Jim, UPDATED POST ON POTENTIAL VIAGRA SIDE EFFECTS. the post you asked was #4582:
Side effects of Phosphodiesterases and ?VIAGRA, the GOLDEN ????? STANDARD for ED therapy ???:
Here is a reprint from GOODMAN & GILLMAN,
Standard US Medical School Textbook of Pharmacology, 1997 edition.
Please note the following important abstracts from the textbook:
- "Many organs, including cardiac muscle, contain members of ALL known PDE isoenzyme families (Bode et al., 1991: Nicholson et al., 1991).".
- In fact, the retina contains PDE 3 which is the SAME PDE as in the PENIS. So Sildenafil may NOT be as specific as it is touted to be and may well indeed have the retinal side effects.
- "The specificity of the "selective" inhibitors noted in Table 34-8 is restricted for most PDE isoenzymes to a relatively narrow concentration range"
That means that as you increase the dose of Viagra ( and some patients may be temtedc to do that ) then
Viagra will inhibit a whole bunch of other PDE enymes which are necessary for the heart etc to fuction, with
disastrous effects.
"In addition, most of these inhibitors have other known pharmacoloaical activities "
That means that chances are that Viagra has other pharmacologic effects that need to be identifoed.
======================================
Chapter 34 Page 833
PHARMACOLOGICAL TREATMENT OF HEART FAILURE
PHOSPHODIESTERASE
INHIBITORS
****
Although agents such as theophylline and caffeine had been identified as nonspecific cyclic GMP and cyclic AMP phosphodiesterase (PDE) inhibitors over 30 years aao, it was not until the 1980s that a number of PDE isoenzyme subclass-specific inhibitors became available ' Table 34-8 briefly summarizes the classification scheme suggested by Beavo and Reifsnyder (1990) for these isoenzymes, each the product of distinct but related gene families, based on known primary amino acid or CDNA sequence. Much information also has become available on the tissue and cellular distribution of PDE isoenzymes (which may vary somewhat from species to species) as well as their subcellular localization and links to specific cyclic GMP- and cyclic AMP-dependent sicnalinc, pathways. Many organs, including cardiac muscle, contain members of all known PDE isoenzyme families (Bode et al., 1991: Nicholson et al., 1991). The specificity of the "selective" inhibitors noted in Table 34-8 is restricted for most PDE isoenzymes to a relatively narrow concentration range, with nonspecific inhibition evident at higher concentrations. In addition, most of these inhibitors have other known pharmacoloaical activities. Dipyridamole, for example, is an antagonist of adenosine uptake and metabolism. Several inhibitors of the type III PDE family are useful in the treatment of heart failure.
Table 34-8
Known Cyclic Nucleotide
Phosphodiesterase Isoenzvmes inhibitors
Vinpocetine
Milrinone
Amrinone
Pimobendan
Cilostamide
Enoximone
Peroximone
Vesnarinone
Rolipram
Zaprinast
Dipyridamole
And..now.we..have...SIDENAFIL/VIAGRAA.,yeaah..
-------------------------------------------------------------------
Goodman next reviews the phosphodiesterase inhibitors now available in the market. Please note the power of these drugs to do harm, especially in ORAL formulations :
******************************
AMRINONE and MILRINONE
===============================================
Although parenteral formulations of AMRINONE (INOCOR) and MILRINONE (PRIMACOR) have been approved for short-term support of the circulation in advanced heart failure, in longer term prospective trials using- ORAL formulations, both medications often caused intolerable side effects.
exhibited
-minimal Iongterm efficacy, and, in the doses used,
-caused increased mortality in heart failure patients.
Both drugs
-are bipyridine derivatives and relatively selective inhibitors of the cyclic GMP-inhibited, cyclic AMP PDE (type III) family;
-cause vasodilation with a consequent fall in systenmic vascular resistance; and increase both the force of contraction and velocity of relaxation of cardiac muscle
.
Both drugs
are effective when given either as single agents or, more commonly, in combination with other oral and/or intravenous drugs for S H O R T E R M treatment of patients with severe heart failure
due to systolic right or left ventricular dysfunction.
Intravenous infusions of both drugs must be initiated by a loading dose followed by a continuous infusion. For amrinone, typically a 0.5-btglkg bolus injection is followed by a 2- to 20-Ag/kg per minute infusion. Milrinone is approximately 10-fold more potent than amrinone. A loading dose of milrinone is usually 50 Aglkg, and the continuous infusion rate ranges from 0.25 to 1.0 Ac,@kg per minute. The elimination half-lives of amrinone and milrinone are 2 to 3 hours and 30 to 60 minutes, respectively, and are approximately doubled in patients with severe heart failure.
Clinically significant thrombocytopenia ( CAUSES BLEEDING ) occurs in 10% of patients receiving amrinone but is rare with milrinone.
Because of its greater selectivity for PDE III isoenzymes, shorter half-life, and fewer side effects,
milrinone is the agent of choice
among currently available PDE inhibitors for short-term parenteral inotropic support in severe heart failure.
---------------------------------------------
Plese note the following paragraph, ( the capitalization and exclamation marks are mine. The rest is original textbool including everyword). The high mortality of current phosphdiesterases as a family in general :
FURTHER DEVELOPMENT !! of ORAL formulations
of this class of agents, including the related drugs enoximone and piroximone,
was HALTED !
following the premature termination of the Prospective Randomized MIlrinone Survival Evaluation (PROMISE) trial (Packer et al., 1991),
which documented
-a 53% increase in mortality
in patients with NYHA class IV heart failure randomized to receive milrinone. In addition, patients with moderate as well as severe heart failure
-were more likely to require hospitalization or to
experience serious adverse effects
(e.g.,hypotension or syncope) than patients receiving placebo.
These unfavorable results had been presaged by a smaller trial that compared oral milrinone to digoxin or placebo (DiBianco et al., 1989). Not only was there no sustained hemodynamic improvement in the milrinone group, but the incidence of adverse events, particularly cardiac arrhyflunias, was greater in patients who received milrinone, either alone or in combination with digoxin.
==========================
BENZIMIDAZOLE PDE INHIBITORS
============================
Benzimidazole derivatives with class III PDE inhibitor activity have been developed and evaluated in patients with heart failure.
PIMOBENDAN
==========
Pomobendan has undergone extensive clinical testing and appears to be effective and generally well tolerated in patients with moderate to severe heart failure (Rector and Cohn, 1992). Importantly, improvements in exercise tolerance andfrequency of heart failure symptoms appear to be sustained in patients receiving pimobendan, unlike amrinone or milrinone. This may be due to a second mechanism of action of these agents, probably unrelated to PDE inhibition, that involves "sensitization" of cardiac contractile elements to intracellular Ca2l.
While the proarrhythmic (IRREGULAR HEART BEAT----->CARDIAC ARREST)
potential of pimobendan may be lower than that of other PDE inhibitors, the adverse survival data reported for milrinone appear to have
discouraged further development
of pimobendan for treatment of heart failure in the United States.
********************************
A number of new agents that are similar to pimobendan and have "Ca2'-sensitizing activity", but which exhibit less PDE III inhibitory activity, currently are being developed and are now undergoing clinical trials.
VESNARINONE
==========
Vesnarinone (OPC-8212) is an ORALLY active positive inotropic agent with moderate vasodilator activity that appears to act via multiple mechanisms. It is a relatively selective inhibitor of an isoform of a cyclic GMP-inhibited cyclic AMP phosphodiesterase found in human myocardial and kidney tissue (Meacci et al., 1992), but is 10-fold less potent an inhibitor of the PDE III isoform found in human aortic tissue and platelets (Masuoka et al., 1993). Vesnarinone also has been shown to affect sarcolemmal membrane voltageactivated Na- and K' channels, effects that could contribute to the drug's positive inotropic effect. It also indirectly enhances Ca2l influx through voltage-activated Ca2l channels due to its class III PDE inhibitory activity. The sum of these actions leads to a decrease in heart rate and prolongation of action potential duration, effects that are the opposite of those observed with other class III PDE inhibitors. Also, vesnarinone has been shown to decrease production of some inflammatory cytokines by lymphocytes by an unknown mechanism.
Vesnarinone was shown to decrease mortality in one multicenter randomized placebo-controlled trial (Feldman et al., 1993). Patients already receiving optimal medical therapy, most of whom had NYHA class III symptoms, were randomized to receive either placebo or vesnarinone at one of two doses (60 mg or 120 mg/day).
The higher dose arm of the trial was
=terminated early=
because of
== increased mortality==
in patients receiving active drug
. However, patients receiving 60 mg/day of vesnarinone had a greater than 50% reduction in mortality at 12 weeks compared to those who received placebo. In addition, symptoms of heart failure and quality of life improved in the group given 60 mg/day of vesnarinone, confirming the results of earlier, smaller trials. Follow-up trials are in progress to determine if these data can be replicated and to define further the optimal dose range and subsets of heart failure patients most likely to benefit from this drug.
************************
Well I think this is enough reading for today;....arrhythmia...proarrhythmic drugs, syncope, cardiac standstill, stroke, heart attack, bleeding,thrombocytopenia,.. 79 year old patient, 60 year old, 45 year old....
We need to very carefull who we prescribe Viagra to. " Same father same son", gg. Look at Viagra's family.
Furthermore when I hear Urologists ( ie physicians NOT trained to handle systmic drugs in general- Urologists mainly cut an dput tubes in people, telling me that Phosphodiesterases are safe , Zebra, and Misslil as good intenists say: " Oh no, here we go again !! ".
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
For good measure here is the SCIENCE study on the retina:
Retinal Degeneration in Mice Lacking the,gamma
Subunit of the Rod CGMP Phosphodiesterase
Stephen H. Tsang, Peter Gouras, Clyde K. Yamashita,
Hild Kjeldbye, John Fisher,* Debora B. Farber, Stephen P. Goff-,
The retinal cyclic guanosine 3',5'-monophosphate (CGMP) phosphodiesterase (PDE) is a key regulator of phototransduction in the vertebrate visual system. PDE consists of a catalytic core of a and b subunits associated with two inhibitory g ( gamma ) subunits. A gene-targeting approach was used to disrupt the mouse PDE-g gene. This mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa. In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEap dimer was formed but lacked hydrolytic activity. Thus, the inhibitory -g subunit appears to be necessary for integrity of the photoreceptors and expression of PDE activity in vivo
ooooooo
Our results indicate that an interaction between the gamma subunit and PDE ab is essential for the proper activation of PDE and that all three subunits may be essential for assembly of a stable, active holo enzyme. The genetic loss of PDEGamma is manifested as an increase in cGMP content in the developing mutant retinas.
The hi cGMP concentrations may keep cGMP-gated cationic channels open
____________________________________________________________________ continuously and lead to an excessive energy load on the rod
____________________________________________________________
photoreceptors resulting in degeneration.
_________________________________________
***********************************
S.H. Tsang, J Fisher, S. P. Goff, Howard Hughes Med co nstitute, Department of Biochemistry and Molecular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
P Gouras and H. Kjeldtye, Edward Harkness Eye Institute, Department of Ophthalmology, Columbia University, College of Physicians and Surgeons, New York, NY 10O32, USA.
C.K. Yamash la and C. S. Farber, Jules Stein Eye Institute. Molecular Biology Institute and Department of Ophthalmology UCLA School of Medicine, Los Angeles, CA 90095, USA.
'Present address: Regeneron Pharmaceutcas, Tarry lesson, NY 10591. USA,
SCIENCE - VOL. 272 - 17 MAY 1996
***********************************
COMMENT (mine ):
Viagra studies have shown that patients get " blue halos " around their visual field.It is easy to link that to Sildenafil/Viagra's inhibition of PDE ( phosphodiesterase), which in essence is not different than what the above study did, ie, genetically destruy it. The study clearly shows that the retina NEEDS PDE around to inhibit/keep the level of cyclicGMP low because if cGMP rise then the retina is continuosly stimulated which lesds to retinal degeneration.
But that is exactly what Viagra does!!: keep cGMP high in the corpora
cavernosa to cause penile vasodilatation!!
It appears to me that whereas penile tumescence is good, " retinal tumescence!! " leads to premature blindness degeneration.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
And finally here is what was reported in News week(partial reprint ), about " blue halos in patients "
NOVEMBER 17, 1997 NEWSWEEK 67
The third pill, Pfizer's Viagra:
marketing studies have includ-
ed men with varying degrees of
impotence,
The drug's most
common side effects include in-
digestion and headaches, and
some users report visual dis-
turbances, such as a loss of color
perception or a halo effect. But
those effects are transitory. Ex-
perts are hopeful that low-dose
co mbinations of the new pills
will boost benefits and reduce
side effects".
*******************************************
Well you can't have it both ways Jim : you either jack up Viagra dose to get a better erection but then you ran the risk of side effects in the eye,retinal degeneration, plus possible cardiac effects,plus possible drub-interactions etc etc.; Or , you keep the dose low to minimize sideffects then in that case you get only aa ten minute erection as was the mean ( 12.5 min ) in the Viagra study in the Internat Jour of Impotence.
TA |
