Tratamento da Disfunção Erétil Masculina
GILBERTO DE NUCCI
Dúvidas
[email protected]
Site
www.gilbertodenucci.com
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
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
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
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.
Pênis exposto de tartaruga
Chelonoides carbonaria - Posição do falo em
repouso na cloaca
Scand J Public Health. 2010 Jul;38(5):445-56. Epub 2010 May 21.
Sexual problems in 18-67-year-old Norwegians.
Traeen B, Stigum H.
Source
Department of Psychology, University of Tromsø, Tromsø, Norway. [email protected]
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
18-67 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 60-67-year-old women with university education (52%); orgasm problems in 18-29-year-old women with less than
university education (32%); genital pain in 18-29-year-old women with less than university education (19%); premature ejaculation problems in
18-29-year-old men with less than university education (27%); delayed ejaculation problems in men with less than university education (12%);
erectile dysfunction in 60-67-year-old men (34%); and lubrication problems in 60-67-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.
Definição
A disfunção erétil masculina é a
incapacidade em obter ou manter
uma ereção peniana rígida o
suficiente para que ocorra
penetração.
Estudo epidemiológico de DE em
Massachusetts
• Prevalência de DE em homens de 40–70 anos.
17%
N = 1290
25%
48%
10%
Feldman HA et al. J Urol. 1994;151:54-61.
Normal
Minimal ED
Moderate ED
Complete ED
Distribuição por Idade (MA)
1290 Homens
70
60
50
%
40
30
20
10
0
40
DE Leve
50
60
DE Moderada
70
anos
DE Completa
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.
The incidence of concomitant hypertension
and ED with advancing age
Age, years
Incidence of hypertension
and ED, %
56-65
51.4
66-75
62.3
76-85
67.2
86
68,4
Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 – 566 1
CA
CC
Cross-section of the penile distal shaft from human, Cavernosal artery (CA) Corpus
cavernosum (CC)
Arterial Supply
Cavernous a.
Dorsal a.
C. cavernosum
C. spongiosum
Urethral a.
Bulbar a.
Internal
pudendal a.
Venous drainage
Superficial dorsal v.
Cavernous v.
Deep dorsal v.
C.cavernous v.
Circumflex v.’s
Prepostatic
plexus
Urethral v.
C. spongiosum
Bulbar v.
Internal
pudendal v.
Flaccid State
Tunica albuginea
Emissary v.
Erect state
Penile Erection
1
2
3
4
Pud. A.
(ml/min)
25
0
I.C.
(cm H2O)
200
100
0
Cavernous nerve
Pudendal nerve
3
5
6
7
Penile Erection
1
2
3
4
Pud. A.
(ml/min)
25
0
I.C.
(cm H2O)
200
100
0
Cavernous nerve
Pudendal nerve
3
5
6
7
Causas conhecidas de DE
•
•
•
•
•
•
•
•
Depressão
Ansiedade
Doença vascular (arterial ou venosa)
Fatores hormonais
Doença autonômica
Uso de Medicamentos
Trauma (fratura)
Doenças Penianas (Peyronie)
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
Percent distribution of organic causes of ED
Erectile Dysfunction - THE JOURNAL OF UROLOGY
Erectile Dysfunction - THE JOURNAL OF UROLOGY - Vol. 175, S25-S31, March 2006
Beneficial effects of extendedrelease doxazosin and doxazosin standard on sexual health - BJUINTERNATIONAL |97, 559 – 566 1
Regulação Periférica
1. Mediadores Contráteis
Noradrenalina (NA)
Rho A
Endotelina-1 (ET-1)
Prostaglandina F2a (PGF2a)
Tromboxano A2 (TXA2)
Angiotensina II
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).
RhoA-GDP
RhoA-GTP
MLC Phosphatase
(Active)
MLC
SM: Relaxed
Penis: Erect
Rho-Kinase
Phosphatase
phosphatase (?)
MLC Phosphatase~P
(Inactive)
MLC-P
SM: Contracted
Penis: Not Erect
MLC kinase
Calmodulin-Ca2+
[Ca2+]i
Inhibition of Tonic Contraction—A Novel Way to Approach Erectile Dysfunction? - Journal of Andrology, Vol. 23, No. 5,
The state of myosin light chain (MLC) phosphorylation in cavernosal smooth muscle (SM)
is regulated by MLC kinase and MLC phosphatase.
Concentration-response curve to phenylephrine (PE) in C.
durissus (snake) aorta in control conditions and treated with the
Rho-kinase inhibitor Y-27632 (10 μM)
Peripheral Regulation
1. Contractant Factors
 Noradrenaline
 Rho A
 Endotelin-1 (ET-1)
 Prostaglandin F2a (PGF2a)
 Tromboxane A2 (TXA2)
 Angiotensin II
Erectile function in anesthetized dog after intracavernous
administration of losartan
Journal of Urology, 157, 1997
Regulação Periférica
2. Mediadores Relaxantes







Óxido Nítrico (NO)
Acetilcolina (ACh)
Neuropeptídeos (VIP, CGRP)
Prostanóides (PGE1)
Histamina
ATP / adenosina
H2S e SO2
NO-cGMP Biochemistry
L-NAME
(-)
GTP
NOS
SGC
cGMP
ARGININE
NO
PDE-5
GMP
(-)
Viagra
NO mediates relaxation of HCC
Hz
4 2 4 8 16
4 2 4
4 2 4 8 16
8 16
W
W
NAA
L-ARG
1g
PE
W
2 min
The New England J. of Medicine, 326, 1992
SNAP relaxes HCC
Hz
4
2
4
8 16
-8 -7.5
-7
-6.5
-6
1g
PE
-5.5
2 min
The New England J. of Medicine, 326, 1992
Effect of M&B on HCC relaxation
Hz
4 2 4 8 16
4
2 4
8 16
W
W
M&B
1g
PE
W
2 min
The New England J. of Medicine, 326, 1992
PNAS, 97, 2000
NO-cGMP Biochemistry
L-NAME
(-)
GTP
NOS
SGC
cGMP
ARGININE
NO
PDE-5
GMP
(-)
Viagra
Structures of PDE5 Inhibitors
CH3
N
CH3
O
N
N
NH
NH
N
N
O
H3C
O
N
O
H3C
S
O
N
CH3
O
O
S
O
N
CH3
N
N
Sildenafil (Viagra ™)
CH3
Vardenafil (Levitra
™)
O
N
CH3
N
N
H
O
O
O
Lodenafil carbonate (Helleva
Tadalafil (Cialis
™)
™)
CH2
CH3
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, 13081-970, 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-1Hpyrazolo[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 (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus
cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 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.
Pharmacological management of
ED (I)
• Orally active inhibitor of PDE5;
CH3
N
O
N
O
• Promotes erection by inhibiting the
degradation of cGMP;
N
• Dosage: 25, 50 or 100 mg;
NH
N
H3C
O
O
CH3
S
N
CH3
Sildenafil
• Erectogenic effect is achieved following
sexual stimulation;
• Tmax: 1 h after administration;
• T1/2: 4-5 h.
Pharmacological management of
ED (II)
CH3
N
N
O
• Novel inhibitor of PDE5;
NH
• Dosage: 5, 10, 20 or 40 mg;
N
H3C
O
O
• Potency and selectivity somewhat superior
to sildenafil;
O
S
CH3
N
N
CH2
CH3
Vardenafil
• Tmax: 0.7-0.9 h after administration;
• T1/2: 4-5 h.
Pharmacological management of ED (III)
O
N
CH3
N
N
H
O
• Dosage: 10, 25, 50 or 100 mg;
• Tmax: 2 h after administration;
O
O
Tadalafil
• T1/2: 17.5 h;
• Long half-life has been associated with an erectogenic
potential of the drug lasting for 24 h.
PDE-5 inhibitor efficacy in successful intercourse. Adapted from
Padma-Nathan,54 Brock55 and Porst56 et al.
Erectile Dysfunction - THE JOURNAL OF UROLOGY
EAU Guidelines on Erectile Dysfunction: An Update - european urology 49 (2006) 806–815
Summary of the key pharmacokinetic data for
the three PDE5 inhibitors
Common adverse events of the three PDE5
inhibitors
EAU Guidelines on Erectile Dysfunction: An Update - european urology 49 (2006) 806–815
Comparative profile of currently available PDE5 inhibitors.
Selectivity ratio = PDE5/PDEx potency
Sildenafil
Tadalafil
(a) PDE5
1
1
(b) PDE6
10
780
(c) PDE11
346
5.5
Vardenafil
1
224
203
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
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© 2 0 0 8 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
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© 2 0 0 8 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
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]. © 2007. 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© 2 0 0 8 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
NO-cGMP Biochemistry
ODQ
(-)
L-NAME
GTP
sGC
(-)
cGMP
NOS
5’GMP
L-ARGININE
NO
PDE5
(-)
PDE5
inhibitors
BAY 41-2272 induces HCC relaxation
CH3
N
O
N
0
O
H3C
O
S
O
N
CH3
N
Sildenafil
(MW 474.46)
CH3
Relaxation (%)
NH
N
40
80
120
F
N
-8
N
N
N
-7
-6
log [Drug] (M)
N
NH2
BAY 41-2272
(MW 360.40)
pEC50
Emax
6.71  0.05
111  5
6.85  0.06
117  5
-5
GCs ativada
Equilíbrio
redox GCs
Estimuladores
GCs:
BAY 41-2272
GCs ativada
Ativadores GCs:
BAY 60-2770
BAY 58-2667
NO
NO
NADPH oxidase
Oxidação
ODQ
ERO
GCs reduzida
GCs oxidada
H.H.H.W. Schmidt et al., 2009
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 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g.
BAY 58-2667, HMR-1766, S-3448, A-778935) 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 NOsGC-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.
Conclusão
O sistema NO-cGMP-PDE5 é importante
para a ereção peniana
Crotalus durissus
terrificus
Effect of L-NAME in phenylephrine induced contraction in corpus
cavernosum from tortoise and mice
Tortoise
Chelonoidis carbonaria (n=1)
Mice
C57BL/6
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.