Sildenafil Citrate: Viagra

By: John F. Payne

What is Sildenafil CitrateWhat is Sildenafil Citrate

Discovery

Mechanism of Action

Pharmacokinetics

Analogs and Other Options

The History of Viagra

• Pfizer originally sought for a PDE inhibitor that might act as a new antihypertensive and antianginal drug.

• Studies were done to see what side effects would come from increased dosages. Volunteers reported back with side effects like head aches, visual problems, and prolongment of penile erections.

• According to the British Press, but not Pfizer, Peter Dunn and Albert Wood invented sildenafil.

The History of Viagra

• Pfizer’s medicinal research team is actually credited with the invention of Viagra.

• Nicholas Terret, one of Pfizer’s chief medicinal chemists, is considered to be the father of Viagra.

The Synthesis of Sildenafil

1. Methylation of 3-propylpyrazole-5-carboylic acid ethyl ester with hot dimethy sulfate.

2. Hydrolysis with NaOH3. Nitration with fuming Nitric Acid4. Carboxamide formation with refluxing thionyl chloride/

NH4OH5. Reduction of Nitro group to Amino6. Acylation with 2-ethoxybenzoyle chloride7. Cyclization8. Sulfonation to the chlorosulfonyl derivative9. Condesation with 1-methylpiperazine

How does an erection How does an erection work?work?

• An erection can be caused by local stimulation or centrally by erotic thought.

Mechanics of an ErectionMechanics of an Erection

• Upon sexual stimulation, the terminals of parasympathetic nerves release nitric oxide.

• The nitric oxide diffuses into the smooth muscle cells and bind with the enzyme guanylate cyclase.

• Guanylate cyclase converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).

Mechanics of an ErectionMechanics of an Erection• cGMP binds to Protein Kinase G (PKG) which causes the

smooth muscle cells to relax, allowing for an inflow of blood. PKG works by many mechanisms, including lowering the cellular Ca+2 levels.

• The inflow of blood causes the sinusoids of the corpus cavernosum to enlarge, which compresses the penile veins.

• Therefore, there becomes a collection of blood inside the penis smooth muscle tissue.

How does Viagra Work??

• Phosphodiesterase 5 (PDE 5) is the enzyme that catalyzes the hydrolysis of cGMP back into GTP.

• Viagra acts competitively with cGMP at the active site of PDE 5.

• So, if Viagra inhibits PDE 5, then there will be an accumulation of cGMP in smooth muscle cells until the Viagra is metabolized (mainly by cytochromes in hepatic metabolism).

Viagra shows good competitive kinetics with cGMP because of the

structural similarities.

Pharmaco• Viagra is rapidly absorbed after oral

administration - Total Bioavailability: 40%

• Its pharmacokinetics are dose proportional over the recommended range

• Viagra is metabolized mainly by hepatic metabolism and excreted mainly in the feces.

SelectivitySelectivity• Sildenafil is very selective for PDE 5, which a great

advantage because there are over 10 classes of PDE’s.

The exact IC50 values are not given for PDE 2, PDE 4, and PDE 6. But, the ratios for PDE 5 versus these isozymes are given above.

Isozyme Ratio IC50 Ratio (nM)PDE 5: PDE 2 1,000PDE 5: PDE 4 1,000PDE 5: PDE 6 10

Isozyme IC50 (nM)PDE 1 260PDE 3 65,000PDE 5 3.0

How did Scientists Tests How did Scientists Tests SubjectsSubjects

• Scientists assessed erections using an instrument called Rigiscan, which measures hardness and duration of erections.

• Also, each subject was given a survey, which measured the ability to achieve erections for sufficient sexual intercourse, and the ability to maintain erections after penetration.

• Also, some subjects were asked to create a diary to write down any feelings or side effects they might have had.

Clinical ResultsClinical Results

• Erectile dysfunction was attributed to organic (58%), psychogenic (17%), or mixed etiologies (24%).

• After 6 months of Viagra treatment, the percentages of men reporting improvement in their erections are below:Organic = 63%Psychogenic = 74%Mixed = 82%

Is this a wonder drug, or Is this a wonder drug, or are there side effects?are there side effects?

• One side effect of Viagra comes from the relatively high selectivity for PDE 6. At peak plasma levels of Viagra, some subjects cannot distinguish between green and blue.

• In placebo controlled studies, only 2.5% of users discontinued the use of Viagra because of negative side effects.

Side EffectsSide Effects

• Some side effects of Viagra:

Headache

Flushing

Dyspepsia

Nasal Congestion

Diarrhea

Urinary Tract Infections

A Major ConcernA Major Concern• Because Viagra is a vasodilator (although mainly locally), it

needs to be used cautiously because it lowers blood pressure.• Viagra should not be given to patients who are taking nitrates,

because nitrates are also a strong vasodilator. The use of both could cause major heart problems.

• Also, the use of CYP3A4 or P450 inhibitors (which are the cytochromes responsible for Viagra metabolism), greatly increases the risk of negative side effects.

Some CYP3A4 inhibitors include Erythromycin, Cimetidine.One major P450 inhibitor is Ritonavir

New Analogs and New Analogs and AlternativesAlternatives

• If you thought that Viagra worked, wait until you have seen Tadalafil, which is a new experimental drug being used in Europe.

• The effects on erectile dysfunction last for 24 hours and the onset of effects take approximately 16 minutes.

TadalafilTadalafil

• Erectile dysfunction is a common complication related to diabetes (affecting 27 to 75% of men with the disease), and diabetes ED is harder to treat than regular ED for many factors.

• However, 76% of men with diabetes ED reported an improvement in erection achievement and maintenance.

• 81% of men with regular ED reported an improvement in their erections.

TadalafilTadalafil

• Another major benefit of Tadalafil is that it is not significantly affected by the impact of age, renal impairment, diabetes, or liver function.

• “These findings suggest that dosing for Tadalafil should be simple and uncomplicated, which is important from a health care professional standpoint.”

Selectivity of TadalafilSelectivity of Tadalafil

• The IC50 ratios for:

PDE 5 vs. PDE 1 through PDE 4 = 10,000

PDE 5 vs. PDE 7 through PDE 10 = 10,000

PDE 5 vs. PDE 6 = 780

So, there are no serious cardiovascular adverse effects nor color vision disturbances.

VardenafilVardenafil

• Vardenafil is an experimental drug that is designed to help ED in men who have undergone prostate surgery.

• In one of the first clinical studies, Vardenafil helped over 50% of men with ED after prostate surgery.

• Tadalafil and Vardenafil are considered to be the second generation of drugs used for ED.

Does Viagra Really Work??