Wednesday, October 06, 2004

"Anti-Head Rush Drug"???
Lessons from Old Drugs

Doing a quick run-through of my usual science sites, I encountered the title above: "Anti-Head Rush Drug". Did it refer to an anti-head drug that gives a rush? An anti-head drug derived from rushes? Rush Limbaugh's latest drug of choice? No, it is a drug that prevents the funny feeling people get in their heads when they stand up too quickly. The funny feeling is caused by a relative lack of oxygen in the brain. This occurs when the postural reflex that is supposed to raise blood pressure, when a person stands up, does not work.  The blood pressure is then too low to get enough blood to the head.  "Orthostatic hypotension" is the technical term for a drop in blood pressure that occurs when standing up.  For most people, this "head rush" is a minor nuisance. For some people, though, it is a serious problem. The corpus callosum previously has made a point about the fact that bad things happen when the brain does not get enough oxygen. I won't belabor that point now.

The challenge with trying to fix this condition, according to Dr. Low, is that most medications that increase blood pressure raise blood pressure in all positions. Thus, the drugs would work for patients with orthostatic hypotension when they stood up, but their blood pressure would be too high when lying down, increasing their risk of stroke. Dr. Low felt that this price was too high, and that treating with medications that raised blood pressure while standing but raised blood pressure while lying down amounted to trading one problem for another.

"We wanted a 'smart drug' that would only increase blood pressure when standing up, and not when lying down," says Dr. Low. Pyridostigmine works at the level of the autonomic ganglion, which has minimal nerve signaling traffic when lying down. When standing up, however, nerve signaling traffic in the autonomic ganglion increases, so the researchers theorized that a drug that affected the autonomic ganglion would improve orthostatic hypotension patients' standing blood pressure but not increase the blood pressure while lying down.

The drug is not a new substance. Rather, it is an old drug that has been found to have a new application. The drug, pyridostigmine (Medscape DrugInfo - registration required), is a drug that interferes with the action of acetylcholinesterase. So it is like a mild version of nerve gas. Acetylcholine is a neurotransmitter that sends signals from nerve cells to muscle cells, telling the muscle that it is time to contract. Acetylcholinesterase is the enzyme that breaks down acetylcholine, thus stopping the signal to the muscle. If the enzyme is blocked, there is no way to turn off the signal.

Nerve gas binds to the enzyme, thus rendering it permanently useless. Pyridostigmine binds loosely to the enzyme. This slows it down, but does not stop it completely from working.

Blood pressure regulation is a complex process. Part of the process involves the parasympathetic nervous system. There are little clusters of nerve cells, called ganglia, that form a part of the parasympathetic system. It these ganglia, acetylcholine is used to send messages. These messages then are transmitted to the muscles in the arteries, telling them to contract. That contraction raises blood pressure. When the drug partially blocks the degradation of the acetylcholine, the message sent to the arteries is stronger. Thus, there is more contraction, and the blood pressure goes up.

It turns out that there is a variety of conditions (diabetes, autonomic neuropathy, multiple system atrophy, pure autonomic failure, Addison's disease, and Parkinson's disease) that cause problems with the blood pressure reflex. These are common, especially in the elderly. The failure of this reflex can lead to falls, which can result in serious injury. Therefore, a safe and effective treatment can be lifesaving.

Why should we care?  Because of the lessons, of course.  This discovery is not the result of high-tech research. Nobody is going to make a lot of money from this; the drug has been around for decades. The reason I like this story is that is shows that a lot of good can come from basic research, and that even old. inexpensive drugs sometimes can be used to have a great positive impact on quality of life.