Download Drugs to treat… SEXUAL DYSFUNCTION

Drugs to treat…
SEXUAL DYSFUNCTION
Medicinal Chemistry
Dr. Buynak
“Keep that Spark Alive”
• Sexual Dysfunction is
estimated to effect 3040% of men and women.
• Its prevalence increases
with age.
• Drug treatment of male
sexual dysfunction has
been given significantly
more attention than that
of women.
Sexual Dysfunction in MEN
• Sexual problems in men include: an
inability to acquire or maintain an
erection satisfactory for sexual
intercourse (impotence or erectile
dysfunction (ED)); a lack of interest in
sex (diminished libido); premature
ejaculation; and delayed or inhibited
ejaculation.
• Erectile dysfunction is the most
common physiological sexual
disorder for men. It was estimated
that in 2005, three-hundred and
twenty two million men world wide
would be affected by erectile
dysfunction.
Physiological mechanisms of
normal penile erections
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http://www.healthcentral.com/animation/408/17/Erectile_D
ysfunction.html
• Stimulation of penile shaft by the nervous
system leads to the secretion of nitric
oxide (NO), causing the creation of cyclic
guanosine monophosphate (cGMP) which
functions to relax blood vessels
(vasodilatation) so erectile tissues in the
corpus cavernosa can fill with blood, and
subsequently cause a penile erection.
Phosphodiesterase type 5 (PDE5) is always
present in the penis and functions to
destroy cyclic GMP, causing
vasoconstriction of erectile tissues and
resulting in the loss of erection. In normal
males, the loss of an erection occurs after
orgasm and ejaculation of sperm.
• Figure 1.1 illustrates how the binding of
Phosphodiesterase 5 inhibits the functioning of
cGMP. PDE5’s active site fits exactly (a lock and
key mechanism) with molecules of cGMP to
make them break down.
ERECTILE DYSFUNCTION
Erectile Dysfunction
• The inability to achieve or maintain an erection
sufficient for satisfactory sexual performance
• Prevalence increases with age, cardiovascular
disease, diabetes mellitus, and hyperlipidemia.
• Diabetes is the most common cause of sexual
dysfunction in men. It has been estimated that
up to 50-60 % of diabetic men have erectile
dysfunction. [1]
• The primary risk factors are smoking, lack of
physical exercise and obesity.
• Erectile dysfunction is strongly correlated with
depressive symptoms and negatively impacts
a man’s quality of life.
• The pharmaceutical industry for treatment of
erectile dysfunction is worth nearly 6 billion
dollars!
Factors that cause the onset of
Erectile Dysfunction
• Psychological causes include, but are not
limited to: fatigue, stress, performance
anxiety, poor self image or lack of
communication with sexual partner/s.
• Major Depressive Disorder (MDD) also has
a strong correlation with sexual
dysfunction in men and women.
• Physical causes include: Urological,
Vascular, neural, Endocrine (hypogonadism
or Hyperprolactinaemia), Iatrogenic, Pelvic
trauma or dietary.
History of Treatment for
Erectile Dysfunction
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1930s: Dr. John R. Brinkley experimented with goat
glands to treat impotence
1948: Masters and Johnson published the book Sexual
Behavior in the Human Male and five years later when
they published Sexual Behavior in the Human Female.
Up until the 1970's it was generally believed that the
majority of male impotence was psychological in nature
and that the mind must be treated and the sexual
situation counseled in order to treat and effectively cure
the problem. But Penile vacuums were also used to erect
the penis by drawing blood into the penile tissue.
1973: American Medical Devices developed inflatable
prosthetic devices
1980: intracorporal injections developed such as
alprostadil
Early 90s an herbal supplement, Yohimbine created but
advised against
1999: Pfzier introduced VIAGRA (sildenafil)
2000: TAP Pharmaceutical Products, developed the first
oral centrally acting drug: Apomorphine HCL, marketed
under the brand name Uprima
1999-2003: vardenafil and tadalafil created
PDE5 Inhibitors: sildenafil,
tadalafil, vardenafil
• Men who have erectile dysfunction often
produce insufficient amounts of NO. So
although they are producing a small
amount of cGMP, it is being broken down at
the same rate, so they cannot maintain an
erection. Viagra, Tadalafil, and Vardenafil
work by selectively inhibiting PDE5, by
binding with PDE5's active site. This
prevents the hydrolysis of cGMP to
inactive GMP, allowing cGMP to
accumulate and prolong the vasodilation
effect, resulting in a stronger and longer
erection.
• All 3 drugs work regardless of the cause of
ED, but all require sexual stimulation for
activation.
Contraindications
• Since PDE5 inhibitors such as
sildenafil, tadalafil, and Vardenafil may
cause transiently low blood pressure
(hypotension), organic nitrates should
not be taken for at least 48 hours after
taking the last dose of tadalafil. Using
organic nitrates within this timeframe
may increase the risk of life-threatening
hypotension.
The figure below shows the
mechanism of action of Viagra, and
the other PDE5 inhibitors, on the nitric
oxide cycle.
A role in fighting infection
• In addition to its role as a vasodilator
and neurotransmitter, NO is produced
by macrophages. These phagocytic
cells of the immune system use NO to
impair DNA synthesis and metabolism
in microorganisms.
And in Septic Shock
• Massive bacterial infections are known
to cause septic shock, the hallmark
characteristic of which is a dramatic
lowering of blood pressure. This is due
to the release of massive amounts of
NO directed against the bacteria; the
unfortunate side effect is the extreme
vasodilation that occurs in response to
NO.
The discovery of Viagra
• Pfizer accidentally fell upon Viagra as a treatment
of erectile dysfunction. They were initially
searching for a vasodilator to treat angina pectoris.
• Their goal was to find a molecule that would bind to
PDE's active site, so that it wouldn’t be able to
convert cGMP to the inactive GMP form. They
studied the structure of the substrate cGMP .
• Compare cGMP and Viagra
•
Similarities…
• The sulfur dioxide (SO2) group of sildenafil
mimics the phosphate in cGMP.
• Both have similar 4-piperidone rings (sixmembered ring with N at one end and C=O
at the other.
• Although similar, they are obviously not a
perfect match. But, an inhibitor doesn't
have to bind in exactly the same way as
substrate. It just has to bind tightly enough
so that it inhibits the substrate (PDE5)
from getting into the active site.
sildenafil (VIAGRA)
• Viagra is the most popular of the PDE5
inhibitors. It is estimated that it has
worked for 20 million men worldwide. It
is administered in 25, 50 and 100mg
doses.
• Taken 1 hour before sexual intercourse
• Maximum dose is once daily
• Window of opportunity: 30 minutes to 4-5
hrs.
• But can be effective for up to 12 hrs.
• side effects, such as: headache, facial
flushing, dyspepsia, dizziness, rhinitis
and abnormal vision.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Tadalafil (Cialis)
• administered orally in 10mg and 20mg
doses
• Instructed to take Tadalafil two hours
before sexual intercourse
• Its efficacy is maintained for at least 36
hours
• The maximum dosing frequency is once
every other day
• Improved erections were reported by
82.8% of treated men. Thirty-six hours
after administration of Tadalafil, 59.2% of
intercourse attempts were successful.
• Side effects: headache, flushing, rhinitis
and back pain/myalagia.
• Safety concern: it also serves as an
inhibitor of PDE11, an enzyme in the
testes, so there is concern on the effect
that it has one sperm and
spermatogenesis
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vardenafil (Levitra)
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higher in vitro potency, more rapid binding to
PDE5, and slower dissociation from this
enzyme than Sildenafil and Tadalafil.
Administered orally on demand in 5, 10 and
20mg doses
Maximum dose administration frequency is
once daily.
There is a window of opportunity from 30
minutes to 4-5 hours after administration.
But, the earliest time to onset of action
leading to successful intercourse can be just
10 minutes!
75% of intercourse attempts were successful
for patients using vardenafil compare with
the 40% success in the placebo group
Treatment with vardenafil in patients with
erectile dysfunction that were previously
unresponsive to sildenafil produced
significant improvements in erectile function
domain score and maintenance of an
erection.
Side effects: headache, flushing and rhinitis
Comparison of sildenafil, vardenafil, tadalafil
• they all are all PDE5 inhibitors with the same
mechanism of action and similar adverse effects.
• They all require sexual stimulation as a
prerequisite and are effective regardless of the
cause of erectile dysfunction.
• Viagra has been around the longest and thus has
the benefit of having long-term safety data. It also
has the highest use and lowest discontinuity of the
three drugs. However, Viagra is also administered
in higher doses than the others.
• Tadalafil has the longest period of onset (2 hours)
and lasts up to 36 hours, whereas as sildenafil is
effective up to 12 hours and vardenafil is only
effective 4-5 hours after administration.
• Vardenafil, however, is the most potent (lowest
maximal concentration) and binds to PDE5 more
rapidly than the others, thus it has a potential time
of onset of 10 minutes.
Centrally Acting Oral Drugs:
Apomorphine HCL (Urima)
• Apomorphine is a centrally acting
drug that improves erectile
dysfunction by enhancing the central
natural erectile signals that normally
occur in the brain during sexual
stimulation.
• It is a non-selective dopamine
receptor agonist and acts mainly on
dopamine D2-like receptors in the
brain.
Apomorphine
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Dopamine
Dopamine functions in the brain as a neurotransmitter,
activating dopamine receptors, and also it is a
neurohormone released by the hypothalamus. Dopamine
acts on the sympathetic nervous system, producing
effects such as increased heart rate and blood pressure.
Male orgasm and ejaculation are under the control of the
sympathetic nervous system.
Apomorphine, as a dopamine receptor agonist
specifically activates the oxytocinergic neurons in the
paraventricular nucleus of the hypothalamus, releasing
erectogenic signals and thus facilitating an erection.
Efficacy rates for erections that are hard enough for
intercourse, range from 48%-55% for patients receiving
apomorphine. It is fast acting and 71% of erections are
achieved within 20 minutes of administration.
Side Effect: nausea
96% of men surveyed preferred sildenafil over
apomorphine as a treatment for erectile dysfunction
HO- Group is needed for activity
2
HO
3
11
4
12
O
13
5
HO
10
15
3
1
11
4
16
HO
H
H
N
H
13
5
9
14
2
HO
10
15
12
9
14
8
6
2
HO
1
N
CH3
3
1
11
4
HO
12
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
10
15
9
8
6
7
Apomorphine
(obtained by treating morphine with
concentrated HCl)
Apomorphine is a D1 and D2 Dopamine agonist
Also used as anti-Parkinsonian, and as emetic agent
NH2
Dopamine
Intracavernous
Pharmacotherapy
• Patients that are not responding to
oral drugs may be offered
intracavernous injections.
• Papaverine and alprostadil are the
main drugs used for intracavernous
treatment.
CH3O
N
CH3
NH
N
H
N
CH3O
HO
N
HO
OCH3
OCH3
Papaverine
Non-specific inhibitor of phosphodiesterase (PDE)
Smooth muscle relaxant and vasodilator
Found in opium
OH
CH3
Phentolamine
-Adrenergic Antagonist
(alpha-blocker)
vasodilator
HO
Epinephrine
Alprostadil (MUSE,
Caverject, Befar)
• Alprostadil causes blood vessels to expand,
increasing blood flow throughout the body.
Thus, by increasing blood flow to the penis,
alprostadil helps facilitate an erection.
• Alprostadil is a vasoactive prostaglandin E1.
• It is more effective when used in combination
with phentolamine and papaverine; this is
considered a tri-mix combination therapy.
This tri-mix has an extremely high rate of
efficacy at 92%
• However, alprostadil is normally administered
by itself. Sexual activity is reported after 94%
of injections, a figure that no other sexual
dysfunction treatment option has reached. It
also has an almost immediate onset of action.
• Side Effects: penile pain, prolonged erections,
priapism, and fibrosis
• alprostadil is also now available in a cream,
under the brand name Befar
Alprostadil Brand Names
• Caverject: Direct injection of
papaverine/alprostadil.
• MUSE: alprostadil is produced in
intraurethral pellets; tiny tablets that can be
inserted down into the opening of the penis
with the aid of a minute insertion stick.
• Befar, Alprox, and Topiglan: topical
cream of alprostadil, currently available only
in Asia.
• “Triple Mix”: prostaglandin E1 (PGE1),
papaverine/phentolamine
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Female Sexual
Dysfunction
43% of American women suffer from sexual dysfunction.
(50 million American women!) Highest proportion occures
between the ages of 18 and 29.
Most women can reach orgasm when the clitoris is
stimulated, but only about half of women regularly reach
orgasm during sexual intercourse. About 1 of 10 women
never reaches orgasm.
The World Health Organization International
Classifications of Diseases has divided Female Sexual
Dysfunction into four disorders:
• (1) Desire disorder: a persistent absence of desire
for sexual activity.
• (2) Arousal disorder: a persistent inability to attain
or maintain sufficient sexual excitement.
• (3) Orgasm disorder, a persistent difficulty, delay or
absence of orgasm after sufficient stimulation.
• (4) Pain disorder, persistent genital pain associated
with sexual intercourse or stimulation.
Causes of FSD
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Arousal and orgasmic disorders can be caused by a lack of
blood circulation to the clitoris and genital area and may be
related to medical conditions such as:
Menopause
Vascular disease
High blood pressure
Diabetes
Pelvic trauma
Other conditions related to poor blood flow
Fluctuations in the levels of estrogen and testosterone
hormones, which occur monthly and during pregnancy, can
affect sex drive.
In postmenopausal women, sex drive may be reduced because
estrogen levels decrease. Sex drive may also be reduced in
women who have had both ovaries removed.
A reduction in sex drive may result from depression, anxiety,
stress, or problems in a relationship. Use of certain drugs,
including anticonvulsants, chemotherapy drugs, -blockers (
Antihypertensive Drugs), and oral contraceptives, can also
reduce the sex drive. So can drinking excessive amounts of
alcohol.
Women who have undergone treatment for breast or ovarian
cancer are at high risk for sexual dysfunction.
Testosterone
• Most commonly used drug for treatment of
FSD, especially in post-menopausal women.
• Works to stimulate sexual desire.
• Extremely low doses required- 20mg
administered subcutaneously every three
weeks.
• Creams, patches, and combinations with
estrogen and progesterone are being
developed.
• Side effects: masculinization and could
cause liver toxicity in high doses.
• Intrinsa is a Testosterone patch.
Estrogen (Premarin)
• Available in pill, cream or injection
• Used to help relieve menopause symptoms
that occur due to decrease in levels of
estrogen such as vaginal dryness, itching
and discomfort.
• Side effects of conjugated estrogens
include headache, abdominal pain,
nervousness, nausea, back pain, joint pain
and vaginal bleeding. Patients may also
experience vaginal spotting, loss of
periods or excessively prolonged periods,
breast pain, breast enlargement and an
increase or decrease in sexual drive.
Viagra and Befar for
women…
• Due to Viagra’s PDE5 inhibition it
may improve vaginal engorgement
and lubrication. Viagra for women is
called Avlimil and was created in
2003.
• 84 percent success rate of
decreasing symptoms of female
sexual dysfunction, but It doesn’t
have FDA approval yet.
• Befar, the topical alprostadil cream,
may be used to treat Female Sexual
Arousal Disorder. It would cause
clitoral stimulation by
vasodilatation.
References
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Hatzimouratidis, Konstantinos. Hatzichristou, Dimitrios. A Comparative
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[1] http://www.seekwellness.com /mensexuality/#diseases
[2] http://www.ch.ic.ac.uk/local/projects/p_hazel/mode2.html
[3]http://en.wikipedia.org/wiki/Impotence Wikepedia Encylopedia:
Impotence, Vardenail, Tadalafil
[4] www.ardana.co.uk/glossary.html
[5] www.ivf-infertility.com/help/glossary/ghi.php
[6] Erectile Dysfunction information center
[7] http://www.chemsoc.org/chembytes/ezine/1999/viagra.htm
[8]
http://www.rosalindfranklin.edu/cms/biochem/walters/walters_lect/walte
rs_lect.html
http://www.urometrics.com/products/eros/ Female Sexual Dysfunction:
Eros Therapy.
www.nbc4.com/health/ 1946545/detail.html “Doctor Weighs In On
Female Viagra: Herbal Supplement Marketed As Female Stimulant”
January 30, 2003
Smith, Deborah. “Women and sex: What is ‘dysfunctional’? Monitor on
Psychology: Volume 34, No. 4 April 2003.
http://www.apa.org/monitor/apr03/women.html
Merck Home Manuals. “Women’s Health Issues: Sexual Dysfunction”
http://www.merck.com/mmhe/sec22/ch250/ch250a.html
Conjugated estrogens: Premarin.
http://www.medicinenet.com/estrogens_conjugated/article.htm
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Study of the Options for Teratment of Erectile Dysfunction: Which
Treatment For which Pateint? Drugs 2005, Greece.