Drugs to treat…SEXUAL DYSFUNCTION Medicinal Chemistry Dr. Buynak
“Keep that Spark Alive” • Sexual Dysfunction is estimated to effect 30-40% 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 • http://www.healthcentral.com/animation/408/17/Erectile_Dysfunction.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 • 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.  • 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 • 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 (six-membered 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.
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
vardenafil (Levitra) • 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 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
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.
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
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 • 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 • Hatzimouratidis, Konstantinos. Hatzichristou, Dimitrios. A Comparative Study of the Options for Teratment of Erectile Dysfunction: Which Treatment For which Pateint? Drugs 2005, Greece. •  http://www.seekwellness.com /mensexuality/#diseases •  http://www.ch.ic.ac.uk/local/projects/p_hazel/mode2.html • http://en.wikipedia.org/wiki/Impotence Wikepedia Encylopedia: Impotence, Vardenail, Tadalafil •  www.ardana.co.uk/glossary.html •  www.ivf-infertility.com/help/glossary/ghi.php •  Erectile Dysfunction information center •  http://www.chemsoc.org/chembytes/ezine/1999/viagra.htm •  http://www.rosalindfranklin.edu/cms/biochem/walters/walters_lect/walters_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