Adverse Drug Reactions and Interactions Case File

Adverse Drug Reactions and Interactions Case File

Eugene C. Toy MD, Donald Briscoe, MD, FA  AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA  AFP, FACG

Case 52

A 74-year-old African-American woman presents with the complaint that she has been developing nontraumatic bruises all over her extremities for the last several days. She has also noticed that her stools seem to be a lot darker, almost like "coffee grounds:' She recently relocated to your area to live with her daughter. While this is her initial visit to your office, she has had refills available for all of her current medications and previously been at her baseline state of health. Her past medical history is significant for hypertension, postmenopausal state, an irregular heartbeat that she doesn't remember the exact name for, arthritis, and "a touch of diabetes:' Her prescribed medications include hydrochlorothiazide and warfarin. Her over-the-counter medications include aspirin which she started taking since moving to your city, a multivitamin, acetaminophen for her arthritis, and ibuprofen for when her knees really bother her. She also admits to regularly drinking herbal teas.

⯈ What is the differential diagnosis for this patient's presentation?

⯈ What diagnostic studies are indicated?

⯈ Why are the elderly at an increased risk for the development of adverse drug reactions?

ANSWER TO CASE 52

Adverse Drug Reactions and Interactions

Summary: A 74-year-old woman presents with easy bruising and dark stools for several days. She is new to your practice, and takes an antihypertensive medication and an anti-coagulant. She is also taking numerous over-the-counter medications.

• Differential diagnosis: Includes an adverse drug interaction involving warfarin and aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Other (much less likely) possibilities include bleeding from a gastrointestinal malignancy, liver disease, or hematologic abnormality ( eg, acute leukemia or severe thrombocytopenia).
• Necessary diagnostic studies: This patient should have a guaiac-based test for occult blood in the stool conducted in the office, a STAT complete blood count (CBC), a prothrombin time (PT) with international normalized ratio (INR), a comprehensive metabolic panel, and an electrocardiography (ECG). It would be appropriate to consider this patient for observation status in the hospital while her studies are pending if she is orthostatic, or if other signs suggest blood or volume loss that could predispose her to syncope.
• Reasons for increased risk of drug reactions in the elderly: Polypharmacy, decline in renal and hepatic function, and pharmacodynamic considerations including change in body composition and volume of distribution that develop with normal aging.

ANALYSIS

Objectives

1. Understand the scope and risk of the problem of drug interactions and adverse effects.
2. Learn strategies to reduce the risks of adverse drug interactions.
3. Know why the elderly are particularly vulnerable to potential adverse drug reactions.

Considerations

The extensive use of multiple medications, or polypharmacy-including prescribed, over-the-counter, herbal, and homeopathic products-makes adverse drug reactions and interactions a significant public health concern. Approximately 40% of people age 60 and older take at least five medications daily, and will experience an average of one adverse drug event each year and two-thirds of these patients will require medical attention because of it. Approximately 6.5% of hospital patients experience a documented adverse event secondary to medications. Physiologic changes and the use of multiple medications simultaneously for multiple medical conditions place aging individuals and the elderly at increased risk of adverse events and drug-drug interactions. An estimated 3% to 11% of hospital admissions in the elderly are related to adverse drug reactions.

The patient presented above has numerous risks for the development of adverse events related to her various medications. In addition to her age, the use of warfarin is another risk, as its use should be closely monitored via serial PT/INR measurements. Warfarin also has numerous drug-drug interactions, including an increased risk of bleeding and bruising with the concomitant use of aspirin, NSAIDs, and/or acetaminophen.

Due to her age, the presence of bruising (suggesting an increased PT /INR), and the possibility of melena or hematochezia, this patient should have a fecal occult blood test (FOBT) performed and she should be screened for anemia with a CBC with platelet count. A negative FOBT test does not rule out lower gastrointestinal malignancy, thus if suspicion is high, she should undergo additional testing including colonoscopy. Due to her age and comorbid conditions, she should have a comprehensive metabolic panel to evaluate her glucose, electrolytes, and renal and liver functions, and an ECG to evaluate for signs of ischemia. With the possibility of significant abnormalities on these tests that may require urgent management, it would be reasonable to place her in observation status in the hospital for monitoring and treatment.

If she is found to have a prolonged PT/INR, several therapeutic options are available, depending on the clinical situation and the magnitude of the abnormality. For over-anti-coagulated patients with mildly elevated INR values (eg, 3-4) without evidence of bleeding, temporary discontinuation of warfarin or dose reduction is sufficient. For more elevated INR values in the setting of acute bleeding or spontaneous bruising, oral vitamin K along with stopping the warfarin will correct most abnormalities within a few days. When the INR value is very high (eg, >10), or if there is evidence of acute bleeding and hemodynamic compromise, then intravenous vitamin K and replacement of coagulation factors with a transfusion of fresh frozen plasma (FFP) will rapidly reverse the coagulopathy.

Approach To:

Adverse Drug Reactions and Interactions

DEFINITIONS

BEERS LIST: The Beers criteria for potentially inappropriate medication use in older adults (commonly referred to as the Beers list) is a guideline for healthcare providers to improve the safety in medication prescribing for older adults, to minimize unnecessary medications, and to minimize polypharmacy and drug interactions.

CYTOCHROME P450 (CYP): An enzyme system found mostly in the liver ( but also in the small intestine, lungs, and kidneys) that is composed of more than 50 isoenzymes, and which is responsible for the metabolism of numerous medications. The CYP isoenzymes can be induced, resulting in increased drug metabolism and reduced therapeutic benefit of a medication, or blocked, resulting in decreased drug metabolism and potential for drug toxicity.

STOPP and START TOOLS: T he Screening Tool of Older People's Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) are lists of potentially inappropriate and interactive medications with therapeutic alternatives.

CLINICAL APPROACH

Etiologies of Adverse Drug Effects

Adverse drug effects (ADEs) are defined as any effects experienced beyond the intended therapeutic scope of the drug that have a negative impact on the patient. Adverse drug effects can range from minor symptoms such as nausea or diarrhea, to severe or life threatening including cardiac arrhythmias precipitated by antiarrhythmic or stimulant medications. Other side effects of medications have been found to be beneficial. For example, peripheral a-adrenergic blockers, initially used as antihypertensives, have been found to minimize lower urinary tract obstructive symptoms from benign prostatic hyperplasia and is the most efficacious therapy for this condition. Another example is minoxidil, also an antihypertensive agent, which was found by some users to result in hair growth, so it is now marketed as a treatment for hair loss.

Drug interactions account for 5% to 10% of adverse reactions. Drug interactions may be caused by pharmacokinetic effects, resulting in a change in either the drug's concentration or the drug's effect. Some of these interactions may be predictable, as a consequence of chemical effects secondary to enzymatic effects, protein binding, renal or hepatic interactions, and pharmacodynamic interactions. For example, warfarin may interact with several other medications and dietary factors to increase the active form of this drug to toxic levels, resulting in over-anticoagulation with resultant bruising and hemorrhage.

Drugs also may have additive or synergistic effects caused by using two or more agents designed to produce a desired effect (eg, lowering blood pressure), yet they produce an effect greater than anticipated. An example of this is using a β-adrenergic blocking agent with certain calcium channel blockers (eg, diltiazem, verapamil). Both medications can decrease heart rate, but by different mechanisms of action. Combining the two agents may result in profound bradycardia and hypotension.

Other interactions may be more directly related to the chemical properties of the medications or the solutions in which they are delivered. For example, mixing glargine insulin with other insulin types in the same syringe may result in precipitation of the insulin product, rendering them ineffective. Similarly, some intravenous medications must be administered individually to avoid precipitation and potentiation, while others can be combined.

To avoid misuse of medications in the elderly, and to identify high-risk medications, an expert consensus panel developed a widely used list of medications that should be avoided, called the Beers criteria. Many of these medications are sedating or have anticholinergic effects that increase the risk of falls. Others have narrow therapeutic indexes, increasing the risk of developing toxic serum levels. The STOPP/START criteria have been used to detect adverse drug effects that are either causal or contributory to acute hospitalization in older people at a rate 2.8 times more frequently than compared to Beers criteria. It is imperative that clinicians are aware of equally effective therapeutic alternatives. If a patient is already on these medications, lowering the dose to the minimum effective dose is another way of minimizing risk. To date, there is no effective evidence that use of the Beers criteria, or the START/STOPP criteria reduce morbidity, mortality, or health-care costs.

Drug Metabolism

Medications with a high first-pass hepatic clearance may be particularly susceptible to adverse events caused by alterations in hepatic metabolism. Diseases that change the effective circulatory volume, including congestive heart failure, may also alter the rate of drug or metabolite elimination due to the effects on hepatic and renal blood flow.

The CYP cytochrome system plays a significant role in many real or potential adverse drug events. Although more than 50 CYP isoenzymes have been identified, six of these isoenzymes metabolize 90% of drugs. Alcohol has effects on the 2El isoenzyme, which can produce a hepatotoxic metabolite of acetaminophen. Because of this, the chronic use of alcohol and acetaminophen can induce liver damage, and an acetaminophen overdose, which is already potentially toxic to the liver, has worse outcomes when the patient has been drinking alcohol.

Grapefruit has a substantial impact on the cytochrome P450 3A4 system. Medications that have been found to interact with grapefruit include statins, antiarrhythmic agents, immunosuppressants, and calcium channel blockers. Expert opinion posits that patients should refrain from grapefruit for 72 hours prior to taking medications that may interact with it, or to avoid it altogether if a patient takes one of these drug classes chronically.

Drugs that have a significant first-pass effect may have an effect on metabolism in the liver or absorption in the intestine. For example, increased levels of the 3A isoenzyme may result in alterations in the level, and therefore therapeutic effect, of cyclosporine.

Many drugs are bound to serum albumin. When multiple agents are competing

for the same albumin-binding sites, there is a potential to have greater amounts of

unbound medication, resulting in higher circulating free drug levels. This causes

particular concern for drugs that have a smaller volume of distribution, rapid onset

of action, or narrow therapeutic index.

Renal considerations are related to interaction of drugs at renal sites and decreased renal function. Renal interactions are often a result of alterations in the elimination of water-soluble drugs because of competition for the renal tubular system. These effects may be either positive or negative. An example of a beneficial effect is the concomitant administration of probenecid with penicillin. Probenecid decreases renal excretion of penicillin, resulting in an increased level and therapeutic effect of the antibiotic.

Other renal considerations include decreased kidney function secondary to either disease processes, such as hypertension or diabetes mellitus, chronic kidney disease, or from the natural decline in renal function that occurs with aging.

Many medications have recommendations for alteration in dosing amount and/or interval based on the patient's creatinine clearance. Creatinine is a byproduct of muscle metabolism and older patients may have falsely elevated calculated creatinine clearance rates because they have decreased muscle mass. Creatinine clearance is calculated using the following equation:

Interventions to Reduce the Risk of Adverse Drug Events

There are many possible interventions to reduce the risk of adverse drug events or interactions, especially in the older population, including the following:

• Always use the Beers criteria or STOPP/START criteria when considering medications in the elderly.
• Only prescribe medications that are clearly indicated, yet do not avoid a necessary medication.
• When a patient presents with a new complaint, consider the potential for ADEs in the differential.
• Obtain a history of adverse drug events related to previous and current medications on all patients.
• Maintain a current list of all medications that a patient is taking, including prescribed, over-the-counter, herbal, and homeopathic. Perform medication reconciliation at every visit.
• Instruct your patients to bring in all of their medications regularly to make sure your medication list is accurate.
• Routinely perform drug interaction surveys on patients taking multiple medications. Consider working with pharmacists and using computerized tools available to perform these surveys. Consider rational reductions and discontinuation of medication in elderly patients after consultation with the patient, family, and pharmacists.
• Have knowledge of renal, hepatic, and circulatory issues that affect your patients.
• Consider issues related to individual patients, such as unique genetic or ethnic factors.
• Document and report suspected all ADEs.

COMPREHENSION QUESTIONS

52.1 A 62-year-old man with hypertension, hypercholesterolemia, and benign prostatic hypertrophy (BPH) presents to his physician with increasing muscle aches in his thighs and shoulders and complains of dark, tea-colored urine. These symptoms started about 10 days ago. He has been drinking plenty of fluids as part of a new diet, specifically grapefruit juice. On routine laboratory evaluation, his serum transaminases are elevated to nearly three times the normal limit, serum creatinine is 1.4 mg/dL ( baseline 1.2 mg/dL), and urinalysis reveals 1+ proteinuria. His only medications are lisinopril, simvastatin, and a baby aspirin. Which of the following is the most likely diagnosis in this patient?

A. Drug-induced hepatitis from long-term simvastatin

B. Postrenal azotemia and proteinuria due to BPH

C. Acute kidney injury secondary to aspirin and lisinopril

D. Hepatic enzyme inhibition leading to elevated circulating drug levels

52.2 A 73-year-old man has diabetes mellitus, coronary heart disease, stage 3 chronic kidney disease, and chronic obstructive pulmonary disease (COPD). He has newly diagnosed atrial fibrillation and meets criteria for anticoagulation with warfarin. His current medications include metformin, glipizide, losartan, metoprolol, and ipratropium. Which of the following is the most important consideration in avoiding adverse drug reactions in the elderly?

A. Increased glomerular filtration rate

B. Polypharmacy

C. Increased cardiac stroke volume

D. Increased hepatic blood flow

E. Age and functional status

52.3 A 36-year-old woman presents to your office after appearing very distressed after having a positive pregnancy test. She says that she has taken her oral contraceptive pills (OCPs) consistently at the same time every day for the past year. She has no significant past medical history except for mild depression. The only medication she takes is a prescribed OCP, but admits that she also take vitamins and herbal supplements. Which of the following additional information would be most helpful in discovering why her OCP may have failed?

A. Which OCP she is taking

B. Which herbal supplements she is taking

C. Her number of sexual partners

D. If she has ever been pregnant before

E. What time of day she takes her OCP

ANSWERS

52.1 D. Grapefruit juice inhibits the cytochrome P450 3A4 system that metabolizes simvastatin. This patient has rhabdomyolysis from increased circulating levels of simvastatin. Simvastatin may increase transaminases, but associated cases of hepatitis and liver failure are very rare. The combination of aspirin and lisinopril has not been shown to cause acute kidney injury; a creatinine level of 0.2 mg/dL above baseline levels does not confer acute kidney injury. Moderate proteinuria and a mild elevation in serum creatinine do not constitute postrenal azotemia and proteinuria due to BPH in this patient.

52.2 B. A multitude of factors result in the elderly being particularly vulnerable to adverse drug events. Included among these are polypharmacy, decreased renal and hepatic function, decreased cardiac output, and pharmacokinetic and pharmacodynamic considerations.

52.3 B. Asking which herbal supplements a patient takes is imperative. St. John's wort, a common herbal antidepressant, can induce CYP3A4 and CYP3A5 causing increased metabolism of estradiol and lowering efficacy of OCPs.

CLINICAL PEARLS

⯈ Along with the biochemical changes that occur with aging, several physical conditions may also affect medication compliance. Arthritic patients may have difficulty opening prescription caps (especially childproof caps). Reduced vision may interfere with the ability to properly use a medication. Memory difficulties may cause trouble adhering to regimens involving multiple medications. All of these factors, and many others, need to be considered when prescribing medications to the elderly.

⯈ In elderly patients with new symptoms, consider adverse drug events highly in your differential.

⯈ Many practices have pharmacists as a component of the patient centered medical home (PCMH) model of health care. Pharmacists can be invaluable members of the patient care team in reviewing medications, herbal supplements, vitamins, and potential interactions.

REFERENCES

American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-631. 

Blanco-Reina E, Ariza-Zafra G, Ocana-Riola R, Leon-Ortiz M. 2012 American Geriatrics Society Beers criteria: enhanced applicability for detecting potentially inappropriate medications in European older adults. A comparison with the Screening Tool of Older Person's Potentially Inappropriate Prescriptions.] Am Geriatr Soc. 2014;62(7):1217-1223. 

Gallagher P, Ryan C, Byrne S, Kennedy J, O'Mahony D. STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Tber. 2008;46(2):72. 

Hamilton H, Gallagher P, Ryan C, et al. Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients. Arch Intern Med. 2011;171(11):1013-1019. 

Hill-Taylor B, Sketris I, Hayden J, et al. Application of the STOPP /START criteria: a systematic review of the prevalence of potentially inappropriate prescribing in older adults, and evidence of clinical, humanistic and economic impact.] Clin Pharm Tber. 2013;38(5):360-372. 

Lynch T, Price M. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76:391-396. 

OatesJA. The science of drug therapy. In: Brunton LL, ed. Goodman and Gillman's the Pharmacological Basis of Therapeutics.11th ed. New York, NY : McGraw-Hill Education; 2006:117-136. 

O'Mahoney D, O'Sullivan D, Byrne S, et al. STOPP /START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44(2):213-218. 

Pretorius RW, Gataric G, Swedlund SK, Miller JR. Reducing the risk of adverse drug events in older adults. Am Fam Physician. 2013;87(5):331-336. 

Steinman MA, Hanlon JT. Managing medications in clinically complex elders: "There's got to be a happy medium:' JAMA. 2010;304(14):1592. 

Stump AL, Mayo T, Blum A. Management of grapefruit-drug interactions. Am Fam Physician. 2006;7 4( 4 ):605-608.

WEBSITE RESOURCES

The BEERS criteria can be found at• www.americangeriatrics.org/files/documents/beers/2012AGSB eersCriteriaCitations.pdf 

The STOPP criteria can be found at• www.biomedcentral.com/content/supplementary/1471-2318- 9-5-Sl.doc 

The START tool can be found at• www.ageing.oxfordjournals.org/content/36/6/632.full.pdf

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