Heart drug may do harm
Nitroglycerin has been a mainstay of heart disease treatment for 130 years, relieving chest pain and poor blood flow among patients with coronary artery disease, heart failure and heart attacks. Now comes the suggestion that some forms of it may be damaging.
When nitroglycerin is given continuously through patches and creams, or intravenously to hospitalized heart attack patients, it may injure the lining of blood vessels, researchers from Duke University in North Carolina and several universities in Germany have found.
Given the findings, reported in the February issue of the Journal of Clinical Investigation, the researchers said it was time to subject the compound to clinical trials of its safety and usefulness.
“We’ve simply taken for granted that nitroglycerin is good,” said lead author Dr. Jonathan S. Stamler, a cardiologist at Duke University. “But we haven’t applied the same stringent criteria that have been applied to other important cardiovascular drugs.”
Many of the 7 million Americans with angina and 5 million with heart failure currently take nitroglycerin, first used by Swedish scientist Alfred Nobel in the mid-19th century to make dynamite. Most patients simply pop a pill under the tongue when symptoms develop and -- moments later -- their blood vessels dilate and the pain goes away. For them, nitroglycerin is safe, the researchers emphasized.
But hundreds of thousands are steady users of the drug, a standard therapy of coronary artery disease and heart failure, often developing a phenomenon called nitro tolerance, in which regular amounts become ineffective, requiring larger doses. In the new study, the authors discovered that prolonged use leads the little energy factories inside cells, called mitochondria, to release free radicals that injure the heart and blood vessel walls. Diabetics and heart patients, whose blood vessel walls already are diseased, may be particularly vulnerable to additional damage, Stamler said.
Boosting the dose might make things worse, he added.
Stamler and his coauthors reported that rats treated for three days with nitroglycerin stopped responding to the drug and that their cells produced less of a key enzyme involved in dilating blood vessels. Worse still, the cells’ mitochondria became damaged and began spitting out harmful free radicals, a type of cellular rust.
“By giving this to patients in the absence of hard evidence that we’re helping them in the long run, there is the potential that we might actually be doing them a disservice,” Stamler said.
Although not part of the study, other heavily prescribed nitroglycerin-like pills, such as Imdur (isosorbide mononitrate) or Isodil (isosorbide dinitrate), also become less effective with continuous use and may produce the same kind of damage, Stamler said. He and his colleagues are studying ways to prevent tolerance and damage by giving antioxidant-like drugs along with nitrates. They’re also trying to develop a new class of drug to replace nitrates.
In the meantime, Stamler suggested that doctors be more cautious, prescribing the lowest possible doses of nitrates for shorter periods. One solution has been to give patients little medication breaks, such as removing the patch for a few hours each day.
Dr. Uri Elkayam, director of the heart failure program at USC, says such breaks may be sufficient to avoid damage. He estimated that about 40% of heart failure patients take nitrates, some continuously.
The study underscores the need for physicians to prescribe nitrates intermittently, he said, adding that a blood pressure drug called hydralazine, which also acts as an antioxidant, seems to prevent tolerance and may prevent the formation of free radicals.
