Doctors beware: These Rx drugs can damage major organs

By Naveed Saleh, MD, MS
Published December 3, 2020

Key Takeaways

In the United States, more than 131 million people take prescription drugs. Thanks to advances in technology and drug development, more Americans than ever take them. Older people and those with chronic conditions are most likely to take medications—they’re also the populations at increased risk for adverse reactions.

Adverse effects of prescription drugs can impact major organ systems, including the lungs, liver, and kidneys. Here’s a look at five examples that warrant special attention.

Amiodarone and the liver

Amiodarone is a potent antiarrhythmic agent and thyroid-hormone structural analog that can remain in liver tissue long after therapy is discontinued, leading to various forms of liver disease. The annual incidence of clinically apparent liver disease is up to 1%, with higher doses and longer duration of therapy playing roles. Symptoms of hepatotoxicity include fatigue, weight loss, and nausea, as well as mild jaundice in some cases. Signs include hepatomegaly and mild-to-moderate elevations in serum aminotransferase and alkaline phosphatase levels. 

Severe hepatotoxicity leads to progressive weakness, weight loss, ascites, and hepatic encephalopathy, indicative of end-stage liver disease. Overall, severe amiodarone-induced hepatotoxicity presents similarly to alcoholic liver disease—both clinically and histologically. But, with amiodarone toxicity, AST and ALT rise to a similar degree, unlike alcoholic liver disease where AST rises more than ALT. Patients on the drug require baseline testing for liver enzyme levels followed by testing every 6 months, with the agent discontinued if liver enzymes persistently number over twice the upper limit of the normal range. Even so, the benefit of such monitoring to prevent liver injury remains to be elucidated.

According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), various mechanisms underlying hepatotoxicity are suggested. “The cause of amiodarone hepatotoxicity appears to be direct damage to lipid bilayers and disturbance of lysosomal and/or mitochondrial function. Amiodarone appears to be a potent inhibitor of phospholipase A accounting for the accumulation of lipid-rich material in lysosomes,” the agency wrote.

“The pattern of injury also suggests mitochondrial injury and dysfunction with resulting microvesicular fat and ballooning degeneration, which leads to fibrosis and Mallory body formation. The acute liver injury from intravenous amiodarone has been variously attributed to idiosyncratic toxicity, hypersensitivity and toxicity of the vehicle (polysorbate 80),” according to NIDDK.

Chemotherapy and the lungs

Any form of chemotherapy can damage the lungs, but lung toxicity is most common with bleomycin, busulfan, carmustine, and cyclophosphamide. Between 1% and 10% of those taking these drugs develop drug-induced interstitial lung disease (DILD). Studies involving bleomycin have demonstrated damage mostly affects the lung base, with symptoms developing within 4 weeks or after 10 weeks of chemotherapy initiation. 

DILD due to busulfan toxicity usually occurs following 3-4 years of therapy.  Although cyclophosphamide may lead to later damage, it can also cause early-onset DILD, with such damage occurring with an incidence of less than 1%.

“Lung injury that is induced by pneumotoxic agents gives rise to alveolitis and edema. In response to injury to the lung parenchyma, there is an immediate requirement to initiate tissue repair and restore barrier function,” wrote the authors of a review article published in The Open Medicine Respiratory Journal.

“Acute injury may progress to chronic inflammation and eventually lead to fibrotic change that ultimately interferes with gas exchange,” they added. “Chemotherapeutic drugs can additionally cause a direct toxic reaction, and direct toxicity usually occurs over time before manifesting clinically induced pulmonary fibrosis,” 

Allopurinol and the liver

Allopurinol is a xanthine oxidase inhibitor used to treat gout. This drug is notorious for causing a rare but sometimes-fatal hypersensitivity reaction resulting in acute liver injury. Signs and symptoms are immunoallergic in nature and include rash, fever, eosinophilia, arthralgia, facial edema, lymphocytosis, and lymphadenopathy.

It typically takes between 2 and 6 weeks for acute liver injury secondary to allopurinol to manifest, with increases in hepatocellular enzymes, cholestatic enzymes, or both. Death can occur directly due to liver failure or due to allergic manifestations including toxic epidermal necrolysis, renal dysfunction, pancreatitis, or vasculitis. Predisposing risk factors for allopurinol hypersensitivity include Black race and pre-existing kidney disease.

Aminoglycosides and the kidneys

Clinicians fear the capability of aminoglycosides to cause acute kidney injury (AKI). In addition to leading to lengthy hospital stays and increased risk of developing chronic kidney disease, AKI can be deadly. Notably, vancomycin coadministration, high aminoglycoside trough levels, and heart failure are all independently associated with aminoglycoside-induced AKI, according to the results of a retrospective study published in Nephron.

When aminoglycosides are used to treat endocarditis or multi-drug resistant infections, they can accumulate in the proximal tubular cells and interfere with phospholipid metabolism, thus resulting in tubular epithelial cell death and acute tubular necrosis. Moreover, renal vasoconstriction and mesangial contraction can further impair kidney function. 

In light of these risks, expert guidelines recommend against using aminoglycosides in patients at high risk of AKI. 

Proton-pump inhibitors and the kidneys

In 1992, researchers first noted that the use of proton-pump inhibitors (PPIs) predicted acute interstitial nephritis (AIN). (Early researchers also observed that kidney function did not return to baseline in those with AIN, thus suggesting chronic kidney disease.) Despite the identification of AIN risk, this condition continues to elude diagnosis because patients with the condition often don’t manifest typical symptoms, which include rash, fever, eosinophilia, and other hypersensitivity reactions. Moreover, diagnostic tests are often suboptimal for detection.

More recently, observational studies have strongly correlated PPI use with the development of chronic kidney disease (CKD). In an editorial published in the Journal of the American Society of Nephrology, the authors made some relevant recommendations: 

“[T]he message for physicians and patients is that PPI use should be discouraged when a clear cut indication does not exist, despite the apparent short-term safety. In those who require PPI therapy to treat acid-related gastrointestinal disease, some form of surveillance (serum creatinine and/or urinalysis testing) should probably be undertaken,” they wrote.

“Practitioners prescribing these drugs should be aware of both the short-term AIN and AKI risk as well as the long-term CKD risk,” they added. “PPI-induced AIN should be considered in patients with unexplained serum creatinine rise or urinalysis abnormalities, prompting nephrology consultation and possibly kidney biopsy to verify (or rule out) AIN.” 

Patients who use over-the-counter PPIs make monitoring for the development of kidney disease even more challenging, they noted.

The authors stopped short of asserting that PPIs no longer be sold over-the-counter. They did advise, however, that physicians ask their patients about the use of these drugs, and recommended that patients with acid-related gastrointestinal disease switch from prescription PPIs to H2 blockers. Clinicians should also keep in mind that steroids can be used to treat AIN.  

Bottom line

Although most prescription drugs are safe when taken as advised, clinicians should keep an eye out for drugs that can cause major organ damage, especially in high-risk populations. Fortunately, alternatives to these drugs often exist. Moreover, close monitoring of symptoms and lab values is likely prudent in certain instances.

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