Stress Relief

While reading the New York Times last week I came across an article announcing the passing of Dr. James W. Black, a noted Scottish pharmacologist, and while I am reluctant to write two drug-related blog posts in a row I feel obliged to dedicate a few words to his accomplishments.

Back in the mid-1950s doctors were eager to have more choices available to treat cardiac angina.  Nitroglycerin had existed in one form or another for several decades but fell short of providing adequate relief for many with coronary stenosis.  Coronary artery bypass surgery (CABG) was yet to be developed and the advent of catheter-based coronary repair (angioplasty, stenting) was decades away.

While most researchers in the field were looking for ways to increase the amount of oxygen-rich blood available for starving heart muscle, Dr. Black sought a different approach.  He theorized that one could improve a patient’s chest pain by decreasing the metabolic demand of the heart and consequently allowing the muscle to function on less blood.

Scientists had already worked out the concept of cardiac muscle protein receptors that bind adrenalin and noradrenalin (epinephrine and norepinephrine), but the clinical scientific community was not focusing in this direction.  Dr. Black expanded on the existing research and sought a chemical that would specifically target the beta-adrenergic receptor—the trigger of the so-called “fight or flight” response.

His initial attempt yielded pronethalol, a substance that quite nicely blocked the beta-receptor and relaxed the contractile work of the heart.  Unfortunately this chemical was also quite toxic.  In 1964 Dr. Black developed the first safe and effective beta-blocker, and nine years later propranolol (Inderal) entered the US market as the pilot drug in a class that has come to be a mainstay in the world of cardiology.

For his work Dr. Black (and two others) was honored with the Nobel Prize in Medicine in 1988, but he didn’t stop there.

After his success with propranolol in 1964 he immediately launched an effort at producing a chemical that would block the production of stomach acid.  The fruit of his efforts to block the H2-receptor in the lining of the stomach was the drug cimetidine (Tagamet).  Those of you old enough to remember the “plop plop fizz fizz” jingle will recall what a breakthrough this development represented in 1979.  Thousands of patients suffering from ulcers and intractable reflux were spared the surgeon’s blade by adopting the use of this class of drugs (called H2 blockers—Zantac, Pepcid, and the like).

Dr. Black was knighted in 1981 and, after creating the world’s first blockade of stress on the heart and on the stomach, he spent some time as a university chancellor and then transitioned into retirement. I can’t think of another researcher who nearly single-handedly came up with two seminal medical therapies in unrelated fields.  It would be like Guglielmo Marconi discovering the transistor radio and the iPod.  Or like the Wright brothers developing the airplane and in-flight movies.  Or like Thomas Edison inventing the light bulb and the phonograph.  Oh, wait.  I guess Tom Edison did do that.

If only Dr. Black had enjoyed his youthful scientific curiosity longer I’m sure he’d have come up with cures for cancer, the common cold, baldness, and the nerdy desire to post blog articles every week.

Now it’s time to segue into the clinical portion of my article and focus a little on beta-blockers.  While propranolol was first in its class it is no longer widely used because of its frequent side effects.  It’s still prescribed to migraine sufferers, people with benign hand tremors and those who suffer from excessive perspiration when engaging in public speaking (I’ve never tried it for this but people tell me it works wonders).

Cardiac angina is considerably less common these days because most people with lifestyle-limiting coronary disease can receive full resolution of their symptoms with stent placement or bypass surgery.  Hypertension remains a common indication for the more modern beta-blockers such as metoprolol (Lopressor) and atenolol (Tenormin).  These medications can also treat the palpitations associated with atrial rhythm abnormalities such as atrial fibrillation.

Of interest is the use of beta-blockers in congestive heart failure.  As recently as the early nineteen nineties, when I started my internship, these drugs were regarded as contraindicated in patients with weak hearts.  It stands to reason if you think about it: adrenalin increases the frequency and vigor of cardiac contraction, and blocking this effect will slow and weaken the resulting pulse.  In medical school we were taught to assiduously avoid beta-blockers in these individuals.

But it turns out that just the opposite is true.  Think of beta-adrenergic stimulation (with adrenalin and noradrenalin) as the big, burly guy who beats the drum on the old Roman slave ships.  Sure, his incessant percussion frightens the frail slaves into rowing faster for a while, but after a time it just leads to early fatigue and failure of the system.  Patients with heart failure actually have higher than normal levels of adrenalin in their system—their bodies sense the low blood flow and release the hormone hoping to squeeze out a little more cardiac output.  Over time, though, the constant whipping of the heart leads to deterioration of the muscle cells and worsening of heart failure.

Numerous studies have demonstrated the benefit that comes from giving the heart a reprieve by adding certain types of beta-blockers such as carvedilol (Coreg) and extended-release metoprolol (Toprol XL).  Weak hearts can actually heal over time (to some degree, anyway) if you remove the stress of adrenalin.  In the world of congestive heart failure, beta-blockers have now emerged as the cornerstone of therapy.

I’ve been unable to find any interviews with Sir James Black in the last years of his life and I’d be interested to hear what he thought of the durability of his discoveries.  Decades later, beta-blockers and H2-blockers remain incredibly common and useful.  Dr. Black should be proud of his accomplishments.