inhibitors, or inducers. A substrate is a drug that is acted upon by an enzyme; an inhibitor is a drug that reduces the ability of CYP450 enzymes to metabolize other drugs; and an inducer is a drug that up-regulates or increases the metabolic capabilities of CYP450 enzymes (ie, the opposite of an inhibitor).²⁰ The following examples highlight common drug-drug interactions:

Enzyme induction—this type of drug interaction occurs when 1 drug up-regulates certain CYP450 enzymes in the liver, causing a more rapid clearance of another drug.¹⁹ For instance, rifampin (an inducer) up-regulates the liver enzyme cytochrome P-2C9 (CYP2C9), which causes this enzyme to become more effective.²¹ Warfarin is a substrate for CYP2C9. When a patient who is currently taking warfarin begins treatment with rifampin, the desired blood thinning effects of warfarin are reduced substantially as a result of the accelerated metabolic activity of CYP2C9.²¹ Consequently, the dose of warfarin must be increased so patients receive the intended anticoagulant effects of the drug.

Enzyme inhibition—this type of drug interaction occurs when 2 agents are competing for the same enzyme.¹⁹ One of the competing drugs is an inhibitor of the enzyme while the other is a substrate. For example, clarithromycin is a potent inhibitor of the enzyme CYP3A4. Nifedipine is a substrate that is broken down or metabolized by CYP3A4. When these two medicines are administered simultaneously, the blood pressure lowering effects of nifedipine are prolonged because clarithromycin binds to or inactivates CYP3A4.²² This specific drug interaction can usually be managed by using azithromycin in place of clarithromycin, considering it is not thought to inhibit CYP3A4 enzymes.²² With regard to enzyme inhibition, let's consider the following pharmacy practice example.

Pharmacy practice

ML is a 35-year-old female who presents to the pharmacy with a prescription for ciprofloxacin 500 mg that is to be taken twice daily for the next 7 days. She is being treated for a urinary tract infection (UTI). ML has allergies to penicillin, cephalexin, nitrofurantoin, and sulfamethoxazole-trimethoprim; the reaction that is listed in the patient’s profile for each of these allergies is difficulty breathing. While entering the prescription into the patient’s profile, the pharmacy technician is quickly warned about a serious drug interaction involving ciprofloxacin and the patient’s muscle relaxant, tizanidine. The pharmacy technician asks ML if she is currently using the medication. ML indicates that she has to take her muscle relaxant daily otherwise she cannot make it through the day or sleep. The pharmacy technician takes the appropriate measure and notifies the pharmacist. After taking into consideration all of ML’s allergies, what medication may be safe to use in this situation?

Background information

Tizanidine is a substrate for the enzyme cytochrome P-1A2 (CYP1A2) and ciprofloxacin (a fluoroquinolone) is potent inhibitor of CYP1A2; therefore, when these drugs are co-administered, ciprofloxacin blocks the metabolism of tizanidine, causing increased plasma concentrations of tizanidine in the body. In fact, when patients ingest tizanidine 1 hour after a dose of ciprofloxacin, the plasma concentration of tizanidine may increase 10-fold, dangerously potentiating its hypotensive and sedative effects.²³ As a result, the co-administration of these agents is contraindicated. However, not every fluoroquinolone is a potent inhibitor of CYP1A2. For instance, levofloxacin has limited involvement with CYP1A2 enzymes, and its co-administration with tizanidine creates less risk compared with that of ciprofloxacin.²⁴ Therefore, in certain situations when therapeutic options are limited, levofloxacin may be a potential treatment option in patients who are not considered high risk and cannot interrupt select therapies that are metabolized by CYP1A2.

Pharmacy practice—follow up

The pharmacist calls ML’s physician and discusses the drug interaction concern between ciprofloxacin and tizanidine. Because ML’s allergy profile is complicated and eliminates many therapeutic options for UTIs, the physician asks for the pharmacist’s opinion regarding potential oral therapies. Since the majority of oral medications traditionally used for UTIs cannot be recommended in ML’s case, the pharmacist informs the physician that levofloxacin provides adequate coverage for likely urinary pathogens and has limited involvement with CYP1A2 enzymes. The physician “okays” the substitution of levofloxacin 500 mg once daily for 5 days. The pharmacist counsels ML about potential hypotension and increased sedation with the co-administration of these drugs and advises her to limit the use of tizanidine, if possible, for the ensuing 5 days. For reasons like the above-mentioned scenario with ML, it is important that pharmacy technicians pay close attention to drug interaction warnings that appear during the order entry process and to convey these drug interaction alerts to pharmacists.

Complexation—this type of drug interaction occurs when 2 different drugs attach to each other, resulting in decreased absorption. For example, ferrous sulfate binds to the antibiotic cefdinir, reducing its absorption and antibacterial activity. If a patient is required to take these products simultaneously, cefdinir should be administered at least 2 hours before or after taking ferrous sulfate to reduce the likelihood of complexation.²⁵ However, not all complex-forming drug interactions are harmful. For instance, activated charcoal is sometimes administered to patients who overdose on select medications, provided it is administered within a certain time frame.²⁶ Studies show that activated charcoal is most likely to reduce the absorption of an offending substance if it is administered within 1 hour of its ingestion.²⁶

Additive interactions—this type of interaction occurs when 2 drugs with similar mechanisms of action produce an overall effect that is equal to the sum of the individual drug effects.¹⁹ For instance, an example of an additive interaction would be the co-administration of ibuprofen and acetaminophen. If taken together, a patient would likely experience the pain- and fever-reducing effects of both drugs; however, the sum of the additive effects (pain and fever reduction) is similar to what would be expected if the patient was exposed to each drug individually. Therefore, this type of drug interaction is considered additive.

Synergistic interactions—this type of interaction occurs when 2 co-administered drugs produce an overall effect that is greater than the sum of the individual drug effects.¹⁹ For instance, patients with prosthetic heart valves who undergo surgical procedures are at risk of acquiring a bacterial infection caused by the microorganism Enterococcus faecalis. When used alone, gentamicin is ineffective against E faecalis; however, when used in combination with vancomycin, the antibacterial effects of gentamicin are enhanced.¹⁹ Because the overall clinical effect is greater, vancomycin plus gentamicin is considered a synergistic drug interaction.

Potentiation—this type of interaction occurs when a drug with no real clinical benefit of its own increases the activity of another drug.¹⁹ An example of this interaction is observed with the drug amoxicillin-clavulanic acid, which consists of 2 separate active ingredients: amoxicillin and clavulanic acid. Clavulanic acid has negligible antimicrobial effects when given alone. However, when it is used in combination with amoxicillin, clavulanic acid improves the antimicrobial effects of amoxicillin by inhibiting enzymes produced by certain bacteria that would otherwise inactivate most penicillins.²⁷

Antidotes—an antidote is a drug or substance that reverses the effect of another drug.¹⁹ For example, if a patient takes too much diazepam (a benzodiazepine), there is a chance he or she could become unresponsive. In these circumstances, the drug flumazenil is usually administered because it binds to the benzodiazepine receptor site and reverses the effects of diazepam within a matter of minutes.¹⁹

AGE, GENDER, AND GENETICS

It is important to note that individuals have varying amounts and types of intestinal and hepatic CYP450 enzymes.¹ This is called genetic variation. These individual variations are acquired and generally stable over the course of a lifetime.¹ Consequently, the extent of some food-drug and drug-drug interactions are not predictable from patient to patient. Further, the enzyme cytochrome P-2D6 (CYP2D6) is responsible for the metabolism of approximately 20% to 25% of all marketed drugs.²⁸ Some individuals, however, have acquired a distinctive form of this enzyme, which has proved to be less effective at metabolizing certain drugs.²⁸ For example, CYP2D6 is the enzyme responsible for the metabolism and activation of tamoxifen, a drug that is commonly used for the prevention and treatment of breast cancer. In select studies involving tamoxifen, patients with modified CYP2D6 have demonstrated an increased number of relapses and poorer quality of life compared to patients without its modified enzymatic form.²⁸ The take away message is that individuals’ clinical responses to drugs are influenced by several factors, including genetics, age, and gender. To further highlight the effect of age and gender on drug response, the following example is presented:

Pharmacy practice

MJ is a 58-year-old female who routinely gets her blood pressure medications from your pharmacy. Today, she is picking up her first refill for zolpidem 10 mg. According to MJ, the medication is helping her sleep, but she is often very tired in the morning. She seems very concerned and asks you if this is a common complaint. After gathering patient- and medication-related information from MJ’s profile, you present her question to the pharmacist.

Background information

Female gender and advanced age have been identified as risk factors for the long-term use of zolpidem and other sleep-related medications.²⁹ With regard to zolpidem, it is important to note that its clinical effects differ by gender; zolpidem is eliminated from the body more slowly in women than men, which may increase the risk of driving impairment following a night of rest. According to driving simulation studies, zolpidem blood levels above a certain threshold have been linked to impaired driving performance. Further, pharmacokinetic studies have demonstrated that a substantial number of patients are often above this threshold the morning after taking zolpidem.²⁹ As a result, in 2013, the FDA approved label changes specifying new dosing recommendations for zolpidem products because of next-morning impairment associated with driving and other activities requiring mental alertness. The updated dosing recommendations follow³⁰: (1) the initial dose of immediate-release zolpidem products (Ambien, Zolpimist, and Edluar) is 5 mg for women and either 5 mg or 10 mg for men; and (2) the recommended initial dose of extended-release zolpidem (Ambien CR) is 6.25 mg for women and either 6.25 or 12.5 mg for men. By lowering the recommended starting dose of zolpidem products in women, the potential risk for these morning-after effects may be reduced. Notably, product labeling for the middle-of-the-night sublingual zolpidem product (Intermezzo) remains unchanged as it was released to market with a lower dosage for women than men.²⁹

Not only do the effects of zolpidem differ by gender, but age and liver impairment influence dosing recommendations as well. For instance, the bioavailability of zolpidem in patients who have liver impairment can be up to 5 times higher compared with those who have normal liver function.²⁹ As a result, the recommended dose of zolpidem in those who have liver impairment (as well as elderly patients) is as follows^29,30: 5 mg/day for the immediate-release formulations, 6.25 mg/day for the extended-release formulation, and 1.75 mg/day for the fast-acting sublingual formulation.

Pharmacy practice—follow up

To address MJ’s concerns regarding next-day tiredness after the use of zolpidem, the pharmacist discusses product labeling and reviews the zolpidem MedGuide with her at the counseling window. At the conclusion of the conversation, he recommends that she discuss her next-day symptoms with her health care provider so they can collectively determine the best course of sleep therapy for her moving forward.

CONCLUSION

The role of the pharmacy technician is evolving. Many technicians are taking on more advanced responsibilities, including those more traditionally performed by a pharmacist.³¹ In community and hospital pharmacy settings, technicians are contacting prescribers for clarification of prescriptions, participating in quality assurance activities, screening medication orders for dangerous medical abbreviations, as well as inputting new prescription data.³¹ As a result, it is important that technicians understand the different factors that can affect drug delivery, including age, genetics, underlying disease states, food, and drug-drug interactions. Although it can be very difficult, and nearly impossible, to recall every potential drug interaction, most pharmacies have computer applications that interface with order entry systems, which function to flag potentially dangerous interactions when entering new prescriptions.³² When these safety alerts occur, it is important that they are not bypassed without a pharmacist’s review. However, none of the drug interaction applications are of much benefit if the patient’s complete drug and allergy history are not stored in the computer database.³² For this reason, it is important to confirm all OTC and prescription medications that a patient is taking before entering and/or dispensing new medications.³² Also, when new or existing patients provide updated drug or allergy information at the pharmacy or over the telephone, pharmacy technicians must take the time to upload the information into the patient’s profile. If specific questions arise during this process, pharmacy technicians should not hesitate to contact the pharmacist for assistance.³²

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