Pde 5 in the treatment of erectile dysfunction

PDE-5 inhibitors: list, dosage, composition, instructions for use, side effects, indications and contraindications

The article will talk about PDE-5 inhibitor drugs. It is known that due to Erectile dysfunction, the work of other organs and systems is not disturbed, it does not harm the health and life of a man, but such a sexual disorder is very difficult to perceive from a psycho-emotional point of view. A man has to worry about the quality of erection and potency for almost his entire adult life, even if there are no visible reasons for concern.

At present, there are a large number of natural remedies that help prevent erectile disorders, and strong erection stimulants for complete dysfunction. The most effective are PDE-5 inhibitors, or type 5 phosphodiesterase inhibitors, which provide a man with a 100% erection, regardless of the etiology of the disorder and its severity.

What are the causes of erectile dysfunction?

If earlier various psychological problems were considered the main causes of erectile dysfunction, now the opinion has changed. It is now known that the violation in 80% of cases is of organic origin and appears as a complication of various somatic diseases.

Main organic causes: hypogonadism (dyshormonal conditions); angiopathy; neuropathy.

The prevalence of pathology of the heart and blood vessels is very high, more than 50% of the stronger sex with such diseases have erectile dysfunction, but not every patient uses PDE-5 inhibitors - a kind of "gold standard" in the treatment of defects in sexual function. Why is it so? Unfortunately, up to the present time, patients are extremely wary of such drugs, despite the fact that their effectiveness has already been proven.

General therapeutic principles

Before selecting tablet type 5 phosphodiesterase inhibitors for the treatment of disorders of the reproductive system, each man must determine the mental and somatic prerequisites for such disorders. The following factors can affect an erection:

• the presence of concomitant systemic pathologies in the body;
• use of strong drugs;
• lifestyle (bad habits, passive pastime, overeating);
• frequent depression and stress.

Expert help

If, after the elimination of such prerequisites for dysfunction, the violation does not go away, you can first use the help of a sexologist or psychotherapist. A conservative treatment method can be a correction of nutrition, playing sports, giving up addictions, losing weight, and eliminating stressful situations that lead to depression. Among other things, an erection can be restored by treating the underlying disease, such as hormonal disorders, diabetes, etc.

What does the treatment involve?

Medicated treatment involves:

• sublingual and oral use of tablets;
• injections into the urethra or cavernous bodies of vasoactive drugs.

Alpha-1 blockers or PDE5 inhibitors shortly before intercourse may also help to achieve a stable erection.

Special Instructions

It should be noted that taking such medications is possible only after consulting a doctor. He will determine the dosage acceptable in each case, since if used irrationally, the drug may be ineffective or cause side effects.

Appropriateness

The use of PDE-5 inhibitors is reasonable, as evidenced by the following facts:

• These drugs are adapted first-line treatments;
• the use of such funds has been going on for more than 30 years;
• repeated clinical trials have proven their effectiveness;
• drugs are easy to use;
• In practice, millions of men have proven the safety of such funds.

Instructions for the use of drugs

At present, phosphodiesterase type 5 inhibitors are the most popular in the treatment of erectile dysfunction, which have valuable pharmacokinetic properties, are clinically effective and relatively harmless.

Pharmaceutical companies produce a large number of drugs that stimulate erection. PDE-5 inhibitors include the following drugs.

"Sildenafil". It is also a selective PDE5 inhibitor, which was first produced in 1996. Film-coated almost white or white round tablets, biconvex, with an almost white or white core on a cross section.

The active ingredient is sildenafil nitrate, in one tablet - 28.09 mg, which corresponds to 20 mg of sildenafil. Auxiliary components: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate.

The film coating contains talc, hypromellose, titanium dioxide, polyethylene glycol 4000 (macrogol 4000).

The tablet should be taken one hour before intimate intercourse, the approximate daily dosage ranges from 50 to 100 mg. The effect of the drug lasts for four hours.

Phosphodiesterase type 5 inhibitor drug "Vardenafil". This is an advanced and new highly selective inhibitor that has been proven to be highly effective in biological equivalents by repeated clinical studies (in the form of monohydrochloride trihydrate).

This drug is taken once a day thirty minutes before intimacy, its effect lasts 4-5 hours. The daily dosage is approximately 10-20 mg of vardenafil.

Tadalafil is a selective inhibitor that has been on the market for a while, but is highly effective in restoring erectile dysfunction. "Tadalafil" is currently produced in the form of tablets, in which the active ingredient contains 2.5; 5; 20 and 40 mg. As an active active element, the drug "Tadalafil" includes a chemical substance of the same name. In the form of excipients, the preparation contains the following components: giproloza; lactose; croscarmellose sodium; microcrystalline cellulose; magnesium stearate; sodium lauryl sulfate; titanium dioxide; triacetin.

The principle of action and structure are somewhat different from Sildenafil, its selectivity is less than that of the first agent. The effectiveness of the composition of the tablets lasts 36 hours. The drug should be taken in an amount of 10-20 mg shortly before intimacy. In addition, such a remedy is allowed to be combined with alcohol and food, which is an indisputable advantage for patients.

"Udenafil". A modern reversible selective inhibitor that makes it easy for a man to achieve an erection. Tablets should be taken 30-90 minutes before possible sexual contact, and its effect will last for 12 hours. It is very important to comply with all the conditions that are specified in the instructions, since drugs of this type have contraindications and side effects.

"Avanafil". The next representative of the group of PDE-5 inhibitors, which also promotes vasodilation and allows blood to flow to the intimate organs more easily, providing an erection by 100%. The tablets contain avanafil as an active ingredient. The composition of the drug also includes mannitol, hydroxypropylcellulose, fumaric acid, calcium carbonate, iron oxide and magnesium stearate.

The medicine should not be taken if there is an allergic reaction to at least one of the components listed above. The therapeutic efficacy of the drug is 80%, the tablet must be taken 15-20 minutes before the upcoming sexual contact. The effectiveness of the drug lasts for six hours, it can be combined with alcohol and food. In this case, the average dosage is approximately 100 mg per day.

What can be achieved?

It is worth noting that most drugs of this type to stimulate erectile function allow for vascular expansion, muscle relaxation, and thanks to this, it will be much easier to achieve an erection.

In addition, such products are not recommended to be combined with the intake of alcoholic beverages or fatty foods, as this may to some extent reduce the absorption and effectiveness of the tablets.

Before taking the erectile-restoring pills listed above, each man should consult the optimal dosage of a particular inhibitor, since an overdose can cause significant side effects.

Contraindications for taking PDE5 inhibitors

It is known that drugs with synthetic components in any case have a well-defined list of contraindications, can cause a number of side effects.The same can be said about PDE-5 inhibitors, which are contraindicated in the following situations:

• the person has not reached the age of majority;
• hypersensitivity to components;
• concurrent use of tablets containing organic nitrates;
• disorders and pathologies of the functionality of the heart and blood vessels, in which increased sexual activity is unacceptable;
• taking Doxazosin and other erection drugs;
• vision loss due to anterior non-arterial ischemic optic neuropathy;
• chronic kidney failure and use of similar stimulants more than twice a week;
• alabsorption, lactase deficiency, or lactose intolerance;
• Glucose-galactose malabsorption.

Side effects

The most typical undesirable effects of the irrational use of type 5 phosphodiesterase inhibitors are vomiting, nausea, headaches, visual disturbances (light perception and lack of concentration), dizziness, rhinitis and swelling of the nose, shortness of breath, redness of the face. If these symptoms occur, you should consult a doctor.

Interaction between Trazodone and phosphodiesterase type 5 inhibitors

Trazodone is a selective serotonin reuptake inhibitor, it also blocks 5-HT2A receptors and moderately inhibits serotonin reuptake.

Trazodone can be used both as a separate treatment course and in combination with other drugs for getting rid of erectile dysfunction, including androgens and phosphodiesterase type 5 inhibitors, that is, they are combined with each other, their interaction is effective.

Pharmacological group - Potency regulators

Potency regulators - a group of drugs that includes various drugs used to treat erectile dysfunction.

Erectile dysfunction (ED) - the inability to achieve and/or maintain an erection sufficient for sexual intercourse - remains an important social and medical problem worldwide. According to modern concepts, sexual stimulation activates the parasympathetic nervous system. Vascular smooth muscle cells metabolize cGMP by phosphodiesterase type 5 (PDE5). With relaxation, smooth muscle cells contract, 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 reduced vascular sensitivity to cGMP, lack of compression of the penile veins as a result of connective tissue proliferation, or a combination of these causes. It is believed that ED in 80% of cases occurs 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 mellitus, atherosclerosis, etc. The occurrence of ED can be facilitated by drug therapy, such as thiazide diuretics, non-selective beta-blockers, sympatholytics, etc.

For many centuries, in order to prolong sexual longevity, various stimulants have been used, mainly of plant origin, many of which were aphrodisiacs and had hallucinogenic, psychostimulant and other properties. For example, for many centuries in oriental medicine, a 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. A certain contribution to the study of the biological properties of the seahorse was made by Hirohoto (1901-1989), the penultimate Japanese emperor, who was interested in marine biology and left a number of interesting works in this area.

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

Among the drugs for the treatment of erectile dysfunction, the following groups can be distinguished: I) drugs that increase the level of nitric oxide: 1) selective PDE5 inhibitors: sildenafil citrate, tadalafil, vardenafil; 2) NO-synthase activators - Impaza (homeopathic remedy); II) alpha-blockers: 1) selective alpha2-blockers: yohimbine (yohimbine hydrochloride); 2) non-selective alpha-blockers: phentolamine; III) prostaglandin E analogs: alprostadil; IV) means of complex composition; V) androgens: testosterone; VI) myotropic antispasmodics: papaverine.

Phosphodiesterase inhibitors are the first line of treatment for ED. The mechanism of action of all three drugs in this group is the same: they have a peripheral effect, selectively inhibiting cGMP-specific PDE5, which is responsible for the breakdown of cGMP in the cavernous bodies.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 act up to 5 hours, tadalafil - up to 36 hours. 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 cavernous bodies, PDE5 is found in small amounts in platelets, smooth muscle tissue of blood vessels and internal organs, and in skeletal muscles. Inhibition of PDE5 in these tissues can lead to an increase in the antiaggregation activity of platelet nitric oxide in vitro, suppression of the formation of platelet aggregates, and peripheral arteriovenous dilatation in vivo. Between drugs there are clear differences in activity against PDE6, which plays an important role in the conversion of light impulses into nerve impulses 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 do not have an inhibitory effect on PDE11.

For all PDE5 inhibitors, the onset of action is approximately the same (after 30-60 minutes), but the duration varies significantly. The effect of tadalafil is manifested longer than others (up to 36 hours). Take the drugs 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 peaks after 1 hour, and tadalafil after 2 hours. Absorption occurs mainly in the small intestine; intake of fatty foods does not cause a delay or deterioration in the absorption of tadalafil, but reduces and slows down the absorption of sildenafil citrate and vardenafil. The half-life of sildenafil citrate and vardenafil from blood plasma is 3-5 hours, and tadalafil is 17-21 hours. Despite the long half-life, tadalafil does not have the ability to accumulate, equilibrium concentrations are reached on the fifth day with daily intake. The parent substances and major metabolites are almost completely bound to plasma proteins. Sildenafil citrate, vardenafil and tadalafil are metabolized in the liver, with the participation of the CYP3A4 isoenzyme, and to a lesser extent - CYP2C9. CYP3A5 is also involved in the metabolism of vardenafil. The selectivity of the action of metabolites is preserved, the activity is more than 50% lower than the initial substances. Tadalafil metabolites are inactive.

All PDE5 inhibitors have a similar mechanism of action, which is associated with their effect on NO / cGMP. They enhance the antihypertensive and microcirculation-improving effects of NO donors, incl. nitrates, therefore, patients receiving such drugs should not be prescribed PDE5 inhibitors. With the simultaneous use of inhibitors of the cytochrome P450 CYP3A4 enzyme (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.

In addition to PDE5 inhibitors, endotheliotropic drugs include the homeopathic preparation Impaza. Impaza contains affinity-purified antibodies (a mixture of homeopathic dilutions C12, C30 and C200) to human endothelial NO-synthase (NO-synthetase) - an enzyme involved in the production of nitric oxide

Unlike PDE5 inhibitors, which increase the effect of nitric oxide by slowing down the breakdown and accumulation of cGMP, Impaza directly affects the production of nitric oxide by the vascular endothelium. The results of preclinical and clinical studies suggest that long-term use of Impaza not only contributes to the normalization of indicators characterizing the sexual sphere (including erectile function, libido, etc.), but also improves the endothelial function of blood vessels. Impaza is the drug of choice in patients suffering from cardiovascular diseases, tk. does not affect the level of blood pressure, does not adversely affect the coronary circulation. It should be noted that, as a rule, ED is also detected in IHD, and PDE5 inhibitors are contraindicated for these patients, who in most cases receive nitric oxide donors (nitrates).

Yohimbine (yohimbine hydrochloride) is an alkaloid derived from the bark of the West African tree Corynanthe yohimbe and the roots of Rauwolfia serpentina.It is a selective blocker of central and peripheral presynaptic alpha2-adrenergic receptors. In high doses, it blocks postsynaptic alpha-adrenergic receptors. In moderate doses, it causes vasodilation of the pelvic arteries, which helps to improve erectile function (strengthens erection, prolongs the time of sexual intercourse), stimulates spermatogenesis. Due to the action on the central nervous system, it improves mood, increases motor activity, sexual desire, and can increase anxiety. In a number of clinical studies, the effectiveness of yohimbine did not exceed placebo. The above properties make it possible to use the drug for the prevention and treatment of the psychogenic form of erectile dysfunction, as well as a tonic for men. Yohimbine (yohimbine hydrochloride) is prescribed in courses (if necessary, repeated) lasting up to 10 weeks. Yohimbine (yohimbine hydrochloride) should not be combined with drugs that affect mood, incl. with antidepressants.

The main mechanism of action of phentolamine is a non-selective blockade of postsynaptic alpha1-adrenergic receptors, which leads to a disruption in the transmission of adrenergic vasoconstrictor impulses. Due to this, phentolamine mainly acts as a detumescence blocker and is more often used in combinations (see papaverine below). It is used in the form of intracavernous injections and in tablets orally.

Alprostadil is 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, increases blood flow and improves microcirculation, which leads to an adequate erection. Does not affect ejaculation and fertilization. One of the possible mechanisms of action of the drug is due to the ability of alprostadil to bind to specific receptors on the cell surface and change the activity of adenylate cyclase. This leads to an increase in the concentration of cAMP in cells, a decrease in the content of free intracellular calcium and relaxation of the smooth muscle fibers of the cavernous arteries, which improves the functioning of the veno-occlusive 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 with intraurethral administration is absorbed from the urethral mucosa into the spongy body. Effects develop within 5-10 minutes after administration and last 30-60 minutes. Part of the administered dose is distributed into the cavernous bodies (through collateral vessels), the remainder - into the venous network of the perineum; Once in the central venous circulation, alprostadil is almost completely eliminated from the systemic circulation by the lungs; T1 / 2 - 0.5-1 min. It is metabolized to form various PGE1 derivatives. It is used immediately before sexual intercourse.

Simultaneous use of alprostadil with other drugs injected into the corpora cavernosa can lead to erection prolongation or priapism. The simultaneous use of alprostadil with myotropic antispasmodics (papaverine, bendazol) and alpha-blockers can also lead to a prolonged erection. Alprostadil may enhance the effect of antihypertensive and vasodilators.

Means of complex composition are preparations and biologically active additives of plant and animal origin. They have different mechanisms of action: the active substances that make up their composition (phytosterols, biostimulins, natural tocopherols) have a tonic, stimulating and tonic effect. These drugs have proandrogenic activity, stimulate spermatogenesis, reduce sperm viscosity, and have anti-inflammatory and antimicrobial effects. By acting on the central mechanisms of erection and testicles, they restore/increase libido, sexual satisfaction, and the production of full-fledged sperm. They improve physical and mental performance, eliminate overwork, have a weak sedative effect. Pharmacokinetics and features of the interaction of drugs of complex composition are not well understood. As a rule, they are prescribed in courses, with the exception of topical preparations.

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 set of diagnostic tests for erectile dysfunction. Complex drugs are more often used for psychogenic ED, with a decrease in sexual activity in old age.

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

In some diseases and conditions, the use of potency regulators is contraindicated: hypersensitivity, anatomical deformity of the penis; diseases that can cause priapism - sickle cell anemia, leukemia, etc.; severe somatic pathology in which sexual activity is contraindicated (in particular, acute myocardial infarction, suffered within the last 90 days, unstable angina or angina that occurs during intercourse, heart failure of NYHA class 2 or higher, developed within last 6 months, uncontrolled cardiac arrhythmias, arterial hypotension, uncontrolled arterial hypertension, stroke within the last 6 months). It is not recommended to use these drugs in patients with mental and intellectual disorders. PDE5 inhibitors and yohimbine are contraindicated in severe renal and hepatic insufficiency. In addition, PDE5 inhibitors are contraindicated while taking NO donators, incl. nitrates (increased antihypertensive and antiplatelet action) and beta-blockers (possibility of developing hypotension), with retinitis pigmentosa. They should be used with caution in patients with aortic stenosis or obstructive hypertrophic cardiomyopathy, 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 in history and the presence of mental illness. Alprostadil is contraindicated in venous thrombosis and increased blood viscosity.

The androgen testosterone and the myotropic agent papaverine are less important in the treatment of ED than PDE5 inhibitors, yohimbine and alprostadil.

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

Papaverine is used for intracavernous injections; high concentrations are used, at which a double hemodynamic effect is manifested - the expansion of the penile arteries and the narrowing of the veins, which leads to the activation of the veno-occlusive 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 effects. In order to reduce the risk of priapism and cavernous fibrosis, combinations are used: papaverine + phentolamine (bimix), papaverine + phentolamine + alprostadil (trimix).

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

In clinical trials, good results have been obtained, indicating the effectiveness of opioid receptor antagonists naloxone and naltrexone in idiopathic ED. The action of these drugs is presumably associated with a change in the level of hormones released in the central nervous system or a decrease in inhibitory impulses from the spinal cord or sacral parasympathetic ganglion. Studies of the efficacy and safety of opioid receptor antagonists are ongoing.

An agonist of D1- and D2-dopamine receptors of the hypothalamus, apomorphine, which promotes erection, is also undergoing clinical trials. The drug is prescribed sublingually, intranasally and s / c (for diagnostic tests).

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

The influence of VIPa (vasointestinal peptide) - a neurotransmitter that provides vasodilatation, on the erection process continues to be studied. When administered intracavernously, it affects tumescence, so it should only be used in combination with phentolamine.

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

First line therapy in the treatment of erectile dysfunction

Oral drugs for the treatment of impotence

Erectile dysfunction treatment: Sildenafil

The action of sildenafil begins half an hour to an hour after ingestion and can last up to 12 hours. Its effectiveness decreases with the intake of heavy fatty foods, which slows down its absorption.

Pharmacokinetic parameters of sildenafil are given in the table at the end of the article. Negative manifestations are usually insignificant and disappear on their own. The proportion of cases with drug withdrawal due to complications is comparable to placebo.

Impotence treatment: tadalafil

Vardenafil for the treatment of erectile dysfunction

This drug went on the market in 2003. It starts working half an hour after taking it, but its effect can also be weakened by heavy fatty foods. As an initial dose, 10 mg is recommended, then it can be changed in accordance with the response to the drug and the side effects that have occurred.

In laboratory tests, Vardenafil showed an order of magnitude greater efficacy than sildenafil, but this, however, does not mean the same difference in clinical efficacy. Pharmacokinetic parameters of vardenafil are given in Table. 5. In the table. 6 shows its side effects, which are usually minor and limited to the duration of use.

The results of 12 weeks of treatment gave about the same results as Tadalafil. But in the group of patients with diabetes, he gave an improvement in erection in 72% of men.

Main pharmacokinetic parameters of drugs used to treat ED