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Phosphodiesterase Type 5 Inhibitors - a Priority Direction for the Treatment of Erectile Dysfunction of Various Origins

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Phosphodiesterase Type 5 Inhibitors - a Priority Direction for the Treatment of Erectile Dysfunction of Various Origins Turkish Journal of Physiotherapy and Rehabilitation; 32(3) ISSN 2651-4451 | e-ISSN 2651-446X PHOSPHODIESTERASE TYPE 5 INHIBITORS - A PRIORITY DIRECTION FOR THE TREATMENT OF ERECTILE DYSFUNCTION OF VARIOUS ORIGINS Gafarov R.R.1, Bobokulov N.A.1, Batirov B.A.1, Muradov S.S.2 1 Samarkand State Medical Institute, 2 Sogda Medical Centre Erectile dysfunction (ED) is a condition in which a man is unable to achieve and maintain an erection to a degree sufficient for successful intercourse. ED is a serious problem affecting both the psychosocial state of the man and his partner [1]. In the ED development, the role of bad habits is great, for example, among smoking men it occurs 20% more often than among nonsmokers [2,3]. ED is associated with various comorbid conditions such as hypertension, hyperlipidemia, metabolic syndrome, lower urinary tract symptoms (LUTS) or benign prostatic hyperplasia (BPH), cardiovascular disease, psychological factors, diabetes mellitus, post-radical prostatectomy, antidepressant medication and antihypertensive drugs, etc. (Table 1). Table 1. Pathophysiology of ED [4]. Vasculogenic Recreational habits (i.e., cigarette smoking) Lack of regular physical exercise Obesity Cardiovascular diseases (e.g. hypertension, coronary artery disease, peripheral vasculopathy) Type 1 and 2 diabetes mellitus; hyperlipidaemia; metabolic syndrome; hyperhomocysteinemia Major pelvic surgery (e.g., radical prostatectomy) or radiotherapy (pelvis or retroperitoneum) Neurogenic Central causes Degenerative disorders (e.g., multiple sclerosis, Parkinson's disease, multiple atrophy, etc.) Spinal cord trauma or diseases Stroke Central nervous system tumours Peripheral causes Type 1 and 2 diabetes mellitus Chronic renal failure; chronic liver failure Polyneuropathy Surgery (major surgery of pelvis/retroperitoneum) or radiotherapy (pelvis or retroperitoneum) Surgery of the urethra (urethral stricture, urethroplasty, etc.) Anatomical or structural Hypospadias; epispadias; micropenis Phimosis www.turkjphysiotherrehabil.org 3773 Turkish Journal of Physiotherapy and Rehabilitation; 32(3) ISSN 2651-4451 | e-ISSN 2651-446X Peyronie's disease Penile cancer (other tumours of the external genitalia) Hormonal Diabetes mellitus; Metabolic Syndrome; Hypogonadism (any type) Hyperthyroidism Hyper- and hypocortisolism (Cushing's disease, etc.) Panhypopituitarism and multiple endocrine disorders Mixed pathophysiology pathways Chronic systemic diseases (e.g., diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure, chronic liver disorders, hyperhomocysteinemia, hyperuricemia, etc.) Psoriasis; gouty arthritis; ankylosing spondylitis; non-alcoholic fatty liver; chronic periodontitis; open-angle glaucoma; inflammatory bowel disease, chronic fatigue syndrome, allergic rhinitis, obstructive sleep apnoea, depression Iatrogenic causes (e.g. TRUS-guided prostate biopsy, etc.) Drug-induced Antihypertensives (i.e., thiazidediuretics, beta-blockers) Antidepressants (selective serotonin reuptake inhibitors, tricyclics) Antipsychotics Antiandrogens (GnRH analogues and antagonists; 5-ARIs) Recreational drugs (e.g., heroin, cocaine, marijuana, methadone, synthetic drugs, anabolic steroids, excessive alcohol intake, etc.) Psychogenic Generalised type (e.g., lack of arousability and disorders of sexual intimacy) Situational type (e.g., partner-related, performance-related issues or due to distress) Trauma Penile fracture Pelvic fractures GnRH = gonadotropin-releasing hormone; 5-ARIs = 5α-reductase inhibitors. Erection, being the simplest, most persistent component of male sexuality, is at the same time its most vulnerable component. In general, male sexuality manifests itself through four successive stages: 1 - libido, 2 - erection, 3 - ejaculation, 4 - detumescence. Among all the manifestations, it is an erection that is first formed and debuts, which is observed even in infancy. That is, long before the formation of attraction, the first ejaculation and orgasm. This initially programmed significance of an erection predetermines its high resilience and elementarity, on the one hand, and extreme sensitivity to various kinds of psycho-traumatic influences, on the other. This is due to the subordination of the erection mechanism to the higher centers in the cerebral cortex, when, for example, negative emotions through these centers directly affect both the quality of an erection and the possibility of its occurrence in general [5]. The simplicity and elementary nature of an erection is only an apparent phenomenon. Erection is a complex phenomenon that is provided by the nervous, vascular and hormonal systems interaction. In response to sexual stimulation, impulses from the cortex of the frontal and temporal lobes of the cerebral hemispheres are transmitted to the amygdala (one of the most important centers of erection). Then the impulses are transmitted along the nerve pathways to the parasympathetic centers of the spinal cord, located at the S2-S4 level. With sexual stimulation, parasympathetic impulses begin to prevail. It is accompanied by the release of the main mediator of erection - nitric oxide (NO) through parasympathetic non-cholinergic, non-adrenergic nerve www.turkjphysiotherrehabil.org 3774 Turkish Journal of Physiotherapy and Rehabilitation; 32(3) ISSN 2651-4451 | e-ISSN 2651-446X endings. The nitric oxide release leads to relaxation of the smooth muscle cells of the corpora cavernosa trabeculae, a decrease in the peripheral arterioles resistance and an increase in arterial blood flow. During an erection, the smooth muscles relaxation of the corpora cavernosa trabeculae and the arterioles vasodilation leads to an increase in blood flow several times, which expands the sinusoidal spaces, while the cavernous bodies are filled with blood, the penis lengthens and increases. The expansion of the sinusoids leads to compression of the intrathecal venous plexuses. In addition, stretching the tunica albuginea compresses the emissary veins, thereby minimizing the blood outflow. All these processes lead to an increase in intracavernous pressure up to about 100 mm Hg (phase of full erection). During masturbation or intercourse, when the bulbocavernosus reflex is triggered, the sciatic-cavernous muscles strongly compress the base of the blood-filled cavernous bodies and the penis becomes even harder, while the intracavernous pressure reaches several hundred millimeters of mercury (the phase of rigid erection). At this stage, the flow and outflow of blood temporarily stops. Contractions of the sciatic-cavernous and spongy- cavernous muscles are provided due to the somatic innervation of the penis, which is carried out by the pudendal nerve (n. pudendus) [3,6,7]. Sympathetic impulses are responsible for the flaccid state of the penis by providing tonic contraction of the smooth muscles of the trabeculae and the arteries of the corpora cavernosa - the spiral arteries. In a sluggish state, inflow through narrow and tortuous helicine arteries is minimal and there is free outflow through the intrathecal venous plexus. NO, which is released by nerve endings and endothelium, activates the enzyme guanylate cyclase. Guanylate cyclase, in turn, increases the synthesis and intracellular concentration of the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP alters the activity of a number of specific protein kinases that are involved in protein phosphorylation and ion channel function. The action of protein kinases leads to the opening of potassium channels and hyperpolarization of smooth muscle cell membranes, the accumulation of calcium in the endoplasmic reticulum and blocking the entry of calcium ions into cells due to the closure of calcium channels [6,8]. This leads to a decrease in the concentration of calcium in the cytoplasm, relaxation of smooth muscles and the appearance of an erection. The phosphodiesterase type 5 enzyme (PDE-5) breaks down cGMP, thereby providing penile smooth muscle contraction and detumescence. Phosphodiesterases of other types were found in the corpora cavernosa, but they do not play a significant role in the erection occurrence. 11 types of PDE are known today. They, in turn, are subdivided into 21 subtypes. PDE isoenzymes play an important role in providing contractions of striated and smooth muscles, vascular tone, endocrine and other organ function [8]. Thus, blocking the PDE-5 enzyme increases the concentration of cGMP and promotes erection [9,10]. Therefore, drugs related to PDE-5 inhibitors are the first line of treatment for ED [11]. The most common PDE-5 inhibitors currently include Sildenafil, Tadalafil, Vardenafil, Udenafil, and Avanafil. Less well known is Lodenafil. Indicators of pharmacokinetics and pharmacodynamics, clinical efficacy of PDE-5 inhibitors, possible adverse events are shown in Tables 2,3. Sildenafil (Viagra ®, Pfizer, USA). The first known of iPDE-5 type. Used in clinical practice since 1998, it has become the drug of choice for most men with erectile dysfunction. Sildenafil is used in doses of 25, 50 and 100 mg. Initially, it is recommended to prescribe the drug at a dose of 50 mg, then, if necessary, titration is possible. Fatty foods slow down the absorption of Sildenafil, reducing its effectiveness. For more than 20 years of use of Sildenafil, it has demonstrated high efficacy (up to 80%) and safety in various categories of patients with ED. Sildenafil, while minimally affecting libido, provides improved erectile function, orgasm, and general satisfaction with sexual activity [12].
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