Gettysburg Medical Center
The Clinical View
by P.E. Hoffsten, MD
10 January 2007

A MEDICAL MYSTERY SOLVED

            One of the basic rules in medicine is that a little bit of several different medications directed to the same disease process work better than a whole lot of one medication.  Thus in treating hypertension, it is better to use small amounts of 2 or 3 drugs than it is to push one drug to its maximum limit.  In the 1980’s, a doctor doing research on how to control the overweight problem in our country investigated a drug regimen using phentermine (Fastin) and fenfluramine (Pondamine).  This became known as the famous phen-fen combination.  The results were fantastic.  People that had been struggling with their weight for years shed pounds with no major effort on their part.  They didn’t have to exercise more.  Somehow they just simply seemed to eat less and were not hungry.  But then the devil intervened.  In 1997, heart doctors from the Mayo Clinic investigated a strange abnormality on the heart valves of several people that had been using the phen-fen program.  It was found that their heart valves became thicker and stiff and no longer functioned normally.  There was at least one associated mortality and several people had to have replacement of their heart valves.

             I was one of many physicians who seriously doubted the connection between the phen-fen program and the heart valve problem.  There were more than 1000 patients in central South Dakota who had used this drug combination and there had been nobody with any heart valve problem.  Be that as it may, fenfluramine (Pondamine) and dexfenfluramine (Redux) were withdrawn from the market and the phen-fen program was over.  Short of gastric surgery, there has been no treatment or drug regimen anywhere near as effective as phen-fen in the last nine years.

            How in the world a pill taken for weight control could cause heart valves to thicken and malfunction remained a mystery.  It was known that there was a disease called the carcinoid syndrome in which too much of a hormone called serotonin was secreted by a tumor in the bowel.  Some people with this type of tumor would develop heart valve problems very much like those noted in the heart valves of a few phen-fen users.  Thus, this provided a fertile area for further research. 

            This week in the New England Journal of Medicine two articles are published and a review presented to explain how fenfluramine and dexfenfluramine caused heart valve problems.  It turns out that serotonin is a ubiquitous hormone in our body and it serves many different purposes.  In our brains, it seems to be a hormone that calms us and prevents anxiety/depression.  Thus, the success of the Prozac family of antidepressants.  Yet in our arteries, this same hormone can cause spasms that cause migraine headaches.  This same hormone seems to be important in bowel function and prevention of constipation. 

            It turns out that this one hormone is a key that fits many different keyholes (receptors) on various organs in our bodies.  For reasons completely unknown, our heart valves have lots of a serotonin receptor called the 5-HT-2b receptor.  On the heart valve, these 5-HT-2b receptors cause growth of the valve.  In normal times, these receptors control and repair the heart valves over the many years of a person’s life.

            But it turns out that fenfluramine over stimulates these particular receptors and makes the heart valve grow too thick.  Instead of having a soft silky parachute-like heart valve, the valve becomes hard, canvas-like and too stiff to function. 

            The article in the New England Journal this week points out that if this hypothesis were true, other drugs on the market that might cause the same kind of problem would need to be watched.  Indeed in the past 10 years, ergotamine methysergide and dihydroergotamine used to treat migraine headache have been shown to cause the same kind of problem.  That hallucinogenic street drug called “Ecstasy (MDMA)” also causes the same kind of problem.  Lastly, two Parkinson’s disease drugs called pergolide and cabergoline have been shown to cause the heart valve problem.  All of these drugs overstimulate the 5HT-2b receptor.  No doubt that these other drugs will now be withdrawn from the market.  That is of course, with the exception of “Esctasy  (MDMA)”.  We never get street drugs off the market. 

            In the discussion regarding these findings, the question always comes up as to why everybody who used Phen-fen didn’t get heart valve problems and when fenfluramine was on the market for 21 years before this abnormality was discovered.  The answer seems to reside in genetic variation.  The sensitivity to different medications is different for everybody.  It was only a very few people who used the drug for an extended period of time that overstimulated their heart valves causing the problem. 

            Some medical mysteries take longer than others to solve but medical research does move forward relentlessly and sooner or later, these questions get answered.

            Afternote:  Last week the column dealt with the perils and benefits of alcohol.  It was pointed out that those individuals who drank an average of two alcoholic beverages a day lived longer on average than those who drank not at all.  I had several inquiries about this point.  Specifically, for those who asked, 14 drinks on Friday night does not carry the same benefit as 2 drinks a night.  While the average is the same, the benefit is not.