New orthostatic hypotension treatment reduces symptoms without causing high blood pressure

A drug traditionally used to treat myasthenia gravis shows potential benefit for reducing symptoms of orthostatic hypotension without raising blood pressure when people lie down, according to results of a double-blind, controlled clinical trial.

A drug traditionally used to treat myasthenia gravis shows potential benefit for reducing symptoms of orthostatic hypotension without raising blood pressure when people lie down, according to results of a double-blind, controlled clinical trial.

Orthostatic hypotension (OH) - a sudden fall in blood pressure when a person stands up - is a common problem in elderly adults as well as in people with Parkinson's disease, multiple system atrophy, diabetes, and a variety of other disorders. OH is caused by a loss of normal function in the autonomic nervous system, which controls the tightening and relaxing of blood vessels necessary to maintain normal blood pressure. People with OH may experience dizziness, lightheadedness, blurred vision, or fainting when they stand.

The standard treatment for OH is a drug called midodrine, which helps to alleviate symptoms. However, standard doses of midodrine also raise blood pressure when people lie down. Now, researchers led by Phillip Low, M.D., of the Mayo Clinic in Rochester, Minnesota, have shown that another drug called pyridostigmine can alleviate many of the symptoms of OH, either alone or in combination with a low dose of midodrine. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and is published in the April 2006 issue of the Archives of Neurology.*

Midodrine and pyridostigmine both work by causing blood vessels to constrict. Midodrine causes this constriction continuously while it is in the bloodstream. On the other hand, pyridostigmine is thought to work by slowing breakdown of the nerve-signaling chemical acetylcholine, which is used by a cluster of nerve cells called the autonomic ganglion. The autonomic ganglion transmits signals from the central nervous system to the peripheral nervous system. Signals from the autonomic ganglion are minimal when people are lying down, but increase dramatically whenever they stand up or undergo other "orthostatic stress" that causes the body to adjust to maintain normal blood pressure. Therefore Dr. Low and his colleagues theorized that pyridostigmine would increase blood pressure only when people stand up, and that it would work in proportion to the amount of orthostatic stress they experience with different activities.

The study compared the use of pyridostigmine, with or without low-dose midodrine, to a placebo in 58 patients with OH due to severe autonomic nervous system failure. The patients received four different treatments in random order on successive days: 60 mg of pyridostigmine alone, pyridostigmine plus 2.5 mg of midodrine, pyridostigmine plus 5 mg midodrine, and placebo. The researchers measured blood pressure and heart rate when the patients laid down and while they were standing, once every hour for 6 hours after the treatment was given. They also rated the patients' symptoms on a scale of 1 to 5, with 5 indicating excellent improvement, and they took blood samples at the start of treatment and 1 hour later in order to see how the treatment affected blood levels of the nerve-signaling chemicals norepinephrine, epinephrine, and dopamine.

The results showed that at 1 hour after a single administration of the study medication, both pyridostigmine alone and pyridostigmine plus 5 mg of midodrine significantly improved blood pressure when the patients stood up, compared with the placebo. None of the treatments caused increased blood pressure when patients were lying down.

"Pyridostigmine is a 'smart drug,'"says Dr. Low. "It only works when you need it."

While the overall effect on standing blood pressure was modest, patients reported a significant improvement in their symptoms. Blood levels of norepinephrine did not change significantly with any of the treatments. Although these findings are encouraging, it is unclear whether continuing long-term administration of pyridostigmine is safe and effective because the current study only evaluated its effect based on a single administration and 1 hour of follow-up.

The response to pyridostigmine was not related to the patient's diagnosis, the researchers note. People who took part in the study had either multiple system atrophy, autoimmune autonomic neuropathy, diabetic autonomic neuropathy, or one of several other conditions. Patients with more severe OH appeared to respond better than those with mild OH, the researchers say.

Dr. Low and his colleagues are now planning studies to look at other types of drugs and drug combinations that might be able to improve symptoms of OH. "Pyridostigmine is not the ultimate answer - it is only partially effective," he says. Researchers also need to determine if higher doses of the drug may work better than the 60-mg dose used in this study, he adds. In addition, Dr. Low's group is planning to test the drug for treatment of postural orthostatic tachycardia syndrome (POTS), which causes an abnormal increase in heart rate when the patient stands and may also include lightheadedness, dizziness, and other symptoms like those of OH.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system. The NIH is composed of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

*Singer W; Sandroni P; Opfer-Gehrking TL; Suarez GA; Klein CM; Hines S; O'Brien PC; Slezak J; Low PA. "Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension." Archives of Neurology, April 2006, Vol. 63, No. 4, pp. 513-518 .