Pharmacological group – potency regulators

Potency regulators   – A group of drugs, including various drugs used to treat erectile dysfunction.

Erectile Dysfunction (ED) – inability to achieve and / or maintain an erection sufficient for sexual intercourse, – remains an important social and medical problem worldwide. According to modern concepts, with sexual stimulation, the parasympathetic nervous system is activated. The release of mediators, in particular nitric oxide (NO, endothelial relaxing factor) from the vascular endothelium of the cavernous bodies leads to the accumulation of cyclic guanosine monophosphate (cGMP) in the cavernous tissue and the relaxation of the smooth muscle cells of the walls of the bearing arteries and cavernous bodies. Filling the cavernous bodies with arterial blood causes compression of the venules and blocking the outflow of blood from the penis (veno – occlusive mechanism) – an erection occurs. Vascular muscle cells metabolize cGMP using phosphodiesterase type 5 (PDE5).

With relaxation, there is a reduction in smooth muscle cells, a decrease in blood flow through the arteries and an increase in venous outflow. ED may be due to insufficient vasodilation due to cGMP deficiency or decreased vascular sensitivity to cGMP, lack of compression of the penile veins as a result of proliferation of connective tissue, or a combination of these causes.

ED is considered to occur in 80% of cases due to various organic causes and in 20% – due to psychological factors. Often there is a combination of these factors. Among the causes of ED are age, smoking, the presence of diabetes, atherosclerosis, etc. Medical therapy, such as diuretics of the thiazide series, non-selective beta-blockers, sympatholytics, etc., can contribute to the occurrence of ED.

For many centuries, in order to prolong sexual longevity, various stimulants have been used, mainly of plant origin, many of which belonged to aphrodisia and have hallucinogenic, psychostimulating and other properties. For example, for many centuries in eastern medicine, seahorse has been used to enhance sexual function and overcome sexual weakness, eliminate frigidity in women, premature ejaculation in men, and increase the fullness and brightness of orgasmic sensations.

In the past, effective therapy for potency disorders was associated with intracavernous administration of drugs, but now the number of highly effective oral medications has increased.

Among the drugs for the treatment of erectile dysfunction are the following groups:

  1. I) Nitric oxide boosters:

1) selective PDE5 inhibitors: sildenafil citrate, tadalafil , vardenafil ;

2) NO synthase activators   – Impaza (homeopathic remedy);

  1. II) alpha- blockers :

1) selective alpha 2 -blockers : Yohimbin ( Yohimbina hydrochloride);

2) non-selective alpha blockers: phentolamine ;

III) prostaglandin E analogs : alprostadil ;

  1. IV) means of complex composition;
  2. V) androgens: testosterone;
  3. VI) myotropic antispasmodics: papaverine.

Phosphodiesterase inhibitors are first-line drugs for the treatment of ED. The mechanism of action of all three drugs of this group is the same: they have a peripheral effect, selectively inhibiting cGMP- specific PDE5, which is responsible for the disintegration of cGMP in cavernous bodies.

Due to the blockade of PDE5 and stabilization of cGMP , this group of drugs enhances the effect of nitric oxide, which activates guanylate cyclase , which leads to an increase in cGMP , relaxation of smooth muscles of the cavernous bodies and blood supply to them. There is no direct relaxing effect on the smooth muscles of the corpora cavernosa. Numerous clinical studies have proven the efficacy and safety of PDE5 inhibitors for the treatment of ED. These drugs differ in duration of action: sildenafil citrate and vardenafil are up to 5   h, tadalafil   – up to 36   h. The effect is manifested only with sexual arousal. The long-term effectiveness of tadalafil allows you to restore the spontaneity and naturalness of sexual relations.

Sildenafil citrate and vardenafil have a similar chemical structure, while tadalafil differs significantly from them in structure and pharmacokinetic properties.

In addition to the smooth muscles of the corpora cavernosa, PDE5 is contained in small amounts in platelets, vascular smooth muscle tissue and internal organs, and skeletal muscle. Inhibition of PDE5 in these tissues can lead to an increase in the antiaggregation activity of platelet nitric oxide in vitro, suppression of platelet aggregation and peripheral arteriovenous dilatation in vivo

There are obvious differences between the drugs in activity with respect to PDE 6 , which plays an important role in the conversion of light pulses into nerve pulses in the retina. In addition, these three drugs differ in activity against PDE11.

Tadalafil is 14 times more selective for PDE5 than for PDE11, but does not inhibit this enzyme at therapeutic doses. To date, it has been found in various tissues of the human body ( for example, in the heart, thymus, brain, and ovaries), but its role in metabolism remains unexplored. Sildenafil citrate and vardenafil have no inhibitory effect on PDE11.

In all PDE5 inhibitors, the onset of action is approximately the same (after 30–60 min), but the duration varies significantly. The effect of tadalafil (up to 36 hours) appears longer than others . Take the drug inside, about 1 hour before sexual intercourse. All three drugs (sildenafil citrate, vardenafil and tadalafil ) are rapidly absorbed in the gastrointestinal tract.

Absolute bioavailability is different: sildenafil citrate – 40%, vardenafil 15%. The concentration of sildenafil citrate and vardenafil reaches a peak after 1 h, and tadalafil – after 2h.

Absorption occurs mainly in the small intestine; ingestion of fatty foods does not cause a delay or deterioration in the absorption of tadalafil, but reduces and slows down the absorption sildenafil citrate and vardenafil . The elimination half-life of sildenafil citrate and vardenafil from plasma is 3–5 h, and tadalafil – 17–21   h. Despite the long half-life, tadalafil does not have the ability to cumulation, the equilibrium concentrations are reached on the fifth day with a daily intake. The parent substances and major metabolites are almost completely bound to plasma proteins. Metabolized sildenafil citrate, vardenafil and tadalafil in the liver, with the participation of CYP3A4 isoenzyme, and to a lesser extent – CYP2C9.

CYP3A5 is also involved in the metabolism of vardenafil . The selectivity of the metabolites is preserved, the activity is more than 50% lower than the starting materials. Tadalafil inactive metabolites.

All PDE5 inhibitors have a similar mechanism of action, which is associated with their effect on NO / cGMP. They do not enhance the antihypertensive and microcirculation-improving effect of NO donators, including . nitrates, therefore, patients receiving these drugs should not appoint PDE5 inhibitors. With simultaneous use of cytochrome P450 CYP3A4 inhibitors (HIV protease inhibitors, erythromycin, ketoconazole ), it is advisable to reduce the dose of PDE5 inhibitors. Alcohol intake does not affect the biotransformation of PDE5 inhibitors. When taken simultaneously with acetylsalicylic acid, bleeding time does not increase.

By means endotheliotropic besides PDE5 inhibitors Impaza relates homeopathic preparation. The composition of Impazy includes affinity purified antibodies (a mixture of homeopathic dilutions of C12, C30 and C200) to human endothelial NO synthase (NO synthase)  – an enzyme involved in the production of nitric oxide. Impaza increases the activity of endothelial NO synthase , restores the production of NO by endothelium during sexual stimulation, increases the content of cGMP in smooth muscles and promotes their relaxation, which leads to an increase in the blood filling of the cavernous bodies.

Unlike PDE5 inhibitors, which enhance the effect of nitric oxide due to slower decomposition and accumulation of cGMP , Impaza directly affects the production of nitric oxide by the endothelium of vessels. Preclinical and clinical studies suggest that long-term use Impaza not only contributes to the normalization of parameters characterizing the sexual sphere (incl. Erectile function, libido, etc.), But also improves the vascular endothelial function. Impaza is the drug of choice in patients with cardiovascular diseases, because does not affect blood pressure, does not adversely affect the coronary circulation. It should be noted that, in CHD, as a rule, ED is also detected, and PDE5 inhibitors are contraindicated in these patients, who in most cases receive nitric oxide donors (nitrates).

Yohimbine ( yohimbina hydrochloride) is an alkaloid from the bark of the West African tree Corynanthe yohimbe and roots rawwolfia serpentina . It is a selective blocker of central and peripheral presynaptic alpha 2 -adrenoreceptors. In high doses, it blocks postsynaptic alpha adrenoreceptors . In moderate doses, it causes vasodilation of the pelvic arteries, which helps to improve erectile function (enhances erection, prolongs the time of sexual intercourse), stimulates spermatogenesis. Due to the action on the central nervous system improves mood, increases physical activity, sexual desire, can increase anxiety. In a number of clinical studies, efficacy of yohimbine did not exceed placebo. The above properties allow the use of the drug for the prevention and treatment of the psychogenic form of erectile dysfunction, as well as a general tonic for men. Yohimbine ( yohimbina hydrochloride) is prescribed in courses (if necessary   – repeated) up to 10 weeks. Yohimbine (yohimbine hydrochloride) should not be combined with drugs affecting mood, incl. with antidepressants.

The main mechanism of action of phentolamine   – non-selective blockade of postsynaptic alpha 1 -adrenoreceptors, which leads to impaired transmission of adrenergic vasoconstrictive impulses. Due to this, phentolamine mainly acts as a detumescence blocker and is more commonly used in combination (see below for papaverine). It is used in the form of intracavernous injections and in pills orally.

Alprostadil   – An analogue of prostaglandin E , applied topically. With intracavernous or intraurethral administration, it has a relaxing effect on the smooth muscles of the cavernous bodies, helps to increase blood flow and improve microcirculation, which leads to an adequate erection. Does not affect ejaculation and fertilization. One of the likely mechanisms of action of the drug due to the ability of alprostadil bind to specific receptors on the cell surface and alter the activity of adenylate cyclase . This leads to an increase in the concentration of cAMP in the cells, a decrease in the content of free intracellular calcium and the relaxation of the smooth muscle fibers of the cavernous arteries, which improves the functioning of the veno – occlusal mechanism. On the other hand, alprostadil is an antagonist of compounds involved in the transmission of nerve impulses in alpha adrenergic synapses and inhibits the presynaptic release of norepinephrine into the cavernous bodies of the penis.

Alprostadil, when administered intraurethrally, is absorbed from the urethral mucosa into the spongy body. Effects develop within 5–10 min after administration and last 30–60 min. Part of the administered dose is distributed in the cavernous bodies (through the collateral vessels), the remainder   – in the venous network of the perineum; alprostadil that has entered the central venous bloodstream is almost completely eliminated from the systemic circulation by the lungs; T 1/2 – 0.5–1 min. Metabolized with the formation of various derivatives of PGE 1. It is applied immediately before sexual intercourse.

The simultaneous use of alprostadil with other drugs injected into the cavernous body, can lead to delayed erection or priapism . Simultaneous use of alprostadil with myotropic antispasmodics (papaverine, bendazole ) and alpha- blockers can also lead to prolonged erections . Alprostadil may enhance the action of antihypertensives and vasodilators.

Means of complex composition are drugs and dietary supplements of plant and animal origin. They have different mechanisms of action: the active substances in their composition ( phytosterols , biostimulins , natural tocopherols) have a tonic, stimulating and tonic effect. These agents have proandrogenic activity, stimulate spermatogenesis, reduce sperm viscosity, have anti-inflammatory and antimicrobial action. Influencing the central mechanisms of erection and testicles, restore / increase libido, sexual satisfaction, the production of complete sperm. They improve physical and mental performance, eliminate fatigue, have a weak sedative effect. When applied topically, these tools enhance erection by increasing the blood supply to the cavernous bodies of the penis. Pharmacokinetics and features of the interaction of drugs of complex composition are not well understood. They are usually prescribed courses, with the exception of topical preparations.

The indications for prescribing drugs from the main groups of potency regulators are common: erectile dysfunction of neurogenic, vascular, psychogenic, or mixed etiology. Alprostadil is also used to conduct a pharmacological test in a complex of diagnostic tests for erectile dysfunction. Drugs of complex composition are more often used for psychogenic ED, with a decrease in sexual activity in the elderly.

Regulators of potency have a number of side effects common to the whole group. These include headache, dizziness, skin rash; priapism. In addition, when using PDE5 inhibitors, there are flushing of the face, visual impairment when taking sildenafil citrate and vardenafil (color changes , increased sensitivity to light, blurred vision), nasal congestion. When using Yohimbine (Yohimbine hydrochloride), hypertension, tachycardia, orthostatic collapse, agitation, tremor, irritability, anxiety may develop, or a decrease in diuresis may occur. The use of alprostadil may be accompanied by pain in the penis, bleeding from the urethra, urinary incontinence, pain in the pelvic region, lower back, abdomen; hematoma, itching, swelling and inflammation may occur at the injection site.

In some diseases and conditions, the use of potency regulators is contraindicated: hypersensitivity, anatomical deformation of the penis; diseases that priapism can cause   – sickle cell anemia, leukemia, etc .; severe somatic pathology, in which sexual activity is contraindicated (in particular, acute myocardial infarction, suffered in the last 90 days, unstable angina or angina, occurring during sexual intercourse, heart failure of the 2nd and higher class in the NYHA, developed during last 6 months, uncontrolled cardiac arrhythmias, arterial hypotension , uncontrolled arterial hypertension, stroke suffered in the last 6 months). It is not recommended to use these drugs in patients with mental and intellectual disabilities.

PDE5 inhibitors and yohimbin are contraindicated in severe renal and hepatic failure. In addition, PDE5 inhibitors are contraindicated while taking NO donators, incl . nitrates (increased antihypertensive and antiplatelet action) and beta-blockers (the possibility of hypotension), with retinal pigment dystrophy. They must be used with caution in patients with aortic stenosis or hypertrophic cardiomyopathy obstructive type, in the presence of severe arterial and orthostatic hypotension.

Yohimbine ( yohimbine hydrochloride) is contraindicated while taking adrenomimetics , a tendency to tachycardia. Restrictions to its use are gastric ulcer and duodenal ulcer history and the presence of mental illness. Alprostadil contraindicated in venous thrombosis and increased blood viscosity.

Smaller, in comparison with PDE5 inhibitors, yohimbin and alprostadil , androgen testosterone and myotropic agent papaverine play a role in the treatment of ED.

Testosterone   – natural biologically active androgen. His devices are used for substitution therapy. There are both injectable forms and oral. The indication for use is erectile dysfunction caused by hypogonadism.

Papaverine is used for intracavernous injections; high concentrations are used, at which the double hemodynamic effect is manifested – dilation of the penile arteries and narrowing of the veins, which leads to activation of the veno-occlusal mechanism. In addition, papaverine is a non-selective phosphodiesterase inhibitor. When used in high concentrations, side effects of papaverine appear: the development of cavernous fibrosis, priapism, hepatotoxicity, systemic action. To reduce the risk of priapism and cavernous fibrosis, the following combinations are used: papaverine + phentolamine (bimix), papaverine + phentolamine + alprostadil (trimix).

In addition to the above funds, as a regulator of potency, clinical trials of the potassium channel activator Minoxidil are undergoing clinical trials. With ED, it is used as a solution applied to the head of the penis. Due to the opening of the potassium channels causes the expansion of arterioles and an increase in blood flow.

In clinical trials, good results were obtained, indicating the effectiveness of opioid receptor antagonists naloxone and naltrexone in idiopathic ED. The action of these drugs is presumably associated with changes in the level of hormones released in the central nervous system or a decrease in inhibitory impulses from the spinal cord or sacral parasympathetic node. The study of the efficacy and safety of opioid receptor antagonists has not been completed.

Also undergoing clinical trials is an agonist of D1-and D2-dopamine receptors of the hypothalamus apomorphine, contributing to the occurrence of erection. The drug is prescribed sublingually, intranasally (for diagnostic tests).

Antidepressant trazodone selectively inhibits serotonin uptake in the CNS. It has a peripheral non-selective alpha-adreno-blocking effect and, when administered intracavernously, induces a tumescence. However, according to clinical studies, intracavernous administration of trazodone is not an effective way to treat ED. At the same time, it is possible to use trazodone in disorders of libido and potency and as an antidepressant in patients with ED.

The effect on the erection process of the vasointestinal peptide, a neurotransmitter providing vasodilation, continues to be studied. When administered intracavernously, it affects the tumescence, therefore it should be used only in combination with phentolamine.

Other potential correctors for ED are melanocortin receptor agonists (melanotan). Of great interest are work in the field of gene therapy of ED and the study of vascular endothelial growth factor. Identification of molecular genetic causes of ED and the development of new highly effective and safe drugs – the subject of further research in this area.