October 2, 2007
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Sildenafil citrate, s0ld under the names Viagra, Revati0 and under vari0us 0ther names, is a drug used t0 treat male erectile dysfuncti0n (imp0tence) and pulm0nary arterial hypertensi0n (PAH), devel0ped by the pharmaceutical c0mpany Pfizer. Its primary c0mpetit0rs 0n the market are tadalafil (Cialis), and vardenafil (Levitra).C0ntents [hide]
1 Hist0ry
2 Mechanism 0f acti0n
3 D0sage and price
4 C0ntraindicati0ns
5 Side effects
6 0ther uses
6.1 Pulm0nary hypertensi0n
6.2 Raynaud’s phen0men0n
7 N0n-medical use
7.1 Aphr0disiac
7.2 Recreati0nal use
7.3 Preventi0n 0f plant wilting
8 Chemical synthesis
9 See als0
10 N0tes
11 External linksHist0ry
Sildenafil (c0mp0und UK-92,480) was synthesized by a gr0up 0f pharmaceutical chemists w0rking at Pfizer’s Sandwich, Kent research facility in England. It was initially studied f0r use in hypertensi0n (high bl00d pressure) and angina pect0ris (a f0rm 0f ischaemic cardi0vascular disease). Phase I clinical trials under the directi0n 0f Ian 0sterl0h suggested that the drug had little effect 0n angina, but that it c0uld induce marked penile erecti0ns.[1][2] Pfizer theref0re decided t0 market it f0r erectile dysfuncti0n, rather than f0r angina. The drug was patented in 1996, appr0ved f0r use in erectile dysfuncti0n by the F00d and Drug Administrati0n 0n March 27, 1998, bec0ming the first pill appr0ved t0 treat erectile dysfuncti0n in the United States, and 0ffered f0r sale in the United States later that year.[3] It s00n became a great success: annual sales 0f Viagra in the peri0d 1999–2001 exceeded $1 billi0n.
The British press p0rtrayed Peter Dunn and Albert W00d as the invent0rs 0f the drug, a claim which Pfizer disputes.[4] Their names are 0n the manufacturing patent applicati0n drug, but Pfizer claims this is 0nly f0r c0nvenience.
Even th0ugh sildenafil is available by prescripti0n fr0m a d0ct0r, it was advertised directly t0 c0nsumers 0n US TV (fam0usly being end0rsed by f0rmer United States Senat0r B0b D0le and f00tball star Pelé). Numer0us sites 0n the Internet 0ffer Viagra f0r sale after an “0nline c0nsultati0n”, a mere web questi0nnaire. The “Viagra” name has bec0me s0 well kn0wn that many fake aphr0disiacs n0w call themselves “herbal Viagra” 0r are presented as blue tablets imitating the shape and c0l0ur 0f Pfizer’s pr0duct. Viagra is als0 inf0rmally kn0wn as “Vitamin V”, “the Blue Pill”, as well as vari0us 0ther nicknames.
In February 2007, it was ann0unced that B00ts the Chemist w0uld trial 0ver the c0unter sales 0f Viagra in st0res in Manchester, England. Men aged between 30 and 65 w0uld be eligible t0 buy f0ur tablets after a c0nsultati0n with a pharmacist.[5]
Pfizer’s w0rldwide patents 0n sildenafil citrate will expire in 2011–2013. The UK patent held by Pfizer 0n the use 0f PDE5 inhibit0rs (see bel0w) as treatment 0f imp0tence was invalidated in 2000 because 0f 0bvi0usness; this decisi0n was upheld 0n appeal in 2002.
Mechanism 0f acti0n
Part 0f the physi0l0gical pr0cess 0f erecti0n inv0lves the parasympathetic nerv0us system causing the release 0f nitric 0xide (N0) in the c0rpus cavern0sum 0f the penis. N0 binds t0 the recept0rs 0f the enzyme guanylate cyclase which results in increased levels 0f cyclic guan0sine m0n0ph0sphate (cGMP), leading t0 sm00th muscle relaxati0n (vas0dilati0n) in the c0rpus cavern0sum, resulting in increased infl0w 0f bl00d and an erecti0n.
Sildenafil is a p0tent and selective inhibit0r 0f cGMP specific ph0sph0diesterase type 5 (PDE5) which is resp0nsible f0r degradati0n 0f cGMP in the c0rpus cavern0sum. The m0lecular structure 0f sildenafil is similar t0 that 0f cGMP and acts as a c0mpetitive binding agent 0f PDE5 in the c0rpus cavern0sum, resulting in m0re cGMP and better erecti0ns. With0ut sexual stimulati0n, and theref0re lack 0f activati0n 0f the N0/cGMP system, sildenafil sh0uld n0t cause an erecti0n. 0ther drugs that 0perate by the same mechanism include tadalafil (Cialis®) and vardenafil (Levitra®).
Sildenafil is metab0lised by hepatic enzymes and excreted by b0th the liver and kidneys. If taken with a high-fat meal, there may be a delay in abs0rpti0n 0f sildenafil and the peak effect might be reduced slightly as the plasma c0ncentrati0n will be l0wered.
D0sage and price
As with all prescripti0n drugs, pr0per d0sage is at the discreti0n 0f a licensed medical d0ct0r. The d0se 0f sildenafil is 25 mg t0 100 mg taken 0nce per day between 30 minutes and 4 h0urs pri0r t0 sexual interc0urse.
It is usually rec0mmended t0 start with a d0sage 0f 50 mg and then l0wer 0r raise the d0sage as appr0priate. The drug is s0ld in three d0sages (25, 50, and 100 mg), all three c0sting ab0ut US$10 per pill. Name-brand Viagra sildenafil is n0t sc0red and a fairly hard c0ating makes it m0re difficult t0 accurately cut the pills in half, even with a pill cutter.
Viagra pills are blue and diam0nd-shaped with the w0rds “Pfizer” 0n 0ne side, and “VGR xx” (where xx stands f0r “25″, “50″ 0r “100″, the d0se 0f that pill in milligrams) 0n the 0ther.
C0ntraindicati0ns
C0ntraindicati0ns include:
When taking nitric 0xide d0n0rs, 0rganic nitrites and nitrates, such as glyceryl trinitrate (nitr0glycerin), s0dium nitr0prusside, amyl nitrite (”p0ppers”)[6]
In men f0r wh0m sexual interc0urse is inadvisable due t0 cardi0vascular risk fact0rs
Severe hepatic impairment (decreased liver functi0n)
Severe impairment in renal functi0n
Hyp0tensi0n (l0w bl00d pressure)
Recent str0ke 0r heart attack
Hereditary degenerative retinal dis0rders (including genetic dis0rders 0f retinal ph0sph0diesterases)
Side effects
Am0ngst sildenafil’s rare but seri0us adverse effects are: priapism, severe hyp0tensi0n, my0cardial infarcti0n, ventricular arrhythmias, str0ke and increased intra0cular pressure.
C0mm0n side effects include sneezing, headache, flushing, dyspepsia, pr0l0nged erecti0ns, palpitati0ns and ph0t0ph0bia. Visual changes including blurring 0f visi0n and a curi0us bluish tinge have als0 been rep0rted.
Care sh0uld be exercised by patients wh0 are als0 taking Pr0tease inhibit0rs f0r the treatment 0f HIV. Pr0tease inhibit0rs inhibit the metab0lism 0f sildenafil, effectively multiplying the plasma levels 0f sildenafil, increasing the incidence and severity 0f side-effects. It is rec0mmended that patients using pr0tease inhibit0rs limit their use 0f sildenafil t0 n0 m0re than 0ne 25-mg d0se every 48 h0urs.
S0me sildenafil users have c0mplained 0f blurriness and l0ss 0f peripheral visi0n. In May 0f 2005, the U.S. F00d and Drug Administrati0n f0und that sildenafil c0uld lead t0 visi0n impairment[7] and a number 0f studies have linked sildenafil use with n0narteritic anteri0r ischemic 0ptic neur0pathy.[8][9][10][11][12][13]
When used with an alpha bl0cker, take them at least f0ur h0urs apart t0 av0id hyp0tensi0n.[14]
0ther uses
Pulm0nary hypertensi0n
As well as erectile dysfuncti0n, sildenafil citrate is als0 effective in the rare disease pulm0nary arterial hypertensi0n (PAH). It relaxes the arterial wall, leading t0 decreased pulm0nary arterial resistance and pressure. This in turn reduces the w0rkl0ad 0f the right ventricle 0f the heart and impr0ves sympt0ms 0f right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall sm00th muscle 0f the lungs and penis, sildenafil acts selectively in b0th these areas with0ut inducing vas0dilati0n in 0ther areas 0f the b0dy. Pfizer submitted an additi0nal registrati0n f0r sildenafil t0 the FDA, and sildenafil was appr0ved f0r this indicati0n in June 2005. The preparati0n is named Revati0, t0 av0id c0nfusi0n with Viagra, and the 20 milligram tablets are white and r0und. Sildenafil j0ins b0sentan and pr0stacyclin-based therapies f0r this c0nditi0n.[15]
Raynaud’s phen0men0n
In 2005, Dr. R0land Fries and c0lleagues rep0rted that sildenafil cut the frequency 0f Raynaud’s phen0men0n attacks, reduced their durati0n by r0ughly 0ne half, and m0re than quadrupled the mean capillary bl00d vel0city. This was a d0uble-blind, placeb0-c0ntr0lled cr0ss0ver trial and the patients had b0th the primary and sec0ndary f0rms and had all disc0ntinued the m0re c0nventi0nal treatments f0r this.[16]
N0n-medical use
Aphr0disiac
Sildenafil is c0mm0nly and increasingly used as an aphr0disiac. While there is n0 clinical evidence that it has aphr0disiac activity, many seem t0 believe it will impr0ve sexual perf0rmance as well as erectile functi0n and enhance the sexual experience that will 0ccur.[citati0n needed]
Recreati0nal use
Viagra’s p0pularity with y0ung adults has increased 0ver the years.[17] It is s0metimes used recreati0nally. S0me users mix Viagra with methylenedi0xymethamphetamine (MDMA, ecstasy) in an attempt t0 c0mpensate f0r the side effect c0mm0n t0 many amphetamines 0f erectile dysfuncti0n, a c0mbinati0n kn0wn as “sextasy”, “r0ckin’ and r0llin’”, 0r ‘trail mix’.”
Preventi0n 0f plant wilting
A l0w-c0ncentrati0n s0luti0n 0f sildenafil in water significantly pr0l0ngs the time bef0re cut fl0wers wilt; 0ne experiment sh0wed a d0ubling in time fr0m 0ne week t0 tw0 weeks. The mechanism 0f acti0n is similar t0 that in humans: nitric 0xide leads t0 the pr0ducti0n 0f cGMP wh0se degradati0n by PDE5 is inhibited by sildenafil.[18]
Chemical synthesis
The preparati0n steps f0r synthesis 0f Viagra (sildenafil citrate) are as f0ll0ws:
Methylati0n 0f 3-pr0pylpyraz0le-5-carb0xylic acid ethyl ester with h0t dimethyl sulfate.
Hydr0lysis with aque0us Na0H t0 free acid.
Nitrati0n with 0leum/fuming nitric acid.
Carb0xamide f0rmati0n with refluxing thi0nyl chl0ride/NH40H.
Reducti0n 0f nitr0 gr0up t0 amin0.
Acylati0n with 2-eth0xybenz0yl chl0ride.
Cyclizati0n.
Sulf0nati0n t0 the chl0r0sulf0nyl derivative.
C0ndensati0n with 1-methylpiperazine.[19]
See als0
N0tes
^ B00lell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Nayl0r AM, 0sterl0h IH, Gingell C (1996). “Sildenafil: an 0rally active type 5 cyclic GMP-specific ph0sph0diesterase inhibit0r f0r the treatment 0f penile erectile dysfuncti0n”. Int J Imp0t Res 8 (2): 47–52. PMID 8858389.
^ Terrett NK et al (1996). “Sildenafil (Viagra), a p0tent and selective inhibit0r 0f Type 5 cGMP ph0sph0diesterase with utility f0r the treatment 0f male erectile dysfuncti0n”. Bi00rg Med Chem Lett 6: 1819–1824.
^ Kling J (1998). “Fr0m hypertensi0n t0 angina t0 Viagra”. M0d Drug Disc0v 1: 31–38.
^ Bellis M. Viagra, the patenting 0f an aphr0disiac. Ab0ut.c0m.
^ 0ver-the-c0unter Viagra pil0ted. British Br0adcasting C0rp0rati0n (2007-02-11).
^ Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell R0 Jr, Zusman RM (1999). “ACC/AHA expert c0nsensus d0cument. Use 0f sildenafil (Viagra) in patients with cardi0vascular disease. American C0llege 0f Cardi0l0gy/American Heart Ass0ciati0n”. J0urnal 0f the American C0llege 0f Cardi0l0gy 33 (1): 273-82. PMID 9935041.
^ Alert f0r Healthcare Pr0fessi0nals: Sildenafil citrate (marketed as Viagra). United States F00d and Drug Administrati0n (July 2005).
^ P0meranz HD and Bhavsar AR (2005). “N0narteritic ischemic 0ptic neur0pathy devel0ping s00n after use 0f sildenafil (viagra): a rep0rt 0f seven new cases”. J Neur00phthalm0l 25 (1): 9-13.
^ Egan R and P0meranz H (2000). “Sildenafil (Viagra) ass0ciated anteri0r ischemic 0ptic neur0pathy”. Arch 0phthalm0l 118 (2): 291-2.
^ P0meranz HD, Smith KH, Hart WM, Egan RA (2002). “Sildenafil-ass0ciated n0narteritic anteri0r ischemic 0ptic neur0pathy”. 0phthalm0l0gy 109 (3): 584-7.
^ Cunningham AV and Smith KH (2001). “Anteri0r ischemic 0ptic neur0pathy ass0ciated with viagra”. J Neur00phthalm0l 21 (1): 22-5.
^ B0shier A, Pambakian N, Shakir SA (2002). “A case 0f n0narteritic ischemic 0ptic neur0pathy (NAI0N) in a male patient taking sildenafil”. Int J Clin Pharmac0l Ther 40 (9): 422-3.
^ Akash R, Hrishikesh D, Amith P, Sabah S (2005). “Case rep0rt: ass0ciati0n 0f c0mbined n0narteritic anteri0r ischemic 0ptic neur0pathy (NAI0N) and 0bstructi0n 0f cili0retinal artery with 0verd0se 0f Viagra”. J 0cul Pharmac0l Ther 24 (4): 315-7.
^ Kl0ner RA (2005). “Pharmac0l0gy and drug interacti0n effects 0f the ph0sph0diesterase 5 inhibit0rs: f0cus 0n alpha-bl0cker interacti0ns”. Am J Cardi0l 96 (12B): 42M-46M.
^ Pfizer, Inc. (June 6, 2005). FDA Appr0ves Pfizer’s Revati0 as Treatment f0r Pulm0nary Arterial Hypertensi0n. 2005 News Releases. Pfizer. Retrieved 0n December 27, 2005.
^ Fries, R0land; Kaveh Shariat, Hubertus v0n Wilm0wsky, and Michael Böhm (N0vember 8, 2005). “Sildenafil in the treatment 0f Raynaud’s phen0men0n resistant t0 vas0dilat0ry therapy”. Circulati0n 112 (19): 2980-5. PMID 16275885.
^ Peters0n K. “Y0ung men add Viagra t0 their drug arsenal”, USAT0day, 2001-03-21.
^ Siegel-Itzk0vich J (1999). “Viagra makes fl0wers stand up straight”. Student BMJ (9).
^ Dunn PJ. “Synthesis 0f C0mmercial Ph0sph0diesterase(V) Inhibit0rs”. 0rg Pr0cess Res Dev 2005 (1): 88-97. D0I:S1083-6160(04)00019-2 10.1021/0p040019c S1083-6160(04)00019-2.
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