I have often failed to understand how taking ED pills, at least for some one like me when no efforts were made to spare nerves- could cause any harm or even make any difference. Because:
1: for men with functioning nerves, these nerves produce Nitric Oxide(NO) in the penis
2: The NO is itself a vaso-dilator, but ends up producing cGMP and probably also cAMP, which mess with calcium to cause dramatic arterial dilation.
3: PDE5 inhibitor pills inhibit this enzyme which breaks down cGMP, which = more cGMP which = more erection.
4:If the nerves are not working, then no NO= no cGMP. If there is no cGMP to start with, it benefits little to block the enzyme which would break down cGMP if it was present
5: Hence what we observe: no amount of PDE5 will do much of anything for most of us, at least until some nerve healing occurs, if it ever does.
So I figured an injection works by some other mechanism to produce maximal dilation even if NO and cGMP are missing. So I couldn't see what difference pills could make or what problems they could cause since things are already maximally dilated. But I was wrong about
the cGMP.
The kick in the pants is this: injections also work to produce cGMP or the similar cAMP! It seems they sort of work like NO or at least have the same effect of producing cGMP:
www.ncbi.nlm.nih.gov/pmc/articles/PMC2002499/article said...
The mechanism of action of alprostadil is targeted at the end organ. Alprostadil acts directly on the penile and vascular smooth muscle cells to stimulate the production of cAMP with resulting intracellular calcium sequestration and subsequent smooth muscle relaxation, penile tumescence, and eventual erection. It does not depend on NO or an intact nervous system.
So, if some of the injections work like NO to produce cGMP/cAMP, if we add the pills that block the enzyme which breaks these down, then we end up with even more cGMP/cAMP, which = stronger and/or longer lasting erections. Maybe too much for those with some nerve function, but maybe helpful for those with none. And here is another wild card: turns out a nonspecific PDE inhibitor (papaverine) is used in Trimix! Papav works like Viagra!
article said...
Combination Therapy
As in other areas of medicine where multiple drugs with different mechanisms of action are combined to more effectively treat a condition, it was not long before combinations of oral and non-oral therapies were considered for ED.
The basic scientific foundation for combination therapy has long been established. By taking advantage of the different mechanisms of action either to increase corporal smooth muscle relaxation or decrease its contraction, the combination of different injectable agents was found to be synergistic in producing an erectile response.................. Bivalacqua and colleagues21 showed that the erectile response in the anesthetized cat was best when an adenyl cylase agonist (alprostadil), a nonspecific alpha adrenergic receptor antagonist (phentolamine), and a nonspecific PDE inhibitor (papaverine) were used. The response was superior to single agents of similar or other classes. Intracavernosal pressure, penile length, and duration of erection were significantly improved over single agents. When the same authors injected a PDE-4 inhibitor (cAMP specific) with alprostadil, synergy in erectile quality was observed.22 In addition, intracellular levels of cAMP as well as cGMP were increased, suggesting mechanistic “cross talk” between the cAMP and cGMP pathways...............................Sildenafil may also be combined with intracavernosal prostaglandins (PGEs), although most of the reports evaluate the addition of sildenafil to injection-therapy failures.
McMahon and associates31 reported their results in 93 men with mixed etiology ED who had failed high-dose injection therapy. Thirty-four percent responded to sildenafil alone, 31% responded to combination therapy, and 35% did not respond at all and went on to penile prosthesis or vacuum device or were lost to follow-up. None challenged with intraurethral alprostadil had success. In men on combination therapy, 4 discontinued due to adverse events (severe headache, facial and truncal flushing, penile pain, dyspepsia, and dizziness). There were no episodes of priapism.25.............Gutierrez and associates34 added intracavernosal PGE-1 injections in a strictly programmed dosage to 40 men with mixed etiology ED who were unsatisfied with their oral sildenafil therapy. The patients received 4 biweekly 20 μg intracavernous PGE-1 injections along with either placebo or 50 mg of sildenafil capsules. Four weeks after initiation of therapy, the 2 groups were crossed over in terms of oral therapy. The authors found a significantly higher satisfaction rate among the group receiving PGE-1 and sildenafil combination compared with those receiving either sildenafil alone or PGE-1 and placebo. Table 1 summarizes the results of several combination therapy studies..............Summary
With a growing population of men who are initially refractory or become refractory to PDE-5 inhibitors, combination oral and non-oral therapy is of increasing importance. Combination oral and non-oral therapy has been shown to salvage PDE-5 inhibitor, IUA, and ICI failures. The early introduction of ICI or IUA39 has been shown to expedite the return of natural function and expedite PDE-5 inhibitor responsiveness in post-prostatectomy patients. In the published series on combination therapy there have been no cases of priapism, clinical hypotensive episodes, or any serious adverse events, though the total numbers are admittedly small.
So, maybe some of us should be cautious with a combination approach but for some others maybe it is just what is needed?
Your thoughts are appreciated!
Bill