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Sildenafil Citrate: Viagra
By: John F. Payne
What 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
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Methylation of 3-propylpyrazole-5-carboylic acid ethyl
ester with hot dimethy sulfate.
Hydrolysis with NaOH
Nitration with fuming Nitric Acid
Carboxamide formation with refluxing thionyl chloride/
NH4OH
Reduction of Nitro group to Amino
Acylation with 2-ethoxybenzoyle chloride
Cyclization
Sulfonation to the chlorosulfonyl derivative
Condesation with 1-methylpiperazine
How does an erection work?
• An erection can be
caused by local
stimulation or
centrally by erotic
thought.
Mechanics 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 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.
Pharmacokinetics
• 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.
Selectivity
• Sildenafil is very selective for PDE 5, which a great
advantage because there are over 10 classes of
PDE’s.
Isozyme
IC50 (nM)
PDE 1
PDE 3
PDE 5
260
65,000
3.0
Isozyme Ratio IC50 Ratio (nM)
PDE 5: PDE 2
PDE 5: PDE 4
PDE 5: PDE 6
1,000
1,000
10
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.
How did Scientists Tests Subjects
• 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 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 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 Effects
• Some side effects of Viagra:
Headache
Flushing
Dyspepsia
Nasal Congestion
Diarrhea
Urinary Tract Infections
A 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 Alternatives
• 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.
Tadalafil
• 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.
Tadalafil
• 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 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.
Vardenafil
• 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??