On-demand use of tadalafil for erectile dysfunction in special categories of patients

Between the May holidays, it became known that Rospotrebnadzor began to withdraw from circulation the dietary supplements Sealex Forte and Ali Caps, intended to strengthen male potency. The reason is the allegedly detected content of the substance tadalafil in the drugs. This substance was not indicated when registering dietary supplements, so they were considered counterfeit.

Previously, the same fate befell another dietary supplement for men - “Tongkat ali platinum” and “Tongkat ali platinum forte”, in which the pharmaceutical substance tadalafil was also allegedly found. As a result, Rospotrebnadzor banned state registration of these additives.

The main complaint about the drugs is the presence of an active substance that was not declared during registration, since there is nothing dangerous in tadalafil itself - it is contained in almost all dietary supplements for increasing a man’s sexual performance.

Thus, at the end of April 2015, the Association of Manufacturers of Biologically Active Food Additives (SRO NPP BAD), together with the Union of Professional Pharmaceutical Organizations and the Pharmacy Guild, made a test purchase and examined dietary supplements advertised as natural potency stimulants. For analysis, samples of six brands included in the top 10 in terms of sales volumes in Russia in 2014 were selected. The results of laboratory examination showed that they contained undeclared synthetic components of prescription drugs, and in the vast majority of cases it was tadalafil.

On-demand use of tadalafil for erectile dysfunction in special categories of patients

S.I. Gamidov1, 2, T.V. Shatylko3, N.G. Hasanov1, N.A. Naumov1

1 Federal State Budgetary Institution Scientific Center for Obstetrics, Gynecology and Perinatology named after. IN AND. Kulakov" of the Ministry of Health of Russia; Russia, 117997 Moscow, st. Academician Oparina, 4; 2 Federal State Autonomous Educational Institution of Higher Education First Moscow State Medical University named after. THEM. Sechenov Ministry of Health of Russia; Russia, 119991 Moscow, st. Bolshaya Pirogovskaya, 2, building 4; 3 Federal State Budgetary Educational Institution of Higher Education “Saratov State Medical University named after. IN AND. Razumovsky" of the Ministry of Health of Russia; Russia, 410012 Saratov, st. Bolshaya Kazachya, 112 Contacts: Taras Valerievich Shatylko

Introduction

Erectile dysfunction (ED) is one of the most common and widely discussed types of sexual dysfunction in men. Worldwide, 5–20% of men have moderate or severe ED [1]. The prevalence of ED is constantly increasing, and by 2025, according to projections, 322 million men will suffer from this disorder [2]. Despite the fact that ED as such does not affect life expectancy, it significantly worsens the quality of life not only for the patient himself, but also for his partner.

Currently, there are several treatment strategies for ED, which involve non-invasive and invasive methods. According to the recommendations of the European Association of Urology, the 1st line of therapy includes oral administration of phosphodiesterase type 5 inhibitors (PDE-5) [3]. From a chemical point of view, the IPDE-5 molecules are similar in structure to cyclic guanosine monophosphate. Therefore, they can competitively bind to phosphodiesterase and suppress the hydrolysis of guanosine monophosphate, which facilitates the development of erection [4]. Currently, a large number of drugs of the PDE-5 class are proposed, although not all of them have undergone clinical trials and have been approved by the relevant regulatory authorities. Thus, in Russia, drugs are available based on one of 4 active ingredients: sildenafil, tadalafil, vardenafil and udenafil. Their effectiveness and safety are comparable; some unprincipled differences are noted in the structure of adverse events during use [5–7].

Meta-analysis by L. Chen et al. in 2015, showed that sildenafil is characterized by the highest effectiveness and the highest frequency of adverse events, and tadalafil is characterized by average effectiveness and the minimum frequency of adverse events [8]. However, these data require revision, since the meta-analysis included all studies on these drugs. B. Gong et al. conducted a more statistically rigorous meta-analysis, including only those studies that directly compared sildenafil and tadalafil [9]. It turned out that their effectiveness is approximately the same, but patients and their partners prefer tadalafil because of its ease of administration.

An important factor when choosing a drug is its pharmacokinetics. Tadalafil is a selective long-acting PDE-5 inhibitor. Tadalafil should be taken at least 16 minutes before intended sexual intercourse. The half-life of tadalafil in healthy men is 17.5 hours, and it is this pharmacokinetic parameter that makes tadalafil attractive for the symptomatic treatment of ED. Due to its long half-life, it has the longest duration of action of any PDE-5 inhibitor, which can be up to 36 hours. The patient can attempt sexual activity at any time within 36 hours after taking the drug to determine the optimal time for response development. About 52% of patients with severe ED can successfully have sexual intercourse within 30 minutes after taking tadalafil at a standard dose [10]1.

Probably, thanks to these qualities, in the near future, tadalafil will be able to occupy the niche of the main IPDE-5 for the treatment of ED. Drugs based on it entered the market in 2003.

However, it would be wrong to assume that any one drug can be equally suitable for all patients with ED, especially considering the polyetiology and heterogeneity of this syndrome. This article is devoted to the use of tadalafil in special categories of patients with ED.

Tadalafil in patients with metabolic syndrome

There are several different definitions of metabolic syndrome, but they all include 4 features: abdominal obesity, hypertension, dyslipidemia and carbohydrate metabolism disorders. In the absence of therapy and lifestyle correction, impaired glucose tolerance can develop into type II diabetes mellitus. Treatment of ED in patients with diabetes mellitus is not an easy task due to the combination of vasculogenic and neurogenic components of the pathogenesis of ED, as well as the need to take into account the associated cardiovascular risks and the interaction of prescribed drugs with hypoglycemic agents. Despite this, on-demand tadalafil therapy was effective in patients with diabetes mellitus. We note that the effect on lower urinary tract symptoms (LUTS) in these patients was greater with 5 mg tadalafil daily, although this is not the purpose of this article. Interestingly, tadalafil also improved ejaculatory function in patients with diabetes [11]. There are indications that tadalafil reduced fat-to-muscle ratio and waist circumference in men; Presumably, this occurs due to improved insulin secretion, an increase in the number of androgen receptors and inhibition of testosterone aromatization. In addition, an improvement in endothelial function has been confirmed using the Endo-Pat2000 device [12]. Molecular cellular study by E. Maneschi et al. demonstrated that tadalafil influenced the differentiation of preadipocytes and promoted a healthy phenotype by enhancing the expression of genes characteristic of brown adipose tissue, improving mitochondrial structure and normalizing insulin sensitivity in animal models [13].

In addition, metabolic syndrome may be associated with hypogonadism. A significant decrease in testosterone levels in the blood serum can weaken libido, and this turns out to be an additional pathogenetic factor in the development of ED in metabolic syndrome. There is a hypothesis according to which a regular rhythm of sexual activity helps to normalize the level of endogenous testosterone. In a study by L. Ozcan et al. Long-term use of tadalafil increased testosterone levels in patients with ED and metabolic syndrome without hormone replacement therapy [14]. L. Maresca et al. showed that taking tadalafil and regular exercise enhanced each other's effect in patients with ED and metabolic syndrome [15].

Tadalafil in patients with chronic prostatitis or benign prostatic hyperplasia

In 2007, SJ Grimsley et al. suggested that PDE-5 may mediate relaxation of the smooth muscle of the prostate ducts, facilitating the outflow of their contents, including those that initially entered the acini due to urethral-prostatic reflux [16]. M. Kurita et al. found that PDE-5 inhibitors, in particular tadalafil, relieve chronic pelvic pain [17]. Clinically, these results were confirmed in the work of Y. Nishino et al., who examined patients with benign prostatic hyperplasia (BPH), combined with chronic pelvic pain syndrome [18]. However, the above-described effects of taking tadalafil have not yet been widely confirmed and require further study [19]. P.V. Glybochko et al. demonstrated that PDE-5 increases blood flow not only in the arteries of the penis, but also in the prostate gland [20]. This direction is considered particularly promising, since chronic prostatitis can indirectly cause the development of various sexual dysfunctions [21].

We will not touch upon the issue of daily use of tadalafil for LUTS associated with BPH, as we believe that this issue deserves a separate comprehensive discussion. However, it is known that some men with prostate adenoma can obtain a positive clinical effect from taking PDE-5 on demand [22]. In particular, this applies to patients at high risk of progression of BPH who are prescribed 5-alpha reductase inhibitors (finasteride and dutasteride). These are drugs that can reduce the volume of the prostate gland with long-term use and reduce the risk of developing acute urinary retention in older men. The mechanism of action of these drugs is to inhibit the conversion of testosterone to the active metabolite dihydrotestosterone. It is the influence on testosterone metabolism that is often explained by the characteristic adverse events associated with taking finasteride and dutasteride - the appearance of persistent ED, decreased libido and impaired ejaculation. Several studies have confirmed that tadalafil, taken on demand at a dose of 20 mg, is effective against ED in patients taking dutasteride [23, 24].

Data on the effect on erection of another class of drugs actively used for BPH, namely selective alpha-1a blockers (tamsulosin and silodosin), are contradictory. There is a controversial opinion that they have little positive effect on erectile function. In any case, there is no convincing data on the negative effects of tamsulosin and silodosin on erectile function. Consequently, the question arises about their compatibility with IPDE-5, since both classes of drugs, to one degree or another, affect the tone of the vascular walls. Studies have confirmed the safety and good tolerability of combination therapy for LUTS with tamsulosin and tadalafil, which did not increase the risk of orthostatic collapse [25, 26]. The safety and effectiveness of the combination of tadalafil with silodosin has also been proven [27].

Tadalafil for neurogenic erectile dysfunction

Neurogenic ED is the most difficult form of ED to treat conservatively. The reason is that PDE-5, included in the 1st line of therapy, causes relaxation of the smooth muscles of the cavernous bodies as a result of the accumulation of cyclic guanosine monophosphate, formed due to the action of nitric oxide (NO). If the release of nitric oxide from the nitrergic synapses of parasympathetic nerve fibers does not occur, then IPDE-5 essentially has no point of application and is obviously ineffective. Therefore, for severe types of neurogenic ED, intracavernous injections remain the only effective method of conservative treatment [1]. Nevertheless, with at least partial preservation of the innervation of the penis, IPDE-5 have a certain effectiveness, which can be explained by their ability to biochemically amplify a weak NO signal and activate endothelial NO synthase. Thus, sildenafil, tadalafil and vardenafil are effective in some patients with traumatic spinal cord injury [28], the use of other PDE-5 inhibitors in this category of patients has not been studied.

The pathogenesis of ED and concomitant sexual disorders in multiple sclerosis is very complex [29]. The effectiveness of tadalafil in multiple sclerosis has been demonstrated in several studies. G. Lombardi et al. reported good results with on-demand tadalafil 10 mg in men with ED and multiple sclerosis [30]. 1 patient developed headache during therapy, 1 patient developed tachycardia; These are expected side effects that also occur in people without neurological diseases.

Not a single case of autonomic dysregulation was reliably recorded. In a study by D. Francomano et al. The effect of tadalafil not only on erection, but also on the severity of LUTS, which often occurs in patients with multiple sclerosis, has been confirmed [31]. This study also found a change in the ratio of serum testosterone to estradiol levels with tadalafil.

The use of IPDE-5 may be effective in patients with ED due to Parkinson's disease. In patients with other pathologies of the central nervous system, the use of IPDE-5 is limited due to a possible decrease in libido, the development of endocrine disorders with damage to the hypothalamic-pituitary region, and the potential effect of drugs on the neurological status [32].

The use of tadalafil to regulate reproductive function

One of the debatable questions is how justified is the prescription of IPDE-5 to men with ED who are trying to conceive a child. On the one hand, erection is the most important component of the copulatory cycle, and without it natural conception is almost impossible. On the other hand, some experts express an opinion about the potential testicular and spermatological toxicity of IPDE-5.

Non-specific PDE inhibitors such as caffeine, pentoxifylline and theophylline are known to stimulate sperm motility in vitro. Moreover, pentoxifylline is widely used for this purpose as part of assisted reproductive technologies. The effect of these compounds on male fertility in vivo has not been proven [33].

In a study by Y. Yang et al. The effect of tadalafil on sperm motility and acrosome reaction was assessed [34]. Neither in vitro nor in vivo, tadalafil suppressed gamete motility or increased the incidence of premature acrosome activation. However, this study assessed only the immediate period after the introduction of tadalafil into the medium or after its oral administration, and therefore its results do not allow us to exclude late cumulative toxicity.

Attempts have been made to prove the positive effect of IPDE-5 on spermatogenesis. Thus, in a study by A. Corvasce et al. After 12 weeks of taking tadalafil, spermogram parameters in patients with psychogenic ED significantly improved [35], including an increase in ejaculate volume. This fact indicates that the positive effect on sperm parameters could be caused primarily by the normalization of ejaculation. As is known, phosphodiesterase type 5 is expressed in all muscle tissues of the male reproductive tract, which means that influencing the level of this enzyme makes it possible to pharmacologically regulate ejaculatory function [33].

Conclusion

The effectiveness of tadalafil depends on the etiology of ED, the presence of concomitant diseases and the nature of the therapy. Tadalafil can be used in men with diabetes and metabolic syndrome, as it has been shown to be effective in these groups of patients with ED. Tadalafil combines well with typical medications used for BPH. Tadalafil is effective in some cases for neurogenic ED, although with some limitations; Its most promising use is in spinal cord injury and multiple sclerosis. Convincing data indicating a negative effect of tadalafil on fertility has not been published, although it is also premature to draw a conclusion about its positive effect on spermatogenesis and sperm motility.

Undoubtedly, tadalafil at a dosage of 5 mg for daily use has the greatest potential among all the PDE-5 inhibitors on the market, which made penile rehabilitation after treatment for prostate cancer and single-component therapy for ED and LUTS possible. However, taking tadalafil on demand is acceptable and convenient for many men suffering from ED.

The appearance on the Russian market of a generic tadalafil – “Dynamico Long”, produced on the basis of an Israeli substance2 in compliance with modern requirements and quality standards3, may make this treatment option more accessible4 compared to the use of the original tadalafil. It is important that such treatment has a positive effect not only on erectile, but also on orgasmic and ejaculatory functions, and the long duration of the drug helps maintain spontaneity of sexual life and increases a man’s self-confidence [36, 37].

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The article was published in the journal “Andrology and Genital Surgery”, issue No. 4 2022, pp. 15-20

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Andrology and genital surgery 2022 No. 4

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The main side effects of Viagra. Cialis and Levitra and their frequency are summarized in Table 1.

Table 1. Frequency of side effects of certain dosages (mg) of erection pills in %.

The frequency of side effects depends on the dose of the drug and individual sensitivity. It also depends on what you eat the day before using erection pills. On a full stomach, the frequency of side effects, as well as the effectiveness of the drugs, is lower.

An absolute contraindication to taking erection pills is their intolerance (allergy) and the simultaneous use of organic nitrates (Nitroglycerin, Sustak, Nitrong, Nitrosorbide, Erinit, etc.). When taking erection pills and organic nitrates simultaneously, a fatal decrease in blood pressure can occur. It is extremely undesirable and potentially dangerous to prescribe erection pills from the group of PDE inhibitors to patients with the following diagnoses:

• Coronary heart disease with frequent attacks of chest pain.
• Congestive heart failure and significant decrease in blood pressure.
• Significant decrease in cardiac output.
• Complex complex drug therapy for hypertension.
• Drug therapy that can slow down the removal of PDE inhibitors from the body.

The described cases of deaths associated with taking Viagra were most often caused by the combined use of this drug with organic nitrates.

Drugs such as ketoconazole and erythromycin inhibit the removal of PDE inhibitors from the body. Individuals taking these drugs should reduce their dose of erection pills or avoid taking them altogether. Significantly enhances the effectiveness of erection pills, especially in persons with hypogonadism or male menopause (andropause), the simultaneous use of male sex hormones (testosterone).