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Tratamento da Disfunção Erétil Masculina

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1 Tratamento da Disfunção Erétil Masculina
GILBERTO DE NUCCI

2 Dúvidas denucci@gilbertodenucci.com Site www.gilbertodenucci.com

3 ANFÍBIOS A fertilização é interna nos Urodela (salamandras), mas sem a participação de qualquer estrutura que se assemelhe a um falo. A cloaca do macho e da fêmea são pressionadas uma contra a outra para que ocorra a transferência de esperma, ou o macho deposita um pacote de esperma que é subsequentemente apanhado pela cloaca da fêmea. Salamandra

4 A - Hemipênis iniciando eversão. B - Hemipênis evertido
SQUAMATA Na ereção, os hemipênises são invertidos, tanto por ação muscular como por ingurgitamento vascular. Os hemipênises possuem tanto corpos cavernosos como espaços linfáticos. B A A - Hemipênis iniciando eversão. B - Hemipênis evertido

5 SQUAMATA Cada hemipênis é funcionalmente um falo independente do outro. Assim sendo, em cada cópula apenas um hemipênis é introduzido na cloaca da fêmea. Na detumescência o hemipênis é invertido pela ação de músculos retratores. Na fêmea, um par de hemiclitóris pode estar presente no teto da cauda. Hemipênises completamente evertidos

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7 RÉPTEIS 3. Nos Crocodilia e Chelonia há um falo mediano intracloacal
Nos quelônios, o falo consiste de um órgão mediano e dorsoventralmente achatado, que repousa na parede ventral da cloaca. Chelonoides carbonaria - Posição do falo em repouso na cloaca Pênis exposto de tartaruga

8 Sexual problems in 18-67-year-old Norwegians.
Scand J Public Health Jul;38(5): Epub 2010 May 21. Sexual problems in year-old Norwegians. Traeen B, Stigum H. Source Department of Psychology, University of Tromsø, Tromsø, Norway. Abstract AIM: The aim of this study was to describe and analyse the prevalence of sexual problems in Norway. METHODS: The results are based on two samples from 2008, one of which was taken from 1671 web interviews in December among persons ranging from years of age, and the other being a survey on sexual behaviour among a random sample of 12,000 Norwegians between the ages of 18 and 59, taken in April. Main outcome measures: The prevalence of sexual problems during the past 12 months. RESULTS: Generalised linear model analyses showed that the highest expected prevalence of manifest problems was found in the following groups: reduced sexual desire problems in year-old women with university education (52%); orgasm problems in year-old women with less than university education (32%); genital pain in year-old women with less than university education (19%); premature ejaculation problems in year-old men with less than university education (27%); delayed ejaculation problems in men with less than university education (12%); erectile dysfunction in year-old men (34%); and lubrication problems in year-old women living in southeast Norway (29%). Sexual problems correlated negatively with sexual wellbeing. CONCLUSIONS: This research indicates that sexual problems represent a public health problem.

9 Definição A disfunção erétil masculina é a incapacidade em obter ou manter uma ereção peniana rígida o suficiente para que ocorra penetração.

10 Estudo epidemiológico de DE em Massachusetts
Prevalência de DE em homens de 40–70 anos. N = 1290 Feldman HA et al. J Urol. 1994;151:54-61.

11 Distribuição por Idade (MA)
1290 Homens 70 60 50 40 % 30 20 10 40 50 60 70 anos DE Leve DE Moderada DE Completa

12 Sleep Medicine Volume 11, Issue 10 , Pages 1019-1024, December 2010
Prevalence of erectile dysfunction complaints associated with sleep disturbances in Sao Paulo, Brazil: A population-based survey Monica L. Andersen, Rogerio Santos-Silva, Lia R.A. Bittencourt, Sergio Tufik Received 22 February 2009; received in revised form 28 July 2009; accepted 21 August 2009. Abstract Introduction: The aims of this study were to estimate the prevalence of erectile dysfunction (ED) complaints in a population-based sample from Sao Paulo and to determine the associations of ED prevalence with sleep disturbances, testosterone levels, age, body mass index (BMI), socioeconomic factors and selected medical history indicators. Methods: The Epidemiologic Sleep Study (EPISONO) is a population-based study of sleep and risk factors for sleep disturbances in Brazil’s largest city, Sao Paolo. This study adopted a probabilistic three-stage cluster sampling approach for the city of Sao Paulo. Questionnaires that covered medical conditions and sexual and erection complaints were administered and polysomnographies and fasting blood samples were collected. The patient cohort of the current study of ED consisted of 467 men, aged 20–80years at the time of their enrollment in EPISONO. The percentage of men who participated in EPISONO but refused to participate in our study was 2.3%. Results: The prevalence of ED complaints in the study cohort was 17.08% overall. ED complaints ranged from 7.3% in younger men (20–29years old) to 63.25% in older men (>50years old) (adjusted odds ratio [OR]=21.65). The logistic regression model showed that both reduced time spent in REM sleep and fragmented sleep had significant effects as risk factors for ED complaints. Obesity (OR=1.8), low testosterone levels (OR=4.28), low quality of life (OR=4.4), an apnea–hypopnea index over 15 (OR=2.75), and obstructive sleep apnea syndrome (OR=2.13) were also significantly associated with a higher risk of ED complaints. Conclusion: EPISONO study indicates that ED complaints are relatively common phenomena, especially among older men. Adequate sleep patterns and normal or high levels of testosterone, which serve as markers for sexual motivation, may be protective against ED. The prevalence of sleep apnea showed a strong impact on erectile function and subsequently negatively affects sexual activity.

13

14 The incidence of concomitant hypertension and ED with advancing age
Incidence of hypertension and ED, % Age, years  ,4 Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 –

15 CA CC Cross-section of the penile distal shaft from human, Cavernosal artery (CA) Corpus cavernosum (CC)

16 Arterial Supply Cavernous a. Dorsal a. C. cavernosum C. spongiosum
Bulbar a. Internal pudendal a. Urethral a.

17 Venous drainage Superficial dorsal v. Deep dorsal v. Cavernous v.
C.cavernous v. Circumflex v.’s Prepostatic plexus Urethral v. Internal pudendal v. C. spongiosum Bulbar v.

18 Flaccid State Tunica albuginea Emissary v.

19 Erect state

20 Penile Erection 1 2 3 4 3 5 6 7 25 200 100 Cavernous nerve Pud. A.
25 Pud. A. (ml/min) 200 (cm H2O) I.C. 100 Cavernous nerve Pudendal nerve

21 Penile Erection 1 2 3 4 3 5 6 7 25 200 100 Cavernous nerve Pud. A.
25 Pud. A. (ml/min) 200 (cm H2O) I.C. 100 Cavernous nerve Pudendal nerve

22 Causas conhecidas de DE
Depressão Ansiedade Doença vascular (arterial ou venosa) Fatores hormonais Doença autonômica Uso de Medicamentos Trauma (fratura) Doenças Penianas (Peyronie)

23 Male (24 years old) with fracture of the penis
Male (24 years old) with fracture of the penis. Following sexual activity, the patient presented with loss of penile rigidity, pain, hematoma of the penile shaft and hematuria. (a) Retrograde urethrogram reveals associated rupture of the bulbar urethra (arrow). The patient subsequently underwent surgical exploration and repair a Doppler evaluation of erectile dysfunction – Part 2 - International Journal of Impotence Research (2006), 1–6

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25 Percent distribution of organic causes of ED
Erectile Dysfunction - THE JOURNAL OF UROLOGY

26 Erectile Dysfunction - THE JOURNAL OF UROLOGY - Vol
Erectile Dysfunction - THE JOURNAL OF UROLOGY - Vol. 175, S25-S31, March 2006

27 Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 –

28 Regulação Periférica 1. Mediadores Contráteis Noradrenalina (NA) Rho A
Endotelina-1 (ET-1) Prostaglandina F2a (PGF2a) Tromboxano A2 (TXA2) Angiotensina II

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30

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32 Regulação Periférica 1. Mediadores Contráteis
Noradrenalina (NA) – até o momento, o único que aparentemente é clinicamente relevante, visto o uso terapêutico de bloqueadores adrenérgicos (fenoxibenzamina intra-cavernosa, fentolamina por via intra-cavernosa e via oral).

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34 MLC Phosphatase (Active) MLC Phosphatase~P (Inactive)
The state of myosin light chain (MLC) phosphorylation in cavernosal smooth muscle (SM) is regulated by MLC kinase and MLC phosphatase. RhoA-GDP RhoA-GTP Rho-Kinase MLC Phosphatase (Active) MLC Phosphatase~P (Inactive) Phosphatase phosphatase (?) Inhibition of Tonic Contraction—A Novel Way to Approach Erectile Dysfunction? - Journal of Andrology, Vol. 23, No. 5, MLC SM: Relaxed Penis: Erect MLC-P SM: Contracted Penis: Not Erect MLC kinase Calmodulin-Ca2+ [Ca2+]i

35 Concentration-response curve to phenylephrine (PE) in C
Concentration-response curve to phenylephrine (PE) in C. durissus (snake) aorta in control conditions and treated with the Rho-kinase inhibitor Y (10 μM)

36 Peripheral Regulation
1. Contractant Factors Noradrenaline Rho A Endotelin-1 (ET-1) Prostaglandin F2a (PGF2a) Tromboxane A2 (TXA2) Angiotensin II

37 Erectile function in anesthetized dog after intracavernous administration of losartan
Journal of Urology, 157, 1997

38 Regulação Periférica 2. Mediadores Relaxantes Óxido Nítrico (NO)
Acetilcolina (ACh) Neuropeptídeos (VIP, CGRP) Prostanóides (PGE1) Histamina ATP / adenosina H2S e SO2

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40 NO-cGMP Biochemistry (-) (-) L-NAME GTP NOS SGC cGMP ARGININE NO PDE-5
Viagra

41 NO mediates relaxation of HCC
Hz W W NAA L-ARG 1 g W PE 2 min The New England J. of Medicine, 326, 1992

42 SNAP relaxes HCC Hz PE -8 -7.5 -7 -6.5 -6 -5.5 4 2 4 8 16 1 g 2 min
-7 -6.5 -6 1 g -5.5 PE 2 min The New England J. of Medicine, 326, 1992

43 Effect of M&B on HCC relaxation
Hz W W M&B W 1 g PE 2 min The New England J. of Medicine, 326, 1992

44

45 PNAS, 97, 2000

46 NO-cGMP Biochemistry (-) (-) L-NAME GTP NOS SGC cGMP ARGININE NO PDE-5
Viagra

47 Structures of PDE5 Inhibitors
Sildenafil (Viagra ™) Vardenafil (Levitra ™) Lodenafil carbonate (Helleva ™) Tadalafil (Cialis ™)

48 Eur J Pharmacol. 2008 Sep 4;591(1-3):189-95. Epub 2008 Jun 19.
Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, De Nucci G. Department of Pharmacology, UNICAMP, Campinas, SP, , Brazil. Abstract Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed ( microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine ( microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.

49 Pharmacological management of ED (I)
Orally active inhibitor of PDE5; Promotes erection by inhibiting the degradation of cGMP; Dosage: 25, 50 or 100 mg; Erectogenic effect is achieved following sexual stimulation; Tmax: 1 h after administration; T1/2: 4-5 h. Sildenafil

50 Pharmacological management of ED (II)
Novel inhibitor of PDE5; Dosage: 5, 10, 20 or 40 mg; Potency and selectivity somewhat superior to sildenafil; Tmax: h after administration; T1/2: 4-5 h. Vardenafil

51 Pharmacological management of ED (III)
Dosage: 10, 25, 50 or 100 mg; Tmax: 2 h after administration; T1/2: 17.5 h; Long half-life has been associated with an erectogenic potential of the drug lasting for 24 h. Tadalafil

52 PDE-5 inhibitor efficacy in successful intercourse
PDE-5 inhibitor efficacy in successful intercourse. Adapted from Padma-Nathan,54 Brock55 and Porst56 et al. Erectile Dysfunction - THE JOURNAL OF UROLOGY

53 Summary of the key pharmacokinetic data for the three PDE5 inhibitors
EAU Guidelines on Erectile Dysfunction: An Update - european urology 49 (2006) 806–815

54 Common adverse events of the three PDE5 inhibitors
EAU Guidelines on Erectile Dysfunction: An Update - european urology 49 (2006) 806–815

55 Comparative profile of currently available PDE5 inhibitors.
Selectivity ratio = PDE5/PDEx potency Sildenafil Tadalafil Vardenafil PDE PDE PDE

56 LUTS e DE são altamente prevalente em homens > 50 anos
Alfa-bloqueadores são considerados a monoterapia mais efetiva para LUTS causada por HBP. Inibidores de PDE-5 são considerados a monoterapia mais efetiva para DE. LUTS e DE são altamente prevalente em homens > 50 anos

57 Changes in supine and standing blood pressure, expressed as maximum differences from placebo, following co-administration of a single dose of tadalafil 20 mg (maximum therapeutic dose) with alfuzosin 10 mg once daily [10], doxazosin 0.8 mg once daily [9] or tamsulosin 0.4 mg once daily [9]. *Statistically significantly different from placebo (i.e. 95% confidence interval did not contain 0). BP, blood pressure Lower urinary tract symptoms and sexual dysfunction: a common approach - J O U R N A L C O M P I L A T I O N© B J U I N T E R N A T I O N A L | 101 , S U P P L E M E N T 3 , 2 2 – 2 6 – fig 01

58 Impact of alfuzosin 10 mg once daily administered over 3 years on sexual function assessed using the Danish Prostate Symptom Score sexual function domain (DAN-PSSsex) in 689 men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia [22]. The DAN-PSSsex assesses the severity and bother of 3 sexual symptoms: stiffness of erection, volume of ejaculate and pain/discomfort at ejaculation. For men experiencing a given sexual symptom, a weighted score (rated 0 to 9) is calculated by multiplying the symptom score (0–3) by the bother score (0–3). For each sexual symptom, lower values indicate better function/satisfaction. Lower urinary tract symptoms and sexual dysfunction: a common approach - J O U R N A L C O M P I L A T I O N© B J U I N T E R N A T I O N A L | 101 , S U P P L E M E N T 3 , 2 2 – 2 6 – fig 02

59 Impact of alfuzosin 10 mg once daily, sildenafil 25 mg once daily or the combination of both on
International Prostate Symptom Score (IPSS) and International Index of Erectile Dysfunction (IIEF) [31]. © Reprinted with permission from Elsevier. For IPSS, lower scores indicate improvement. For IIEF, higher scores indicate better function. Lower urinary tract symptoms and sexual dysfunction: a common approach - J O U R N A L C O M P I L A T I O N© B J U I N T E R N A T I O N A L | 101 , S U P P L E M E N T 3 , 2 2 – 2 6 – fig 03

60 NO-cGMP Biochemistry (-) (-) (-) ODQ L-NAME GTP sGC cGMP NOS PDE5
L-ARGININE NO PDE5 inhibitors

61 BAY 41-2272 induces HCC relaxation
Sildenafil (MW ) BAY (MW ) pEC50 Emax 6.71  0.05 111  5 6.85  0.06 117  5

62 Equilíbrio redox GCs Ativadores GCs: BAY 60-2770 BAY 58-2667
GCs ativada GCs ativada Ativadores GCs: BAY BAY Estimuladores GCs: BAY NO NO NADPH oxidase Oxidação ODQ ERO GCs oxidada GCs reduzida H.H.H.W. Schmidt et al., 2009

63 Curr Pharm Des. 2010 May;16(14):1619-33.
Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction. Gur S, Kadowitz PJ, Hellstrom WJ. Department of Urology and Pharmacology, Health Sciences Center, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Abstract Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY , BAY , BAY , CFM-1571 and A ) and heme-independent sGC activators (e.g. BAY , HMR-1766, S-3448, A ) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.

64 O sistema NO-cGMP-PDE5 é importante para a ereção peniana
Conclusão O sistema NO-cGMP-PDE5 é importante para a ereção peniana

65 Crotalus durissus terrificus

66 Chelonoidis carbonaria (n=1)
Effect of L-NAME in phenylephrine induced contraction in corpus cavernosum from tortoise and mice Tortoise Chelonoidis carbonaria (n=1) Mice C57BL/6

67 Príapo, Deus grego da fertilidade.
CONCLUSÃO O sistema NO-cGMP-PDE5 de relaxamento do corpo cavernoso está presente desde o aparecimento do pênis primário em répteis. Príapo, Deus grego da fertilidade.


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