Beware of grapefruit juice, warn doctors

The patient didn’t overdose on medication. She overdosed on grapefruit juice. The 42-year-old was barely responding when her husband brought her to the emergency room. Her heart rate was slowing, and her blood pressure was falling. Doctors had to insert a breathing tube, and then a pacemaker, to revive her.

They were mystified: The patient’s husband said she suffered from migraines and was taking a blood pressure drug called verapamil to help prevent the headaches. But blood tests showed she had an alarming amount of the drug in her system, five times the safe level.

Did she overdose? Was she trying to commit suicide? It was only after she recovered that doctors were able to piece the story together. “The culprit was grapefruit juice,” said Dr. Unni Pillai, a nephrologist in St. Louis, Mo., who treated the woman several years ago and later published a case report.

The previous week, she had been subsisting mainly on grapefruit juice. Then she took verapamil, one of dozens of drugs whose potency is dramatically increased if taken with grapefruit. In her case, the interaction was life-threatening.

Last month, Dr. David Bailey, a Canadian researcher who first described this interaction more than two decades ago, released an updated list of medications affected by grapefruit. There are now 85 such drugs on the market, he noted, including common cholesterol-lowering drugs, new anti-cancer agents, and some synthetic opiates and psychiatric drugs, as well as certain immunosuppressant medications taken by organ transplant patients, some AIDS medications, and some birth control pills and estrogen treatments.

“What drove us to write this paper was the number of new drugs that have come out in the last four years,” said Bailey, a clinical pharmacologist at the Lawson Health Research Institute, who first discovered the interaction by accident in the 1990s.
Debate by scientists

How often such reactions occur, however, and how often they are triggered in people consuming regular amounts of juice is debated by scientists. Bailey believes many cases are missed because doctors don’t think to ask if patients are consuming grapefruit or grapefruit juice. Even if such incidents are rare, Bailey argued, they are predictable and entirely avoidable. Many hospitals no longer serve juice, and some prescriptions carry stickers warning patients to avoid grapefruit.

“The bottom line is that even if the frequency is low, the consequences can be dire,” he said. “Why do we have to have a body count before we make changes?”

For 43 of the 85 drugs now on the list, consumption with grapefruit can be life-threatening, Bailey said. Many are linked to an increase in heart rhythm, known as torsade de pointes, that can lead to death. It can occur even without underlying heart disease and has been seen in patients taking certain anti-cancer agents, erythromycin and other anti-infective drugs, some cardiovascular drugs like quinidine, the antipsychotics lurasidone and ziprasidone, gastrointestinal agents cisapride and domperidone, and solifenacin, used to treat overactive bladders.

Taken with grapefruit, other drugs like fentanyl, oxycodone and methadone can cause fatal respiratory depression. The interaction also can be caused by other citrus fruits, including Seville oranges, limes and pomelos; one published case report has suggested that pomegranate may increase the potency of certain drugs.

Older people may be more vulnerable, because they are more likely to be both taking medications and drinking more grapefruit juice.

Under normal circumstances, the drugs are metabolized in the gastrointestinal tract, and relatively little is absorbed, because an enzyme in the gut called CYP3A4 deactivates them. But grapefruit contains natural chemicals called furanocoumarins that inhibit the enzyme, and without it the gut absorbs much more of a drug and blood levels rise dramatically.

Estradiol and ethinyl estradiol, forms of estrogen used in oral contraceptives and hormone replacement, also interact with grapefruit juice. In one case in the journal Lancet, a 42-year-old woman taking the birth control pill Yaz developed a serious clot that threatened her leg several days after she started eating just one grapefruit a day, said Dr. Lucinda Grande, a physician in Lacey, Wash., and an author of the case report.

Some drugs that have a narrow “therapeutic range” – where having a bit too much or too little can have serious consequences – require vigilance with regard to grapefruit, said Patrick McDonnell, clinical professor of pharmacy practice at Temple University. These include immunosuppressant agents like cyclosporine that are taken by transplant patients to prevent rejection of a donor organ, he said.

Still, McDonnell added, most patients suffering adverse reactions are consuming large amounts of grapefruit. “There’s a difference between an occasional section of grapefruit and someone drinking 16 ounces of grapefruit juice a day,” he said.