Although often assumed to be safe, prescription and over-the-counter medications can cause serious adverse reactions, especially in certain high-risk populations. Acetaminophen (Tylenol) and ibuprofen (Advil), just two categories of drugs that can cause adverse reactions, are ingredients in more than 200 OTC and prescription drug preparations.¹ In addition, with the increase in popularity in recent years of “natural” medicine (about 36% of U.S. adults used complementary or alternative medicine in 20022), cases of herbal therapy toxicities are being reported at an accelerated rate.

Specifically, OTC and prescription drugs and even herbal products can target the kidney and liver for drug-induced toxicities. The causes of these toxicities are complex, and certain patient populations are more susceptible than others. Because these reactions can be prevented if users are educated about the risks and screened for risk factors before therapy starts, nurses must be able to identify the drugs and their potential toxicities and monitor requirements to ensure their patients’ safety.

Renal toxicity

It’s common knowledge that certain drug classes — such as the aminoglycoside antibiotics gentamicin (Garamycin), tobramycin (Nebcin), and amikacin (Amikin) and immunosuppresive agents, including cyclosporine (Sandimmune) and tacrolimus (Prograf)—can be harmful to the kidneys and require intense monitoring, but many clinicians do not know the extent of renal damage that may occur with common drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetaminophen, and common lipid-lowering drugs, such as lovastatin (Mevacor).³

Some drugs may be toxic because they reduce blood flow to the kidneys by affecting the renal afferent arteriole. Adequate renal blood flow must be maintained; otherwise, a decreased blood flow to the kidney may result in renal impairment.⁴ Prostaglandins, chemicals present throughout the body, have many functions, including the maintenance of renal blood flow by counteracting the constricting action that certain hormones might have on renal vessels.^1,5,3

NSAIDs: The NSAIDs exert their anti-inflammatory and fever-lowering effects by inhibiting cyclooxygenase (COX), an enzyme responsible for the production of prostaglandins. Prostaglandins are not key renal blood flow mediators in healthy people with normal kidneys, but in people with a decreased blood volume or circulation problems, the kidney depends on the dilating effect of the prostaglandins on renal blood vessels to maintain renal blood flow. Because NSAIDs reduce prostaglandin production, people at greatest risk for renal toxicity are those who already have the above problems. People using diuretics and those suffering from dehydration, severe heart failure, and liver failure with accompanying ascites are the most susceptible to NSAID-induced renal failure.^1,4

Inhibition of prostaglandin synthesis by NSAIDs is also responsible for electrolyte disturbances, such as increased potassium and sodium blood levels. Secretion of aldosterone, a hormone released by the kidneys during hypotensive states, is mediated by the prostaglandins through the renin-angiotensin-aldosterone system (RAAS) cascade. The RAAS cascade is activated to raise blood pressure when blood pressure is low.^1,6

The major function of aldosterone is to increase blood volume in low blood pressure states by retaining sodium and water through the kidney. This action maintains adequate blood pressure when the blood pressure drops. When sodium is retained by the kidney, potassium flows in the opposite direction and is excreted through the kidney. Simply put, when sodium is retained in the body by aldosterone, potassium is excreted. When agents such as NSAIDs decrease the amount of prostaglandins, aldosterone levels are subsequently decreased and potassium levels are increased. This is usually a problem only in people who, in addition to the NSAIDs, are taking drugs that will increase potassium blood levels such as potassium supplements or potassium-sparing diuretics such as spironolactone (Aldactone) or triamterene (an ingredient in Dyazide).^4,5

Because prostaglandins facilitate sodium excretion, some patients also may experience sodium retention when taking NSAIDs. This can cause edema in the extremities and in some instances, increase blood pressure or worsen symptoms of heart failure. People at greatest risk are those with diabetes, renal disease, circulatory complications, and advanced age. This also can interfere with the therapeutic effects of loop and thiazide diuretics, such as furosemide (Lasix) and hydrochlorothiazide (HydroDIURIL).⁵

COX-2 inhibitors: The COX enzyme is present in two forms: COX-1 and COX-2. The COX-1 enzyme is present in the stomach and is responsible for producing prostaglandins that protect the stomach lining. The COX-2 enzyme produces pain mediators when inflammation is present. COX-2 is also responsible for producing prostaglandins in the kidney that maintain renal blood flow in patients with compromised circulation, which decreases renal blood flow.⁷ The traditional NSAIDs inhibit both of these enzymes, while more selective COX inhibitors, such as celecoxib (Celebrex) selectively inhibit the COX-2 enzyme.

Theoretically, the selective COX-2 inhibitors provide anti-inflammatory actions without causing gastric injury but offer no protection against potential renal toxicity. The same patients who are at risk for renal toxicity with traditional NSAIDs are also at risk with the selective COX-2 inhibitors.⁷

ACEIs: The angiotensin-converting enzyme is involved in the RAAS cascade. A class of blood pressure medications, the angiotensin-converting enzyme inhibitors (ACEIs), inhibit this enzyme, thus inhibiting the RAAS cascade. By a negative feedback mechanism, this action increases the amount of prostaglandin, which increases renal blood flow by dilating the renal blood vessels. This effect is especially beneficial and actually protective in diabetic patients but may be detrimental in special patient populations. The ACEIs may worsen conditions when renal blood flow depends on increased renal blood pressure provided by the RAAS, such as in renal artery stenosis or severe heart failure.^4,3

With the NSAIDs, COX-2 inhibitors, and ACEIs, renal function and risk factors should be monitored and assessed before treatment and periodically thereafter. Patients should be educated about the possible side effects and told to notify their physician immediately of any side effects.

Acetaminophen: Habitual use of analgesics has been associated with analgesic-associated nephropathy (AAN) and subsequent end-stage renal disease. This became apparent with the chronic use of phenacetin more than three decades ago. Once this syndrome was recognized, phenacetin was taken off the market in most countries, including the United States, in 1983. Since then, evidence — although inconclusive — has suggested that the long-term use of acetaminophen (a metabolite of phenacetin) and NSAIDs causes AAN.^6,5

Lipid-lowering agents: Lipid-lowering agents such as atorvastatin (Lipitor), fluvastatin (Lescol), and lovastatin (Mevacor) have the potential to cause a complication called rhabdomyolysis. Rhabdomyolysis occurs when there is a breakdown of muscle that, in turn, releases myoglobin, an oxygen-transporting protein found in the muscle. Excess myoglobin excreted through the kidney could lead to renal failure. This is a potential adverse effect of all statins and is especially a concern when statins are combined with gemfibrozil (Lopid); fenofibrate (Tricor); cyclosporine, erythromycin, lipid-lowering doses of niacin; and azole antifungals such as ketoconazole (Nizoral), itraconazole (Sporanox), and fluconazole (Diflucan). Patients taking a statin should be advised to seek medical attention if they experience indications of muscle breakdown, including muscle pain or tenderness.^4,3

Other agents: The nephrotoxic effects of chemotherapy agents including cisplatin (Platinol); immunosuppressive agents, such as cyclosporine (Sandimmune) and tacrolimus (Prograf); and antibiotics, including the aminoglycosides (gentamicin, tobramycin, and amikacin) have been well documented. These agents require intensive monitoring of renal function, including periodic serum creatinine (SCr) and blood urea nitrogen (BUN) levels. In addition, some of these drugs, including cyclosporine and the aminoglycosides, require drug level evaluation for accurate dosing.^4,3

Contrast media is used in various diagnostic and therapeutic procedures including intravenous pyelography, computed tomography scans, and angiographies. Patients with diseases such as diabetes mellitus, multiple myeloma, and liver disease are at risk for renal toxicity when given these agents, although such an adverse effect is uncommon. In addition, dehydration, hypertension, and previous exposure to contrast media also may predispose patients to renal toxicity. Increased hydration, both oral and intravenous, before and after a procedure, can reduce the occurrence of renal toxicity in these patients.³ Patients taking metformin (Glucophage) must discontinue therapy before receiving contrast dye and may continue using the drug 48 hours after the test only if renal function has returned to baseline levels.³

Alternative therapies: Incidents of herbal preparations causing renal failure have been reported.⁸ Aristolochia fangchi from the Mu Tong, or clematis, plant is a common ingredient in diet and eczema preparations in the United Kingdom. People taking this herb presented with end-stage renal disease that eventually required hemodialysis and renal transplants.⁸ Yohimbe, used for erectile dysfunction, has also been shown to cause renal failure.⁹

Liver toxicity

Prescription drugs, such as troglitazone (Rezulin) and cerivastatin (Baycol), were pulled off the market after it was found thatthey caused liver toxicity. Other drugs such as gemfibrozil and isoniazid (Isotamine) require monitoring for liver toxicity. Acetaminophen and some herbal products, available OTC, may also cause liver damage.^3,10

The liver is the major detoxifying organ. It takes substances entering the body and transforms them into water-loving compounds that can easily be eliminated through the kidneys. The liver does this by changing the structure of the compound through various enzyme-dependent chemical reactions. Sometimes these reactions can produce toxic substances that require other chemicals, such as glutathione, which is present throughout the body, to render them harmless. The accumulation of these toxic substances resulting in liver damage is one mechanism of drug-induced liver injury.¹¹

Acetaminophen: Acute acetaminophen overdoses may occur from intentional ingestion or an inadvertent ingestion of large quantities. This may occur if the patient is unaware of dosing schedules and administers the drug too often or combines multisymptom preparations that may contain duplicate acetaminophen ingredients. Acetaminophen dosing is especially complicated when medicating children because pediatric preparations are available in multiple strengths.¹²

Although acetaminophen is known to cause liver damage in acute overdose, it has been implicated in liver toxicity in patients with specific risk factors who take normal therapeutic doses (<4 gm/day).¹¹ Acetaminophen-induced liver toxicity in chronic alcoholics is the one of the most common causes of acute liver failure in the United States.¹² This adverse reaction is so significant that labels on products containing acetaminophen warn that patients who consume more than three drinks daily must consult their physicians before taking the drug.³ These people need to be aware that acetaminophen liver toxicity may occur at therapeutic doses. Poor dietary intake also may predispose a person to acetaminophen toxicity. Therefore, patients who are malnourished (as alcoholics often are) are at risk for acetaminophen liver toxicity.¹¹

NSAIDs: Bromfenac became available in 1997 and was pulled off the market in 1998 because of patient deaths secondary to acute liver failure. In general, hepatotoxicity caused by NSAIDs is fairly rare, about 1 to 10 cases per 100,000 exposures. However, because of the popularity of this drug class, health care professionals need to watch for early signs of hepatotoxicity caused by NSAIDs.

There may be certain risk factors for NSAID-induced hepatotoxicity. For example, ibuprofen usually does not cause significant liver damage; however, patients with chronic hepatitis C may have an increased risk of hepatotoxicity with this drug. Additionally, diclofenac-induced hepatocellular injury is more common in women, the elderly, and osteoarthritis patients.¹³

Other agents: Numerous prescription drugs — including the antidiabetic agents pioglitazone (Actos), rosiglitazone (Avandia), and acarbose (Precose) and the HMG-CoA reductase inhibitors atorvastatin, fluvastatin, and lovastatin — require baseline and follow-up monitoring of liver enzyme tests.^10,14 These tests include aspartate aminotransferase (AST) and alanine aminotransferase (ALT ).¹⁴ It is important to educate patients about the symptoms of liver toxicity because liver damage may be present before the enzymes are elevated. Symptoms include decrease or loss of appetite, fatigue, abdominal pain, dark-colored urine, or jaundice.^10,14

Alternative therapies: Alternative therapies have been implicated in liver toxicity. Chaparral, the herb found in the leaves of the creosote bush, has caused liver toxicity in otherwise healthy adults. Chaparral is taken for its purported claims of antioxidant activity. It has been reported that the herb was taken for 6 to 11 weeks and caused liver toxicity that eventually subsided after the drug was discontinued.¹⁵ Other herbal remedies such as comfrey, germander, and pennyroyal oil are unsafe to take because of their liver toxic effects. People with liver disorders should avoid DHEA/androstenedione, coenzyme Q-10, red yeast, skullcap, and valerian root.¹⁴

In March 2002, the FDA issued a warning about the potential risk of severe liver injury associated with the use of the popular supplement kava. Used to treat sleeplessness, fatigue, and menopausal symptoms, kava has been shown to cause hepatitis, cirrhosis, and acute liver failure.¹⁶

Additional information about alternative therapies is available on the following websites: the National Institutes of Health Office of Dietary Supplements (http://dietary-supplements.info.nih.gov) and the USDA Food and Nutrition Information Center Dietary Supplements and Herbal Information: (http://fnic.nal.usda.gov/nal_display/index.php?info_center=4&tax_level=1&tax_subject=274)

Nursing implications

Accurate and thorough drug histories are necessary in both ambulatory and institutional settings. This includes not only prescription medications, but also OTC drugs and herbal products. It is important to inquire about alternative therapies because patients may omit herbal products simply because they assume that they are safe or “natural.”

A complete patient history is required to assess for risk factors. They include any existing diseases and lifestyle activities, such as alcohol use and dietary intake. In addition, baseline liver and renal tests may be required before therapy is started. Liver function is typically monitored with the liver enzyme tests ALT and AST, while renal function is evaluated by SCr and BUN levels. In some cases, drug levels may be required for dosage adjustment. This information is available from a number of sources, including Drug Facts and Comparisons, the Physicians’ Desk Reference, and Tarascon Pocket Pharmacopoeia (www.tarascon.com). Drug files for PDAs are available from various manufacturers and from publications including the Pharmacist’s Letter (www.pharmacistsletter.com).

Patients must be counseled about the proper administration of drug products. Many OTC cold and allergy medications have multiple ingredients. The consumer needs to be aware of the products’ ingredients to avoid duplicate drug therapy. In addition, parents need to be aware that children’s liquid medications come in different strengths, which may increase the risk of dosing errors. For example, acetaminophen is available in both the 160 mg/5ml and 100 mg/ml (80 mg/0.8 ml) strengths.

Health care professionals have a responsibility to ensure that patients avoid harm. From a medication standpoint, this involves educating patients about the possible risks of prescription and OTC medications and alternative therapies. In addition, patients should be encouraged to consult a health care professional before taking these therapies to make certain they are not at risk for drug toxicities.