Posted by Camilla Cracchiolo RN

In Reply to: pulmonary hypertension and Redux - any common link between them? posted by barrydoc

I've talked to several cardiologists about this, and the answer is no:
there is no reliable way to predict who will develop PPH from anorexant
agents.

Short of inserting Swan-Ganz lines directly into the hearts of
people taking the drugs and getting wedge pressures, there is also no
reliable screening test to detect pulmonary hypertension before some
damage has been done. (Swan-Ganz lines carry the obvious dangers of
infection and cardiac arrthymia and therefore it is not and will be used
for screening purposes.)

Shortness of breath on exertion is the first symptom of PPH and sometimes,
if you stop the drug at the first sign of it, you can avert cardiac
damage. An echocardiogram can be done in a doctor's office or clinic and
is a non-invasive way to determine if there's heart damage and how far it
has progressed. However, it won't detect the early stages of PPH, before
cardiac damage has been done.

The stuff below is from a small FAQ I put together on the subject of the
phentermine/fenfluramine obesity treatment and pulmonary hypertension.
It normally includes abstracts, but because the post is so long, I'll send
the abstracts to you under separate cover. It's also written with
laypeople in mind: your address name suggests you might be an MD, so feel
free to ignore the stuff you already know and cut to the chase, which
begins around item #4.

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1. Serotonin binds to receptors in lung tissue and causes vasoconstriction.

2. Drugs which inhibit the clearance of serotonin from lung tissue
prolong the vasoconstriction and this is what leads to the pulmonary
hypertension, via destruction of alveolar tissue and arterioles from
lack of oxygen. The destruction of lung tissue makes the lungs stiff and
not very pliable. Deoxygenated blood is pumped into the lungs by the
right side of the heart. The blood picks up oxygen and returns to the
left side, to then be delivered to the rest of the body via the left
ventricles. When the lungs are stiff, and the small blood vessels in
the alveoli are constricted, the heart has to pump much harder to get
the same amount of blood in. This is pulmonary hypertension, which you
can have completely independent of high blood pressure in the rest of
the body. The pulmonary hypertension, in turn, is what causes the damage
to the heart. If the heart can't generate enough pressure to get all the
blood into the lungs, it backs up. Over time, this stretches the heart
wall and can also cause great damage to the small valves in the right side
of the heart. This is bad news.

Studies conflict as to whether drug-related pulmonary hypertension has a
better outcome than primary pulmonary hypertension (of unknown cause, in
other words.) Definitely, the fatality rate is very high in people who
develop the illness and often they wind up needing a heart/lung transplant.

3. All anorexant drugs appear to cause pulmonary hypertension to a
greater or lesser degree. The problem is NOT just from the new dex
version of fenfluramine. Plenty of cases have been reported from
fenfluramine alone.

4. Fenfluramine has a relatively strong effect on the clearance of
serotonin from pulmonary tissues compared to other anorexants. Hence its
vasoconstrictive effect is stronger than most other anorexants. The rate
of pulmonary hypertension from fenfluramine appears to be about 1 case
in 40,000.

5. Both phentermine and chlorphetermine are mentioned in several of the
abstracts. (This really confused me until I had gone over the abstracts
several times.) Chlorphentermine appears to be a slightly different
drug with a much higher rate of pulmonary hypertension than phentermine HCl.
and the chlorinated versions of anorexant drugs all appear to have much
more effect on lung tissue than the non-chlorinated varieties.

6. Phentermine HCl by itself does two things:

a. It inhibits serotonin uptake by pulmonary tissues.

b. However, it *also* inhibits serotonin clearance.

As far as I can tell, there *are* reports of pulmonary hypertension in
humans from phentermine alone, although it's much rarer than with
fenfluramine. The only reports of pulmonary hypertension from
phentermine alone that this search turned up were in animal models;
however several of these abstracts mentioned human cases as having
occurred as though it is a well established fact.

7. It's conceivable that phentermine could have an ameliorating effect
on fenfluramine risk, as Dr. Pietr Hitzig asserts, by lowering the rate of
serotonin uptake in pulmonary tissues. However, theoretically the
combination of phentermine and fenfluramine could also act synergistically
and increase the risk of pulmonary hypertension in at least a few
individuals due to the fact that both drugs slow the rate of serotonin
clearance from the lungs. This would depend on whether the reduction in
the rate of pulmonary serotonin uptake is less or more than the reduction in
pulmonary serotonin clearance. This would be determined by quirks
in individual body chemistry, like the amount and exact configuration of
certain enzymes (which can vary slightly for genetic reasons), how much
serotonin the person produces in the first place, etc.

Personally, I think the risk of synergistic reaction is real; at the
very least, it is premature at this point to assert that this risk does not
exist. Whether these drugs can synergistically increase the risk of
pulmonary hypertension can only be determined by studying a large
population over time. The implication of a synergistic effect would be
that the disease might develop faster or be more aggressive.

8. Despite all this, it's very clear that the combination of phentermine
and fenfluramine is the most effective treatment that we have for
obesity.

This conclusion is based upon one of the best studies ever done in
obesity research conducted by Dr. Michael Weintraub, who was at the
University of Rochester at the time. It was a large study (several
hundred people), was conducted for five years and all of the
participants recieved the very best, state of the art help with diet
planning, exercise and support groups. In other words, the above was
the *control* group and the treatment was shown to be more effective than
the very best non-drug therapies. One group was not given any
drugs or placebos. One was given placebos, another was given the real
drugs. Then one group was allowed to continue the drugs after reaching
their goal weight and in one group the drugs were withdrawn.

No doubt about it: the people who got the drugs lost weight faster, it
was easier and those who were allowed to keep taking the drugs did NOT
regain as much weight as those folks in whom the drugs were
withdrawn, although ultimately it looked like the difference between the
two groups was about 10%. Weintraub attributes this both to suppression
of appetite and to changes in the metabolic rate itself. His conclusion
is that it's clear that obesity should not be regarded as merely a 'lack
of will power': instead he believes, with many other researchers, that it is a
profoundly physically based problem, that there is dysregulation of both
the mechanisms which control appetite and satiation and also with the
metabolic rate.

His final conclusion was a new and challenging way to look at treatments
for obesity. Weintraub believes that obesity should be regarded in the
same way that we do high blood pressure. We do not give people high
blood pressure meds to get their blood pressure to within normal range
and then withdraw it and tell folks to just relax a little more. In the
same way, we should not expect people to lose weight and just cope.

Having struggled with my weight all my life, I agree with him. I have
some problems with defining all fat people as having a chronic disease,
since I think our social standards about weight are pretty screwed up and
that a certain amount of fat is part of the normal spectrum of human body
types. However, there are definitely people for whom carrying extra
pounds is dangerous and the preponderance of research does suggest that
certain illnesses are more common in fat people than in thin ones.
(Although it is not clear whether these risks are the result of obesity
or a side effect of a deeper metabolic process; and it is also not clear
how much weight loss reduces these risks in people who don't already have
problems such as high blood pressure or diabetes.)

9. Despite all the publicity about pulmonary hypertension related to
anorexant drugs, these drugs are probably safe for most people.

The Weintraub study did not show any severe complications after 5 years
of use, even when some of the people in the study took very high doses
of these drugs. Some people developed high blood pressure, which often
responded well to anti-hypertensive medication. Paradoxically, the
blood pressure dropped to the normal range in some people who started out
with elevated blood pressure who took the phen/fen combo. Probably this
was a result of the weight loss. Insomnia, restlessness and anxiety were
the most commonly reported mild side effects. NOBODY developed pulmonary
hypertension, even though some of these people took very high amounts of
the drugs for all 5 years.

However:

There does not appear to be any way to predict who will get the
pulmonary hypertension and it is not necessarily reversible when the
drug is discontinued. It's possible that the sample size
(only a few hundred people) in the Weintraub mmay have been too small
to accurately reflect the risk of this relatively rare complication.
Furthermore, at least one study suggests that people who have taken
fenfluramine can develop pulmonary hypertension several years after
discontinuing the drug. This may be a statistical artifact: a
cooincidence, in other words, or perhaps a failure in the way patients
were recruited for the study. However, one study in rats has shown that
long term use of fenfluramine can cause alteration in the number and
type of serotonin receptors in brain tissue. If this study is
confirmed, then it may be due to permanent alteration of pulmonary
serotonin receptors by fenfluramine.

A strong argument can be made that the benefits of weight loss justify
the risk of the drug, at least for certain people. However, there is
debate in the medical community about just who these people are.
PPH is very rare, but it's life-threatening when it occurs.
Also unfortunately, it's entirely possible that people who really need
to lose weight for medical reasons, such as people with diabetes, high
blood pressure and/or heart disease might be at higher risk of developing
pulmonary hypertension, since they already have problems with either
damage to the blood vessels or with increased arterial vasoconstriction
to begin with. These folks need to carefully weigh the risks of this
treatment against the possible benefits.

Many MDs feel that people who only have 10 or 15 lbs. to lose should NOT
take these drugs. There are even a few who think they should be reserved
only for those folks 100% or more over ideal weight. (I'm not even going
to touch the subject of who or what determines the ideal weight for a
person. Suffice it to say that it's a controversial subject.)

The difference in long term weight loss and regain isn't *that*
dramatic. That 10% difference may make be significant to the health of
'severely overweight' people. There are some studies that suggest that
many of the health advantages of weight loss, such as lowering blood
pressure and cholesterol and triglyeride levels can be obtained with the
loss of only 10-20% of body mass. On the other hand, 10% is not very
significant if you've only got a few pounds to lose.

--
"The trick is to keep an open mind, without it being so open
that your brain falls out."

Camilla Cracchiolo, RN camilla@primenet.com

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Shrine of the Cybernetic Madonna BBS 213-766-1356 Los Angeles

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