Magazine Section: Features

Magazine section: Features

What doesn't kill you

New Scientist vol 180 issue 2418 - 25 October 2003, page 38

Dishing out drugs that make your symptoms worse seems like a rash, even dangerous way to treat patients. But it's already common practice for some diseases, and one man argues that doctors should do it all the time. Diane Martindale reports

MIRACLE workers rarely come back for an encore, but in the world of heart medicine one little miracle is bucking the trend. Beta blockers were invented in 1964 and quickly became the most widely used drugs for controlling high blood pressure, saving countless lives. And now they're doing it all over again, this time for congestive heart failure.

A success story for sure, but a deeply mysterious one. For 30 years, doctors were told never, ever to give the drugs to patients with congestive heart failure (CHF). Today, though, doctors dish out beta blockers like smarties and the drugs have proved themselves to be the best medicine available for CHF. Why the U-turn?

At first sight the directive seemed sensible enough - beta blockers reduce the heart's pumping power, and weakening an already-weak heart would seem like the last thing you would want to do. But nearly 30 years ago, quite by accident, a Swedish doctor discovered that giving beta blockers to CHF patients had miraculous long-term effects on their health and longevity. The idea took a while to catch on, but once it had the results were stunning. In clinical trial after clinical trial, beta blockers have been shown to reduce death rates in CHF by anything up to 70 per cent.

"This is the first time in the history of pharmacology that a class of drug has moved from being forbidden to being the best drug for the disease," says Richard Bond, a pharmacologist at the University of Houston in Texas. Bond is one of numerous researchers searching for an explanation for the beta blocker effect, and his work has led him to a startling conclusion. He is convinced that beta blockers are not a one-off, but an example of a more general phenomenon he has dubbed "paradoxical pharmacology".

In short, paradoxical pharmacology means using drugs that make your symptoms worse to make you better in the long run. Treating like with like, if you will. The idea is eerily reminiscent of "hair of the dog" folk wisdom, not to mention homeopathy. Bond, though, believes there is a rational explanation, and says it could be systematically exploited to cure many diseases.

If he's right, then the implications are clear: we might already have a medicine chest full of drugs capable of curing many common diseases, but which no one has tested because common sense insists they can only make you worse. "I think this is the biggest deal in pharmacology," Bond says.

The beta blocker story began in 1975 when Finn Waagstein, a cardiologist at SahlgrenskaUniversityHospital in Gothenburg, Sweden, gave the drug to patients taking CHF medication who also had an excessively fast heartbeat, or tachycardia. As he expected, the beta blockers helped with the tachycardia, but Waagstein noticed something else too - his patients' CHF also improved dramatically.

It shouldn't have worked that way. Beta blockers latch onto receptors called -adrenoceptors on the surface of heart muscle cells. These receptors normally respond to adrenalin, making the heartbeat stronger and faster. Beta blockers obstruct this effect, slowing the heart down, decreasing the force of its contractions and lowering blood pressure.

Waagstein spent the next few years investigating this unexpected result, using animal models to prove that the drugs really worked in CHF. But his research had little impact on the way doctors treated the disease. "It never stuck because of dogma," says Bond. It wasn't until the 1990s that clinical trials testing the benefits of beta blockers in human CHF patients began. The first one to be published, in 1996, was a stunning success. It showed that giving a beta blocker called carvedilol to people with CHF decreased mortality by an amazing 65 per cent (New England Journal of Medicine, vol 334, p 1349). Numerous trials since have produced similarly impressive results (Journal of the American Medical Association, vol 283, p 1295; New England Journal of Medicine, vol 344, p 1659).

That is not to say the effect of beta blockers on CHF is entirely paradoxical. In the first few days or weeks of the treatment, patients do get worse and their risk of dying goes up. But after about two to three months, their hearts are stronger, their health has improved - and their life expectancy has risen dramatically.

Today, most cardiologists agree that beta blockers are the number one drug for CHF, and the focus of research has shifted. "Now that we know it works, everyone is interested in knowing how it works," Bond says.

Adrenalin rush

Here's what we know. After a person suffers heart failure, their body pumps out more adrenalin to make the heart work harder. If a patient is given a drug that mimics the effects of adrenalin, the heart will work even harder and the patient will feel better. Down the road, though, the heart struggles and fails. This happens because the -adrenoceptors no longer transmit the signal as strongly, and also because there is a loss in the total number of receptors. These responses appear to protect against chronic over-stimulation, but for the patient it's a disaster.

If the patient takes a beta blocker, on the other hand, initially the drug will cause a decrease in heart rate, as expected. But several months later, the drug has somehow forced the body to compensate, possibly by increasing the number of -adrenoceptors.

But what's the mechanism? No one knows for sure. Bond, though, has an inkling. He suspects the explanation may lie in some of his earlier work, on a hitherto obscure aspect of the biochemistry of cellular signalling.

According to the orthodox view of signalling, receptors such as the -adrenoceptor sit idly in the cell membrane like errand boys lounging around waiting for something to happen. When a signal arrives they spring into action and relay the message to the inside of the cell. The activating signal is a small molecule called an "agonist" - often a hormone such as adrenalin - which binds to the receptor and switches it on. Receptors also respond to a class of molecules called "antagonists" which bind to them but prevent them from being activated by the agonist (see Graphic). Many drugs are synthetic agonists or antagonists that act on a particular type of receptor.

This is the version of events you'll find in most biochemistry textbooks. But back in 1980, Robert Lefkowitz of DukeUniversity in Durham, North Carolina, proposed an alternative model. He suggested that receptors do not need agonists to activate them, but flip spontaneously between the "off" and "on" states. The two states are in equilibrium - in other words, at any one time perhaps 10 per cent of the receptors on a cell surface are in the "on" position (see Graphic).

In this model, agonists still switch receptors on, but in a different way. They bind to the "on" receptors and stop them from cycling back to the "off" state. This effectively takes them out of play, so to restore the equilibrium more of the "off" receptors flip into the "on" position. The net result is to increase the proportion of receptors that are switched on.

In addition, the model revises the role of antagonists in a way that is the key to the paradox. Some still prevent the agonist from binding to the "on" receptor. Others, though, do something different - they bind to the "off" receptors, dragging the equilibrium in the opposite direction. These antagonists are known as "inverse agonists".

For many years the alternative model was seen only in computer models or cell culture, but in 1995, Bond, Lefkowitz and others proved that some of the body's receptors really do work in this way. They developed transgenic mice that massively overexpressed -adrenoceptors in their heart muscle - up to 200 times more than normal. The mice's hearts behaved as though they were constantly being drenched in adrenalin even when none was there, beating hard and fast all the time. This suggested that some of their -adrenoceptors were spontaneously "on" at all times. What's more, beta blockers were able to damp down the effect. Taken together these results confirmed the alternative model (Nature, vol 374, p 272). Since then dozens more receptors have been shown to work in this way. Their function remains unknown but it may be to set the baseline activation of a system that needs to be "on" most of the time at a low level.

Bond's work was neat but seemed to have little practical importance. "I thought this was a curiosity that about six people - the receptor theorists - needed to worry about, and the rest of us could get on with our lives," he says. But now he thinks that inverse agonism lies at the heart of paradoxical pharmacology.

Here's why. Clinical trials of beta blockers show that not all of them produce the paradoxical effect. Of three that have been tested - carvedilol, metoprolol and bucindolol - only the first two are effective. And, intriguingly, the first two are inverse agonists whereas bucindolol is an ordinary antagonist. Only inverse agonists, it seems, can produce the paradoxical effect.

Bond would be the first to admit that the mechanism is not clear. Even so, other pharmacologists are rallying to his cause. Nigel Shankley at Johnson & Johnson Pharmaceutical Research and Development in La Jolla, California, has been following Bond's work since 1995. He says: "The court is still out about how general inverse agonists are, but I'm convinced that inverse agonists are intimately linked to paradoxical pharmacology."

ceptors in their heart muscle - up to 200 times more than normal. The mice's hearts behaved as though they were constantly being drenched in adrenalin even when none was there, beating hard and fast all the time. This suggested that some of their -adrenoceptors were spontaneously "on" at all times. What's more, beta blockers were able to damp down the effect. Taken together these results confirmed the alternative model (Nature, vol 374, p 272). Since then dozens more receptors have been shown to work in this way. Their function remains unknown but it may be to set the baseline activation of a system that needs to be "on" most of the time at a low level.

Others disagree. Pharmacologist James Black of the Sir James Black Foundation in London, who invented beta blockers and shared a Nobel prize for the work in 1988, says that the effect on CHF merely illustrates the well-known fact that drugs sometimes have different short and long-term effects. These can be opposite, but there is no general pattern. Antidepressants, for example, often take weeks to work but they don't make you worse in the short term. For this reason, Black doesn't like the term paradoxical pharmacology. "I tried to persuade him [Bond] not to use it because it suggests a mystery when there isn't one, and it suggests generality."

Bond, though, is sure that there is a general process. He points out that beta blockers are not the only paradoxical drug. Hyperactive children, for example, are treated with the amphetamine Ritalin, while the skin irritant retinoic acid is a treatment for acne. In neither case do we know exactly how the drug works, but you'd expect both to make the symptoms worse when in fact they make them better.

What is more, Bond has recently produced convincing new evidence in support of his theory. This time he used beta blockers to alleviate the symptoms of another disease that orthodox medicine says should respond badly to them: asthma.

It's not just heart muscle that contains -adrenoceptors. The smooth muscle lining the airways does too, though they are a different subtype (2 rather than 1). These receptors respond to adrenalin, making the muscle relax and dilating the airways. The main treatments for asthma are adrenalin-mimics such as salbutamol. These work well at first, but after a while the drugs lose their effectiveness and the asthma gets worse.

If asthmatics are given beta blockers, their airways constrict and they struggle to breathe, in much the same way that CHF patients get worse at first. What Bond wondered, and what no one had tested, was what happens when asthmatics are given low doses of beta blockers for a long period. Orthodox medicine suggests this is a bad idea, but paradoxical pharmacology says the opposite.

Bond now has unpublished data showing that long-term doses of beta blockers improve the condition of mice with an asthma-like disease, just as they do in CHF. And again, only the inverse agonists help. In other words, it looks as though paradoxical pharmacology works for asthma too. Bond admits it's too early to conclude that there is a general principle, but he points out that his success rate so far is two out of two. Both Black and Shankley find the data compelling and say that Bond has enough evidence to start tests in asthma patients.

But there are hurdles ahead. The biggest problem will be convincing the ethics committees, predicts Black. Although the number of deaths from asthma is rising, patients aren't facing imminent death, as is the case with CHF.

Bond concedes that it might be risky to run clinical trials with drugs that can make you worse, "but people are dying anyway," he says. Asthma deaths increased by 56 per cent between 1970 and 1997 in the US and yet in that time no new class of asthma drugs came on the market. During the 30 years that beta blockers were forbidden for CHF, an estimated 10 million people died prematurely of heart failure. Beta blockers could have saved a large number of them.

Whatever the outcome in asthma, Bond will carry on looking for other diseases where the paradoxical approach might work. He says he already has a few ideas. Experimental treatments for Alzheimer's disease, for example, include stimulating the muscarinic M1 receptor in the brain. Bond thinks that perhaps M1 inverse agonists will work better. Generally, he says, you might try this approach with any disease that is treated using a long-term agonist. "My gut feeling is it could work in 5 to 10 per cent of diseases."

Even if paradoxical pharmacology doesn't prove to be a general principle, Bond's work could still have a lasting effect on drug research, says Black. It has drawn attention to the fact that drug makers rarely study the long-term effects of their drugs, even those that are designed to be used over a long period. They produce a lot of data on the short-term effects of high doses and a lot of data on taking high doses for a long time - toxicology, in other words. But they rarely look at the chronic effects of the active dose. And the chances are, says Black, that some of these long-term effects will prove useful in treating disease.

And so whether Bond's big idea turns out to be right or wrong, he's probably correct on one point. Our medicine chests may well be full of drugs with unsuspected talents, just waiting for someone to do the tests. It looks as though beta blockers won't be the only old drugs making a spectacular comeback.

Diane Martindale

Diane Martindale is a science writer in Toronto