Sildenafil

development history
Sildenafil was developed by Pfizer Inc. in the United States and first entered clinical research as a 5-phosphodiesterase inhibitor for the treatment of cardiovascular disease. Researchers hope that sildenafil can relax cardiovascular smooth muscle by releasing the bioactive substance nitric oxide, achieving the goal of dilating blood vessels and relieving cardiovascular disease. However, clinical studies have shown that the cardiovascular effects of sildenafil do not meet researchers' expectations. As a cardiovascular drug, sildenafil's performance is disappointing and it cannot grow into a successful therapeutic drug. In April 1991, the clinical trial of sildenafil was officially declared a failure, but a side effect reported by participants caught the attention of researchers. Researchers have found that patients are unwilling to hand over the remaining medication after receiving the trial medication. Upon investigation, it was found that this medication improved the sexual life of the patient. After obtaining approval from Pfizer's senior management, researchers conducted research on the effect of sildenafil on the smooth muscle of the corpus cavernosum of the penis, and obtained marketing authorization from the US Federal Food and Drug Administration on March 27, 1998, becoming a product that made Pfizer famous.
overview
Sildenafil was the first oral anti impotence drug to be launched in the United States in April 1998. Many studies have proven it. Nitric oxide (NO) is the main mediator causing smooth muscle relaxation and erection in the corpus cavernosum. Sildenafil is a selective inhibitor of phosphodiesterase (PDE) V, which can enhance the physiological response of penile erection induced by NO release under sexual stimulation. NO is released from nerve endings and endothelial cells and binds to receptors on the smooth muscle of the corpus cavernosum, activating soluble guanylate cyclase in the cells. The latter, with the participation of Mn2+, promotes the conversion of guanosine triphosphate (GTP) to cyclic monophosphate (cGMP). cGMP activates protein kinase G (PKG) and a small portion of protein kinase A (PKA). The activated PKG and PKA lower the level of free Ca2+in the cells by activating Ca2+pumps, leading to relaxation of the smooth muscle of the corpus cavernosum, arterial blood flow, penile congestion, hardness, and erection. PDE V exists in human human spongy tissue and vascular smooth muscle, which can hydrolyze cGMP into GMP and block the NO cGMP pathway that causes penile erection. Sildenafil is a PDE V selective inhibitor that can prevent the degradation of cGMP, thereby enhancing the erectile response to sexual arousal. In vitro experiments have shown that sildenafil has a higher selectivity for PDE V than for other PDE isoenzymes. It has no effect on PDE III involved in cardiac contraction, but can inhibit PDE VI present in the retina at higher doses, affecting vision. Bottled products are only available for imports from the United States and are difficult to purchase domestically.

Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific type 5 phosphodiesterase (PDE5) and is an oral medication used to treat ED. The physiological mechanism of normal penile erection involves the release of nitric oxide (NO) in the body during sexual stimulation. Nitric oxide activates guanylate cyclase in the smooth muscle cells of the corpus cavernosum of the penis, leading to an increase in cGMP levels, causing the smooth muscle in the corpus cavernosum to relax, the cavernous sinus to dilate, and blood to flow in, resulting in penile erection. Patients with erectile dysfunction are mainly caused by smooth muscle relaxation disorders in the corpus cavernosum of the penis. Sildenafil does not have a direct relaxation effect on isolated human sponges, but can enhance the effect of nitric oxide by inhibiting the breakdown of cGMP by PDE5 in the sponge. When sexual stimulation causes local release of nitric oxide, sildenafil inhibits PDE5, increases cGMP levels in the sponge, relaxes the smooth muscle of the sponge, and blood flows into the sponge. Studies have shown that erectile response increases with dose and plasma concentration, and the efficacy can last for 4 hours (but weaker than at 2 hours). In vitro experiments have shown that sildenafil has high selectivity for PDE5, which is over 80 times that of PDE1, over 700 times that of PDE2 and PDE4, and 4000 times that of PDE3. Due to the relationship between PDE3 and the control of myocardial contractility, and the absence of PDE5 in the myocardium, sildenafil has no positive inotropic effect and does not directly affect myocardial contractility. However, sildenafil can cause vasodilation of the systemic blood vessels. When taken orally at a high dose (100mg), it can lead to a decrease in supine blood pressure [with an average maximum decrease of 1.12/0.73kPa (8.4/5.5mmHg)], and the most significant decrease in blood pressure occurs 1-2 hours after medication. Therefore, sexual activity may induce cardiac events during peak blood concentration. The selective effect of sildenafil on PDE5 is only 10 times that on PDE6, which is an enzyme present in the retina. Therefore, sildenafil may cause color vision abnormalities at high doses or blood drug concentrations. In addition to the smooth muscle of the human corpus cavernosum, low concentrations of PDE5 have also been found in platelets, blood vessels, visceral smooth muscle, and skeletal muscle. Sildenafil may enhance antiplatelet aggregation (in vitro experiments), inhibit platelet thrombus formation (in vivo experiments), and dilate peripheral blood vessels (in vivo experiments) by inhibiting PDE5 in these tissues.

Sildenafil is rapidly absorbed after oral administration, taking effect within 10-40 minutes, with an absolute bioavailability of approximately 40%. The peak blood drug concentration (cmax) is reached after oral administration on an empty stomach for 30-120 minutes, and after oral administration after meals for 90-180 minutes. Healthy volunteers take a single oral dose of 100mg, and after 24 hours, the blood drug concentration is about 2ng/ml, with a cmax of 440ng/ml. Abnormal liver function, severe renal insufficiency, or increased area under the curve (AUC) after medication in elderly individuals aged 65 and above. Sildenafil and its major circulating metabolites (N-demethylates) bind approximately 96% to plasma proteins, and the protein binding rate is independent of the total drug concentration. The tissue is well distributed with a distribution volume (Vd) of 105L. Sildenafil is mainly cleared through the liver's microsomal enzymes cytochrome P450 3A4 (CYP 3A4, primary pathway) and cytochrome P450 2C9 (CYP 2C9, secondary pathway). Its main metabolite (N-demethylate) has similar PDE selectivity to sildenafil, with a plasma concentration of about 40% of sildenafil. Therefore, approximately 20% of the pharmacological effects of sildenafil come from its metabolites. The elimination half-life of sildenafil and its metabolites is about 4 hours. 80% of the administered dose is mainly excreted in the form of metabolites through feces, and 13% is excreted through the kidneys. 90 minutes after taking medication, the amount of sildenafil measured in semen of healthy volunteers was less than 0.001% of the administered dose