The physiological basis of erection

Pro-erectile impulses are generated in the parasympathetic erection centers of the limbic system and the hypothalamus, in particular in the para ventricular nucleus and the medial preoptic area, which are the key regions for the central regulation of erection. Perception of sexual (erotic) stimuli, such as visual, imaginary or tactile stimuli, activate a variety of receptors processing the stimulatory signals, which in turn are running via oxytocinergic/ dopaminergic neurons to the spinal parasympathetic reflexogenic erection center, located at the level S2-S4 Parasympathetic nerve fibers, the so-called nervi erigentes, leave the reflexogenic erection center and build along with the sympathetic nerve fibers originating from the superior hypogastric plexus — the inferior hypogastric plexus — which continues in the cavernous nerves. These cavernous nerves contain both sympathetic and parasympathetic fibers and perforate the pelvic floor (urogenital diaphragma) to enter the cavernous bodies at the level where the cavernous crura are diverging.

Erection-initiating neurotransmitters are dopamine (via D2-receptors) and melanocortins, for which five melanocortin receptors (MCR) have been identified, of which the MC-4-R seems of special importance for erection. After entering the cavernous bodies the parasympathetic nerve fibers principally divide into two different nerve terminals: cholinergic (acetylcholine, ACH) nerve terminals ending at the endothelial cells and stimulating nitric oxide (NO)-synthase, which catalyzes the production of NO from L-arginine and 02, and non-adrenergic, non-cholinergic (NANC-peptidergic) nerve terminals at the cavernous smooth muscle cells, from which NO and VIP (vasoactive intestinal polypeptide) are released into the smooth muscle cell. There, NO activates guanylate cyclase, which catalyses the breakdown of guanosine triphosphate into 3’5′-cyclic guanosine monophosphate (cGMP),the key second messenger for erection.

The Phosphodiesterase (PDE) System

Currently the phosphodiesterase system includes 11 families, with a total of more than 50 splice variants (isoforms). The distribution and density of PDEs varies among the different tissues. The PDEs catalyze the breakdown of either cGMP or cyclic adenosine monophosphate (cAMP), which are both second messengers with specific physiologic functions. By hydrolyzing the phosphodiesterase bond of cAMP or cGMP, these second messengers are converted to the biologically-inactive monophosphates, resulting in termination of their physiologic functions.

In addition to PDE-5, which is the most abundant one in the corpus cavernosum, to date at least 13 other PDEs have been identified in the cavernous bodies: PDE-1A, PDE-IB, PDE-1C, PDE-2 A, PDE-3A, PDE-4A, PDE-4B, PDE-4C, PDE-4D, PDE-7A, PDE-8A, PDE-9A, PDE-10A.

Apart from their direct impact on cavernous function, PDE-4 and -5 inhibitors also inhibit proliferation and migration of smooth muscle cells, PDE-3 and PDE-4 inhibition can reduce restenosis after angioplasty procedures, individually, or by acting synergistically, and are therefore under investigation for their potential on angiogenesis.

General considerations for the three PDE-5 Inhibitors

For a better understanding of differences among, and comparisons between the three PDE-5 inhibitors, some terms frequently used in publications have to be explained.

IC50 is defined as the concentration of a PDE-5 inhibitor required to reduce the activity of PDE-5 by 50%. The IC50 values provide an overview of the clinical efficacy of a PDE-5 inhibitor. Generally speaking the lower the IC50 values the more potent and therefore more effective a compound is for this enzyme.

Clinical efficacy

Regarding the clinical efficacy of a PDE-5 inhibitor several tools are used in clinical trials.

Regarding the general assessment question (GAQ): “Has the treatment you have been taking improved your erections?” This efficacy tool does not really tell whether the patient is able to attain an erection sufficient for sexual intercourse or not. This relatively weak efficacy measure is widely used, especially by pharmaceutical companies, because usually it yields the highest success rates.

International index of erectile function (IIEF)

The IIEF was originally developed to evaluate the clinical efficacy of sildenafil (Viagra ®) and became the most accepted and used efficacy tool for drugs assigned to treat erectile dysfunction world wide. It comprises 15 questions in five domains, addressing erectile and orgasmic function, sexual desire, sexual satisfaction and overall satisfaction. Each question has six response options scoring between zero (worst) and five (best result). For evaluation of the erectile efficacy of a drug the IIEF erectile function (EF) domain, comprising questions 1-5 and 15, represents the strongest efficacy tool, with a score >25 indicating a normal erectile function.

Sexual encounter profile (SEP)

The sexual encounter profile relies on the recordings of the patients in the patient diaries distributed to the patients with the study medication and collected at each study visit. The sexual encounter profile comprises the following five questions:

  1. 1 Were you able to achieve at least some erection (some enlargement of the penis?)
  2. 2 Were you able to insert your penis into your partner’s vagina?
  3. 3 Did your erection last long enough for you to have successful intercourse?
  4. 4 Were you satisfied with the hardness of your erection?
  5. 5 Were you satisfied overall with this sexual experience?

SEP question 3 (ability to complete sexual intercourse) turned out to be the most rigorous and most frequently-used efficacy measure in clinical erectile dysfunction trials.

Selectivity

The selectivity of a drug such as a PDE-5 inhibitor provides data on how selective a compound is with regard to the enzyme in question (here PDE-5), on which the efficacy is desired compared to other enzymes (PDE 1-4 and 6-11), and on which an efficacy has to be regarded undesirable.

Therefore the selectivity of a phosphodiesterase inhibitor is assessed by comparing its potency (IC50) to inhibit a phosphodiesterase in question (here phosphodiesterase 1-4 and 6-11), and its potency to inhibit the phosphodiesterase desired (here PDE-5).

The selectivity ratio is used for all three PDE-5 inhibitors to show how selective they are for PDE-5, as compared to anyone of the other ten PDEs. The higher this selectivity ratio is for PDE-5 compared to the phosphodiesterase investigated, the more specific the PDE-5 inhibitor can be considered. In the clinical use all three PDE-5 inhibitors show, at the highest doses, a sufficiently high safety margin to all the other PDEs, except for sildenafil which shows only all -fold higher selectivity ratio for PDE-5, and for vardenafil which shows a 2 5-fold higher selectivity profile for PDE-5 as compared to PDE-6 — an enzyme exclusively located in the retina that is responsible for our color and brightness discrimination abilities. In terms of phosphodiesterase -11, an enzyme just recently isolated in several tissues, without knowing in detail its physiologic function, the selectivity ratio of tadalafil turned out to be only five-fold higher for PDE-5.

Pharmacokinetic issues of the three PDE-5 inhibitors — onset and duration of clinical efficacy

The pharmacokinetic profile of a drug comprises all the different steps between its entry into the body and its elimination. In this regard of special interest is the speed of absorption, which is best defined by the Tmax (time needed to reach the maximum plasma concentrations — Cmax) and T1/2 (half-life), defined as the time it takes for the fall of the plasma-concentrations of a drug to half of its Cmax values. In the clinical setting the Tmax corresponds quite well with the speed of clinical efficacy (onset of erection) and the T1/2 (half-life), with the period of clinical -efficacy

As illustrated in Table 7.2, all three drugs show similar earliest onset of action times, with vardenafil being a bit ahead. In this context it must taken into consideration that both with sildenafil and vardenafil, the pharmacokinetic parameters Tmax, onset of action and Cmax are clearly dependent on food intake; that means that after intake of a high fat (59% fat) meal a delay in Tmax of 60 min and a reduction in Cmax of 29% was observed with sildenafil; similar data are valid for vardenafil. On the other hand, with tadalafil, no food interaction was reported even with high fat meal.

Regarding the duration of efficacy, both with tadalafil and vardenafil, large placebo-controlled, double-blind trials were dedicated to figure out the real window of responsiveness, which is not the case for sildenafil; although two studies with a very limited and thus not representative number of patients were able to show responsiveness of up to 12 hours for sildenafil. Tadalafil steady-state plasma concentrations of 1.6-fold of the applied single dose are attained within five days if given once daily. Less than 0.0005% of the administered tadalafil dose appear in the semen.

Pharmacodynamics

The term pharmacodynamics covers all actions of a drug on the different body organs, and in turn on their functions (for example blood pressure, heart rate, vision). The pharmacodynamic interactions of any drug are influenced by the number of receptors available in the target organ and the affinity of the compound for the receptors in question. So for example it was just recently reported that vardenafil has, with 85%, a clearly higher proportion of high-affinity components to the PDE-5 catalytic site than sildenafil (with 50%) and tadalafil (with 60%). Given the fact that the high affinity components of a PDE-5 inhibitor show a considerably longer dissociation time, this explains why vardenafll showed in clinical use a clearly longer duration of efficacy than could be inferred from its half-life time.

Intrinsic and extrinsic factors, drug-interactions

Efficacy of the three PDE-5 inhibitors

Overdose

Sildenafil: doses of up to 800 mg increased dose-dependently the well-known drug-related adverse events, without occurrence of new side effects currently not seen under therapeutic doses. Tadalafil: single doses of up to 500mg and daily dosing of 100 mg for three weeks (in this study design patients reached tadalafil plasma levels equivalent to 160 mg single dose), resulted in a dose-dependent increase in drug-related adverse events already observed under therapeutic doses, but no new unknown side effects occurred.

Non-responders to PDE-5 inhibitors

Chronic daily dosing of PDE-5 inhibitors

Although all three PDE-5 inhibitors were developed and approved for as-needed use, many experts in this field moved to daily dosing, provided the patients could afford it. Daily dosing of PDE-5 inhibitors at bed time became a successful treatment option in early sexual rehabilitation of patients after nerve-sparing radical prostatectomy. But beyond this indication, daily dosing with PDE-5 inhibitors turned out to be very successful in non-responders to on-demand treatment, supported by personal observations and also increased nocturnal erection events in healthy men. According to personal experience with more than 100 patients currently on daily dosing with tadalafil 5-10 mg, this concept is very promising for organic erectile dysfunction patients with several cardiovascular risk factors, and relieves the patients from scheduling sexual activities. This is especially welcomed by their partners. In addition, chronic dosing with PDE-5 inhibitors, either short-acting (here sildenafil) or long-acting (tadalafil), resulted in improvement of endothelial dysfunction. This holds true not only for the cavernous bodies, but also for the endothelium in the whole vascular system. In this regard it may be speculated that daily dosing with PDE-5 inhibitors may have long-term beneficial effects on the whole vascular system, and perhaps also on voiding difficulties related with benign prostate hyper-plasia, as PDE-5 is widely distributed within the prostate.

Conclusions on PDE-5 inhibitors

As described in the extension to this site, all three PDE-5 inhibitors are very effective and safe and can be applied to nearly all erectile dysfunction patients, with the exception of those under nitrate or NO donor medications and those suffering from very severe eye diseases (retinitis pigmentosa and NAION). In terms of efficacy they are not really distinguishable, although it might quite often happen in the daily routine use of these drugs that one PDE-5 inhibitor produces better erections in an individual than the other one, or one PDE-5 inhibitor might be better tolerated than the other. In this regard it seems to be wise and reasonable to offer the patients the option to try all three drugs in order to choose the optimal one for long-term use. Daily dosing with PDE-5 inhibitors seems to be a very promising new option, especially in difficult to treat patients — provided they can afford it.

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