Pharmacology and Mechanism of Action of Sildenafil Citrate - Coursework Example

Summary of pharmacology and mechanism of action of Viagra- sildenafil citrate August 05, Pharmacology and mechanism of action of sildenafil citrate Pharmacology of drugs refers to the study and classification of drugs, their composition, action, toxicology, and the mechanism of action of the drug (Fricchione and Stefano, 2005). Sildenafil citrate is widely used to treat erectile dysfunction in men, and to increase the libido, and the action of the drug in this area is well documented (Carlson, 1997). However, the drug is also known to increase the fertility of women, affecting the embryo growth, and the drug vasodilates the feto-placental circulation through a cGMP dependent mechanism that shows increased responsiveness to NO (Maharaj, et al. 2009). This paper evaluates the pharmacology, and mechanism of the action of sildenafil citrate, with the focus of its action on mice embryos. Drug composition: Sildenafil citrate was released commercially in 1998 by Pfizer Inc. to treat male erectile dysfunction. The chemical formula is 5-[2-ethoxy-5-(4-methylpiperazine-1-ylsulfonyl) phenyl] -1-methyl-3-propyl-6, 7-dihydro-1-H-pyrazolol [4-3-d] pyrimidin-7-one. The molecular formula is C22H30N6045 (Umrani and Goyal, 1999). Mechanism of drug action in males: The mechanism of action in men is very documented in a number of studies (Boolell , et al. 1996; Goldstein, I. and Feldmen, 1997; Israel, 1998; Steers, 1998; RxList, 2014;).The drug does not directly cause an erection, the action is towards the response to sexual stimulation. It acts by releasing nitric oxide - NO in the penile muscle called corpus cavernosum, when sexual stimulation is given. NO activates guanylate cyclase enzyme, and protects cyclic guanosine monophosphate - cGMP from undergoing degradation by the cGMP-specific phosphodiesterase type 5 - PDE5, formed in the corpus cavernosum of the penis. NO on the penile muscle, bonds with the receptors of guanylate cyclase, and this increases the concentration of cGMP. The next action is a vasodilation of the helicine arteries, and increases the blood flow to the spongy tissue of the corpus cavernosum, thereby causing an erection. This molecular structure is similar to that of cGMP, forming a PDE5 binding agent, and allows for longer and sustained erections. However, the drug cannot act passively, and is only activated when there is sufficient sexual stimulation. The liver breaks down Sildenafil through hepatic metabolism by means of the cytochrome p450 enzymes that are formed by the hepatic isoenzymes, CYP4503A4 and CYP2C9 that metabolise the enzymes to create N-desmethylated sildenafil. Mechanism of drug action in female mice: The focus of this paper is to research the mechanisms of sildenafil citrate on mice embryo. A number of researchers have published their work on this subject (Ferrari, et al. 2002; Hotchkiss, et al. 2005; Kurt , et al. 2004; Langroudi , et al. 2005; Li , et al. 2002). The findings indicate that sildenafil supports the NO-cGMP pathway. Mice that were injected with stronger doses of the drug, produced dead embryos, and it was observed that stronger doses of the drug has a significant growth suppressing impact on the foetuses. A few researchers have explained the action of sildenafil citrate by suggesting that it produces alterations on the free intracellular Ca2+ distribution, which controls cell division in embryos (Webb and Miller, 2003). The Ca2+ flux, and its distribution to different embryo parts are needed for the normal development of the embryo. Depletion of calcium by PDE inhibitors along with the calcium channels that allow flux distribution, are controlled by the phosphorylation that depends on cAMP (Blancato and Seyler, 1990). Any minor changes in cAMP or cGMP, impacts the proliferation of the embryonic cell. Another effect of sildenafil citrate is seen in the property of PDE inhibitor types 3 and 4 that interfere with the DNA synthesis, leading to increase of cAMP, causing further interference with the embryo (Refuerzo, et al. 2006). Next paragraphs provide more details about different studies. Tahsili-Fahadan et al. (2006) conducted a research to examine the properties of sildenafil, and the NO-cGMP pathway in mice. The study involved testing 191 NMRI mice of weight 20-30 grams, and these were placed in cages in groups of 7, in a temperature-controlled room, held at 22 degree centigrade. The mice were conditioned with 12 hours light- dark schedule with food and water. Conditioned place preference method was used to evaluate the effect of drug and non-drug treatments (Snyder and Bredt, 1991). The drug uses the principle that when a primary reinforced is used along with a contextual stimulus, the combination secures secondary reinforcing properties that are formed due to the Pavlovian contingency (Jain, et al. 2001). These again help to obtain a place preference that produces a substantial rise in the duration of the drug-paired place. In their research, Tahsili-Fahadan et al. (2006) examined the conditional place preference in unbiased CPP paradigm, and the effect that the compound of NO precursor L-arginine, nonselective NOS inhibitor NGnitro-L-arginine methyl ester, and the inhibitor ofguanylyl cyclasemethylene blue (MB) on sildenafil-induced CPP, were evaluated. The results indicated the mice that had been given 20-40 mg/ kg dose of sildenafil in the conditioning phase, showed a preference for this treatment. Both doses suppressed the preference induced by sildenafil. The lower doses of sildenafil of 10 mg/ kg that was non-effective along with L-arginine of dosage 60 mg/ kg, showed good place conditioning. The conclusions that were drawn indicate that sildenafil supports the NO-cGMP pathway. Another important research on the effects of sildenafil citrate on mice embryo was presented by Glenn et al. (2009) who examined the effect of cyclic monophosphate–specific type 5 PDE inhibitor, which affects the function of the sperm on early embryo cleavage and fertilisation. In the study, 161 F1 female hybrid mice and male mice were kept in cages in regulated 12 hours light/ dark cycle for two weeks, and fed on a diet of Harlan extruded rodent diet. Males were placed in separate cages, while females were placed in groups, and injected intraperitoneally with 5 IU gonadotropin, to stimulate follicular growth, and after 48 hours, they received injections of 5 IU hCG. The male mice were given an oral dose of different concentrations of sildenafil citrate, 0.06 mg/0.05 mL. After a gap of 12 hours, they were placed in cages with a male, and allowed to mate. After 24 hours, the female mice were killed and their embryos retrieved. The percent of fertilisation was evaluated through the number of oocytes, and number of male/ female pronuclei. It was observed that there is a significant reduction of 33% in the number of fertilised oocytes that mated with males, which had been administered with sildenafil citrate. The study further indicated a relation between the strength of dosage of the drug, and males that had been given lesser dosage produced embryos with more number of blastomeres, while males that were given larger doses, produced dead embryos with small and irregular darkened nuclei along with higher cytoplasmic nuclear ratios. Abou-Tarboush et al. (2011) studied the teratogenic and toxic effects of different doses of sildenafil citrate on foetuses of mice. A sample size of 285 pregnant mice formed the control group, and multiple doses of the drug were administered in the ratio of 6.5, 13, 19.5, 26, 32.5, or 40.0 mg of sildenafil citrate/kg body weight, orally on different days of the gestation. On the 17th day of the pregnancy, the foetuses were removed, and studied for embryo-fetal toxicity, and for skeletal malformations. While none of the foetuses displayed any malformations from the dosage, it was seen that the strength of the dosage had a significant growth suppressing impact on the foetuses. Dosage of 6.5 mg had the least effect, while dosage of 40 mg had the highest effect on the samples. The study also indicated that higher dosage of 26, 32.5 and 40 mg/ kg had fatal embryo-fetal toxicity, when the drug was administered on the days 13-15 of gestation. To conclude, it becomes clear that the use of sildenafil has a detrimental effect on the embryo of mice, and stronger doses lead to increased detrimental effects. The paper examined the different action mechanisms used and discussed some important aspects of the research. References Abou-Tarboush, F. M., Abdel-Samad, M. F. and Al-Meteri, M. H., 2011. Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice. Saudi Journal of Biological Sciences, 18, pp. 135-139. Blancato, J. K. and Seyler, D. E., 1990. Effect of calcium-modifying drugs on mouse in vitro fertilization and preimplantation development. International Journal of Fertilization, 35, pp. 171–176. Boolell, M., Gepi-Atti, S., Gingell, J. and Allen, M., 1996. Si lden afil: a novel effective oral therapy for erectile dysfunction. British Journal Urology, 78, pp. 257-261. Carlson, R., 1997. Sildenafil: an effective oral drug for impotence. Inpharma, 1085, pp. 11-12. 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