Sildenafil

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of Sildenafil
General
Non-proprietary name Sildenafil
other names

1 - {[3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl} - 4-methylpiperazine ( IUPAC )

Molecular formula C 22 H 30 N 6 O 4 S
External identifiers / databases
CAS number
  • 139755-83-2 (sildenafil)
  • 171599-83-0 (sildenafil citrate )
EC number 604-158-7
ECHA InfoCard 100.122.676
PubChem 5212
ChemSpider 5023
DrugBank DB00203
Wikidata Q191521
Drug information
ATC code

G04 BE03 and C02 KX06

Drug class

PDE-5 inhibitors

Mechanism of action

Enzyme inhibition of phosphodiesterase 5

properties
Molar mass 474.58 g · mol -1
Melting point
  • 187-189 ° C
  • 191–202 ° C (as citrate)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302-412
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sildenafil is a drug from the group of PDE-5 inhibitors , a group of vasodilating ( vasodilating ) substances. It became well known as the active ingredient in the drug for the treatment of erectile dysfunction in men, launched in 1998 by the US company Pfizer under the name Viagra . This effect was discovered accidentally during the development of sildenafil as an agent for treating high blood pressure and angina pectoris . In the meantime, a total of more than 100 preparations with the active ingredient sildenafil for the treatment of erectile dysfunction are on the market in Germany from various suppliers.

In addition to being used as a sexual enhancer , Sildenafil has also been approved since 2006 for the treatment of idiopathic pulmonary arterial hypertension and pulmonary hypertension in connection with a connective tissue disease.

Sildenafil was the first drug of the drug class of PDE-5 inhibitors . Colloquially, the name Viagra is sometimes used as a collective term for other drugs in this group of active ingredients, for example Tadalafil ( Cialis ), Vardenafil ( Levitra ) or Avanafil ( Spedra ).

In Germany , Austria and Switzerland , drugs containing sildenafil require a prescription .

history

In the early 1990s, a research team at a Pfizer research institute in Sandwich , England , was looking for a remedy for heart problems. The agent UK-92480 found blocked the enzyme PDE-5. While initial trials on patients had been promising, some men reported multiple erections a few days after taking the drug. The responsible experimenter saw no potential in this effect; Pfizer therefore applied for a patent for the active ingredient as Sildenafil Citrate in 1991 .

After the drug ultimately proved ineffective for heart problems, the sexual effects of the active ingredient were examined more closely. In a study of 300 men in England, France and Sweden, 90 percent reported erections; Side effects were hardly observed. In 1998, Pfizer received approval from the US Department of Health to sell Viagra. This Time magazine reported in a cover story about the potency pill .

In 2003 two other drugs with the same mechanism of action were brought onto the market: Levitra (Bayer) and Cialis (Eli Lilly). A new active ingredient followed in 2012 called Avanafil (Mitsubishi Pharma), which is said to work faster than Viagra; the trade name is Stendra . Spedra ( Berlin-Chemie with the active ingredient Avanafil) has been available in Germany since April 2014 .

In 2007 Pfizer held 47 percent of the world market for substances for erectile dysfunction; in 2013 it was 36 percent. In 2012, Pfizer had sales of $ 2 billion with Viagra.

Mechanism of action

Part of the physical process of erection involves the release of nitric oxide (NO) in the corpus cavernosum . This activates the enzyme guanylate cyclase , which increases the release of cyclic guanosine monophosphate (cGMP). This triggers a slight muscle relaxation in the corpus cavernosum, which enables blood to flow in and thus an erection.

Sildenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE-5), which thus reduces the rate of degradation of cGMP. As a result, when using Sildenafil, normal sexual stimulation will lead to increased blood levels of cGMP in the corpus cavernosum and thus to an increased erection. Without sexual stimulation and activation of the NO / cGMP system, Sildenafil does not induce an erection.

The same mechanism of action also applies to the substances tadalafil, vardenafil and avanafil. Thus, selective PDE-5 inhibitors can be used for the therapy of erectile dysfunction.

Sildenafil is broken down by liver enzymes and excreted by both the liver and kidneys. When ingested with high-fat food, delayed breakdown and reduced effects are to be expected.

application areas

Erectile dysfunction (ED)

When used as a preparation of the ATC G04BE03, sildenafil is effective in doses of 25 mg, 50 mg or 100 mg orally . In a dose escalation study, doses of up to 100 mg of sildenafil produced an erection that was sustained for the duration of sexual intercourse in 69% of male patients , compared with 22% in the placebo group.

The extent and duration of an erection depend on the blood flow and drainage in the erectile tissue of the penis . The blood supply is controlled by circular muscles in the arterial wall of the corpus cavernosum . In the non-erect state, these are tense and close the vessels. However, if the man is sexually aroused, this leads to the formation of cGMP (cyclic guanosine monophosphate) in the affected muscle cells . The muscles relax and the cross-section of the vessels enlarges, causing arterial blood to flow into the erectile tissue and trigger an erection. The molecular counterpart of the cGMP is the enzyme phosphodiesterase-5 (PDE-5), which cleaves the cGMP. Sildenafil works by blocking PDE-5 and ensuring that even small amounts of cGMP lead to an erection. In contrast to sexual enhancers such as alprostadil , which are injected intracavernously (into the erectile tissue of the penis ) or inserted into the urethra, sildenafil only works when the patient is sexually aroused .

Research has shown that arginine can increase the effects. In addition, a kind of dose-saving effect was found with Sildenafil. Arginine also releases nitric oxide , which causes the blood vessels to expand (dilate).

Idiopathic pulmonary arterial hypertension

For this indication, sildenafil preparations now use a side effect to be taken into account in the treatment of erectile dysfunction as an effect. They are then assigned to the anatomical-therapeutic-chemical classification (ATC) C02KX06. In 2006, the first preparation with sildenafil for the treatment of idiopathic pulmonary arterial hypertension (PAH) in patients with NYHA stage II and III came on the market. Critics complained that the approved dosage of 3 × 20 mg was not sufficient for optimal therapy and that the most important studies were carried out with up to 3 × 80 mg sildenafil. However, this dosage is not approved for therapy in Germany. In the meantime, more than thirty preparations of sildenafil from various suppliers for the PAH indication have been approved for oral intake and intravenous injection in Germany.

Off-label and potential areas of application

In addition to the areas mentioned above, an effect and use of Sildenafil for various special clinical pictures is described:

In neonatology, sildenafil has recently been used outside of drug approval ( off-label use ) in extremely premature infants with bronchopulmonary dysplasia (BPD) to reduce pulmonary arterial vascular resistance.

Initial studies have shown that sildenafil can correct the effects of the CFTR protein, which is impaired in the disease cystic fibrosis due to a genetic defect . The use of sildenafil to treat stroke is also discussed .

Doxorubicin is used in the therapy of prostate cancer and has a high cardiotoxicity side effect and in the worst case it can also cause heart failure. Some smaller studies suggest that combining the two drugs increases the chemotherapeutic effectiveness of doxorubicin and reduces its harmful effects on the heart.

Another area of ​​application for sildenafil is in the treatment of Raynaud's syndrome . In this common disease, the blood vessels in the fingers and toes narrow, reducing blood flow to these areas. There is evidence that taking sildenafil will expand the blood vessels in the affected areas again.

A study on pregnant women with an underactive placenta was canceled in 2018. An underactive condition significantly inhibits the growth of an unborn child. Sildenafil should increase the blood flow to the placenta and accelerate the development of the fetus. However, almost 20 percent of women gave birth to children with lung problems, the majority of which died.

In 2004, after several years of research, the pharmaceutical company Pfizer decided to stop developing sildenafil for the treatment of sexual dysfunction in women. Tests on around 3000 women with sexual dysfunction would not have shown sufficient effectiveness. After the great success of Sildenafil in use with men, a similarly profitable market should actually be built for women. However, the company was criticized (especially by the British Medical Journal ) for deliberately creating a clinical picture under the name “female sexual dysfunction” (FSD).

Non-medical use

Due to the popularity of Sildenafil, which is associated with the brand name “Viagra”, a black market has been established since the 1990s for Sildenafil and sildenafil-containing products that operate far beyond their approval.

The drug is said to have a number of effects that are not scientifically justified, such as an increase in libido, an increased erection quality or an increase in penis length. However, studies have shown that the active ingredient hardly shows any effects in healthy people that go beyond the physiological one, with the exception that the recovery time after ejaculation is shortened.

Like other PDE-5 inhibitors, sildenafil serves as an extender for MDMA , which is traded as a recreational drug , in order to counteract the side effects of erectile dysfunction. The addition to amyl nitrite can lead to dangerous additive effects which can lead to death.

A research group was able to show that dissolved in water, sildenafil is able to significantly extend the lifespan of cut flowers.

Restrictions on use and side effects

Contraindications

Simultaneous use of sildenafil with medication containing nitrates (e.g. the nitrolingual spray , which is widely used in older people ) or nitric oxide donors ( amyl nitrite , scene drugs " poppers ") is contraindicated. The combined effect on blood pressure threatens an acute, life-threatening drop in blood pressure.

Apart from this contraindication, use in patients with coronary artery disease poses a risk if successful sexual intercourse is too stressful for the circulation.

Interactions

The metabolism of sildenafil is mediated by the cytochrome P450 (CYP) isoenzymes 3A4 and 2C9. There may be interactions with drugs that are also metabolized with the participation of these enzymes (e.g. ketoconazole , itraconazole , erythromycin , cimetidine , saquinavir ). Furthermore, the strong cytochrome P450 3A4 inhibitor ritonavir can lead to dangerously high sildenafil plasma levels, since the breakdown of sildenafil is inhibited.

Side effects

Side effects occurring after ingestion: headache (10.8%), facial flushing (10.9%), stomach discomfort (3%), rhinitis (4%), abnormal visual perception (2.8%; e.g. blue haze in the Visual field, increased sensitivity to light), reduced ability to react, dizziness, back pain and muscle pain, permanent erection ( priapism ). Cases of non-arteritic anterior ischemic optic neuropathy have been observed. In rare cases, this leads to loss of vision or blindness. The current findings on these side effects led to a corresponding change in the product information for sildenafil in the summer of 2006 . Recently there have also been indications of sudden hearing impairment in connection with the use of sildenafil.

In the past, sildenafil has occasionally been made public through large-scale press releases reporting deaths. However, these occurred in all understandable cases due to non-observance of the contraindications.

Meaning of the trade name Viagra

A box of Pfizer Viagra
An email inbox full of spam

The name Viagra is a legally protected made-up word. It is said to be composed of the terms vigor (Latin for "strength") and Niagara . Incidentally, “Viagra” is homophonic to vyā́ghra व्याघ्र , the Sanskrit word for tiger .

The product has become well known because it is advertised millions of times on the Internet using spam emails. Internet mail order companies, mostly from the USA, send the corresponding tablets all over the world even without the necessary prescription. Aside from the side effects of the active ingredient, you run the risk of receiving counterfeit or contaminated products.

Impact on society

With the launch of Sildenafil, erectile dysfunction was treatable for the first time in many patients without great discomfort. This had far-reaching consequences for the sex life of these patients. On the one hand, many patients who were no longer able to achieve an erection due to diseases such as diabetes, coronary heart disease, etc., were given the opportunity to have a fulfilling love life again.

On the other hand, partners who were "used" to the low-sex state soon complained that their partner had suddenly become more strenuous for them than they would like. It turned out that an intensive consultation not only with the doctor but also with the partner makes sense for the use of Viagra.

Legal position

By mid-2013, around 37 million men had been prescribed 1.8 billion tablets worldwide. Pfizer turned over US $ 24.8 billion.

The manufacture of Sildenafil was patented in Germany until June 22, 2013 ; it could therefore only be brought onto the market by or under license from Pfizer. By the end of May 2013, 28 companies had applied for the production of drugs containing sildenafil. In Austria there were 16 providers. The patent also expired in June 2013 in other western European countries such as Great Britain. In the meantime, several generic sildenafil preparations have been approved throughout the EU and nationally (e.g. in Austria and Germany) that came onto the market after the patent expired. In addition to tablets, chewable tablets and orodispersible tablets are also represented as dosage forms . Pfizer was already offering its own generic on June 1, 2013. Starting in June 2013, monthly sales climbed from 750,000 packs to more than 1.7 million units in June 2014 - an increase of 130 percent. With their generics, Hexal and Ratiopharm have clearly overtaken the original Viagra in terms of sales and - what is more important - also in terms of sales. Together with its own generic, however, Pfizer is still defending first place.

The patent for Sildenafil Citrate expired on June 21, 2013 in Austria, Denmark, France, Germany, Ireland, Italy, the Netherlands, Spain, Sweden, Great Britain and Switzerland. A patent from Pfizer on PDE5 inhibitors was declared invalid in 2000 due to the obvious height of creation and the judgment was confirmed in 2002.

In the US, Sildenafil is available as a generic, at about one-fiftieth the price of the branded product. The branded product cost between $ 25.17 and $ 37.88 in the US in 2015. In the USA, Pfizer held two patents for sildenafil, for the treatment of pulmonary arterial hypertension ( Revatio , lower dose , patent protection 1993–2012) and erectile dysfunction ( Viagra , patent protection 2002–2019). Generic Sildenafil for the treatment of pulmonary arterial hypertension is offered in smaller doses than Viagra in the United States by various manufacturers. Generic Sildenafil may be prescribed off-label for the treatment of erectile dysfunction in the United States . Teva sued Pfizer's patent protection for erectile dysfunction in 2011 and lost. Based on an agreement with Pfizer, Teva will offer Sildenafil from 2017.

In Canada , the patent for use in pulmonary arterial hypertension was declared invalid in 2010 after a lawsuit by Ratiopharm . In 2012, the Supreme Court of Canada ( Teva Canada Ltd. v. Pfizer Canada Inc. ) ruled that the patent for Viagra was invalid from the start due to insufficient information being published at the time of filing, which is required under Section 27 (3) b of the Patent Act have to enable every skilled person to manufacture it. On the day the decision was published, Teva launched generic Sildenafil Citrate on the Canadian market. Pfizer then lowered the price of Viagra in Canada. A revision was refused

There is no patent protection for Sildenafil Citrate in India. It is sold under the trade names Kamagra ( Ajanta Pharma ), Silagra ( Cipla ), Edegra ( Sun Pharmaceutical ), Penegra ( Zydus Cadila ), and Zenegra ( Alkem Laboratories ). In China, the patent protection for Sildenafil is not implemented. In Brazil, the patent protection for sildenafil citrate expired in 2010. Generic Sildenafil Citrate is legally sold in Egypt.

The costs for the active ingredient make up only a small part of the selling price: In 2004 the raw material for Viagra, sildenafil citrate, cost 650 euros per kilogram. From this, 20,000 tablets with a sales value of the branded product of 240,000 euros can be produced, which means a cost share of 0.26 percent for the active ingredient or 0.0325 euros per tablet.

Eligibility for reimbursement

The assumption of costs for the drug in Germany has been controversial since its introduction in the late 1990s; a list of court decisions from social justice (GKV), civil justice (PKV) and administrative jurisdiction (civil service aid regulations of the federal government and the respective states) can be found in the judgment of the Frankfurt am Main Administrative Court of August 12, 2003 (business number 10 E 5407 / 01), as well as the decision of the Administrative Court of Gießen (business number 8 L 326 / 13.GI). The respective courts in all three jurisdictions have generally considered the approval to be justified if there is a medical indication .

Since January 1, 2004, the Statutory Health Insurance Modernization Act of November 14, 2003 ( Federal Law Gazette I, p. 2190 ) in Section 34 Paragraph 1 Clause 7 and 8 SGB V has excluded medicinal products that are used to improve the quality of life . These include u. a. Medicines that are primarily used to treat erectile dysfunction or inducement and increase sexual potency, such as Viagra. According to the text of the law, the cause of the malfunction does not matter. Neither the law nor the drug guidelines (Annex 8) provide for an exception.

Even after the change in the law and the inclusion of aid recipients under SGB ​​II and SGB ​​XII in the statutory health insurance and the jurisdiction of the social courts established by this, the case law did not change. The costs for the treatment of pulmonary arterial hypertension with Revatio are borne by the statutory health insurance companies. The argument often put forward by insurance companies that potency problems in older men are "normal age-related malfunctions" was rejected in September 2004 in proceedings against a private health insurance company before the Dortmund Regional Court (Az .: 2 S 25/04). The Karlsruhe Higher Regional Court also decided - 12 U 32/03 - July 3, 2003; Munich Higher Regional Court - 25 U 4628/99 - August 8, 2000 (NJW 2000, 3442). The LG Cologne (23.O.57 / 02) decided otherwise on August 20, 2003, when it declared erectile dysfunction not to be a disease and Viagra not to be a symptomatic drug.

The Federal Administrative Court ruled on May 28, 2008 that Sildenafil is not eligible for reimbursement under the state aid rules applicable from 2004 (file numbers 2 C July 24 and 2 C 108.07). The Higher Administrative Court of Rhineland-Palatinate ruled on May 17, 2002 ( Az. 2 A 11755 / 01.OVG) decided that sildenafil is a drug, the costs of which may not be excluded from the granting of subsidies , provided a corresponding medical indication (here: erectile dysfunction after prostate cancer surgery ). A ruling by the Düsseldorf Administrative Court on September 2, 2005 (26 K 371/05), which treats tadalafil as a drug that is reimbursable through the aid, was on a similar line . The case law has been criticized many times.

With the judgment of August 12, 2003, the Frankfurt am Main Administrative Court (business number 10 E 5407/01) decided that sickness assistance is to be granted under the Federal Social Welfare Act (Section 37 BSHG) if they cannot help themselves. The social welfare authority was not allowed to refuse the provision of a drug as health aid with reference to the drug guidelines of the statutory health insurance, according to which any treatment of an [erectile dysfunction] with drugs is denied indiscriminately. The guidelines are not relevant when it comes to treating a disease. That is why “cash patients” like welfare recipients are entitled to treatment with Viagra in the event of illness.

The Hessian Administrative Court ruled on October 11, 2004 (reference number: 10 UE 2731/03) that the statutory health insurance modernization law of November 14, 2003 ( Federal Law Gazette I p. 2190 ) from January 1, 2004 in § 34 para. 1 sentence 8 SGB V introduced the exclusion of drugs for the treatment of erectile dysfunction from care within the framework of the statutory health insurance due to the strict accessoryity introduced at the same time in the context of health care under the Federal Social Welfare Act . According to this new version, from January 1, 2004, a beneficiary's claim to assumption of the cost of the drug Viagra in the context of the type of help mentioned is no longer possible.

With a ruling of September 1, 2005, the Hessian State Social Court (business number L 8 KR 80/05 ER) decided that the drug "Caverject" (or "Viagra") is no longer provided as a benefit in statutory health insurance, because of articles 1 No. 22 of the Law for the Modernization of Statutory Health Insurance (GMG) of November 14, 2003 ( Federal Law Gazette I, p. 2190 ), with effect from January 1, 2004, all drugs used to treat erectile dysfunction are covered by the ordinance Excluded from the burden of statutory health insurance.

Commercial preparations

  • Erectile dysfunction: Viagra (EU, CH), Kamagra ( IN ), Silagra ( IN ), Vigoran ( EG ) and other generic drugs
  • Pulmonary hypertension: Revatio (EU, CH)

Web links

Wiktionary: Viagra  - explanations of meanings, word origins, synonyms, translations

literature

Individual evidence

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  3. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of 5- {2-ethoxy-5 - [(4-methylpiperazin-1-yl) sulfonyl] phenyl} -1-methyl-3-propyl-1H, 6H, 7H-pyrazolo is shown, which is derived from a self-classification by the distributor [4,3-d] pyrimidin-7-one in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 10, 2019.
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