1、男性性功能调节药物,Drugs modulating male sexual dysfunction,Sexual functionsexual desire 性欲望 sexual arousal 性唤起sexual intercourse 性交erection 勃起penetration 插入ejaculation 射精sexual orgasm 性高潮 resolution 消退,Sexual functioning includes phases related to desire, arousal, orgasm, and resolution.,Illustration of the
2、 anatomical relationship between the prostate and the neurovascular bundles (NVBs),Neurobiogenesis of ejaculationnPGi = nucleus paragigantocellularis,Drugs regulating male sexual dysfunction,Sexual disorders in men are categorized according to their occurrence in the cycle of sexual response into di
3、sorders of desire, arousal (erectile dysfunction), or orgasm (premature or delayed ejaculation, or anorgasmia), albeit with considerable potential for overlap and concurrence between these disorder groups.,Drugs regulating male sexual dysfunction,In addition to functional sexual disorders, sexual dy
4、sfunction may or may not be associated with organic pathology, disorders of sexual development, gender identity, sexual preference (paraphilia) and sexual behaviour can occur in men.,Drugs regulating male sexual dysfunction,Infertility（不育） Abnormal sexual desire（性欲望异常）Homosexuality（同性恋） Loss of libi
5、do（ 性欲丧失） Abnormal sexual arousal（性唤起异常）Erectile dysfunction（ED, 勃起功能障碍，阳痿） Abnormal sexual orgasm （性高潮异常）Premature ejaculation（PE, 早泄）Delayed ejaculation（延迟射精）or anorgasmia（性快感缺失）,Drugs treating ED2 receptor antagonist: yohimbinePDE5 inhibitors: sildenafil, vardenafil, tadalafilProstaglandin E1 Dru
6、gs treating PE Topical preparations: lidocaineTCA: clomipramineSSRIs: fluoxetine, sertraline, paroxetine, dapoxetine Drugs treating hypogonadism (性腺功能不全)Testosterone,Drugs regulating male sexual dysfunction,Drugs treating ED,Erectile dysfunction (ED) is a common male sexual disorder. ED is defined a
7、s the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance.,Drugs treating ED,Secondary ED,Drugs treating ED,Age-dependent ED,Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation EUROPEAN UROLOGY 5 7 ( 2 0 1 0) 8
8、0 4 8 1 4,2009 European Association of Urology (EAU) guidelines,Recommendations for ED treatment,Drugs treating ED2 receptor antagonist: yohimbine（育亨宾）PDE5 inhibitors: sildenafil（西地那非, Viagra, 伟哥）, vardenafil（伐地那非）, tadalafil, mirodenafil, udenafilProstaglandin E1：intracavemosal injection（海绵窦内注射），tr
9、ansurethral（尿道内给药）,Drugs treating ED,First-line,Second-line,Phosphodiesterase 5 (PDE5) inhibitorsSildenafil（西地那非, Viagra, 伟哥）Vardenafil（伐地那非）Tadalafil; Mirodenafil; Udenafil,Drugs treating ED,Sildenafil,Vardenafil,Milestones in the development of sildenafil for erectile dysfunction and pulmonary art
10、erial hypertension,Drugs treating ED,Pharmacological effectsSelectively inhibiting PDE5, resulting in cGMP-dependent responses:Penile erectionReduction of pulmonary arterial resistance & pressureCardiac vasodilationIncreasing cerebral blood flowNeuroprotection,Drugs treating ED,PDE5,Mechanisms of ph
11、armacological effects of sildenafil,nNOS,eNOS,Possible actions of PDE5 inhibitors on various organ systems,Drugs treating ED,Pharmacokinetics,Drugs treating ED,Clinical uses1) ED Sildenafil: first-line oral therapy; effective at 3060 min; improved erections: 56%, 77%, and 84% of men taking 25, 50, a
12、nd 100 mg; last for up to 12 h. 2) Pulmonary arterial hypertension (PAH) Sildenafil: effective first-line oral therapy; symptomatic PAH who do not have indications for treatment with intravenous prostacyclin; useful in numerous case reports of PAH from a variety of causes.3) Others Neurogenesis; mem
13、ory enhancement; neuroprotection; pain; multiple sclerosis; CVS disorders,Efficacy of sildenafil vs placebo for ED patients,Vardenafil vs placebo,Drugs treating ED,Adverse reactionsheadache (1016%), flushing (512%), dyspepsia (412%), nasal congestion (110%), dizziness (23%), visual abnormalities (2%
14、), back pain/myalgia (6%).Adverse events are generally mild and self-limited by continuous use, and the dropout rate due to adverse events is similar to that seen with placebo.,Prostaglandin E1 (PGE1, Alprostadil ),Drugs treating ED,Pharmacological effects Activating adenylate cyclase cAMP activatin
15、g PKA Ca2+i smooth muscle relaxation,Alprostadil,(+),Drugs treating ED,Clinical UsesSecond-line therapy for EDIntracavemosal injection（海绵窦内注射） 5-40 mg, erection appears after 515 min. Efficacy rates are about 70%, with reported sexual activity after 94% of injections and satisfaction rates of 8793.5
16、% in patients and 8690.3% in partners. Intraurethral administration （尿道内给药） A semisolid pellet (1251000 mg), about 70% of patients are satisfied or very satisfied with treatment.,Drugs treating ED,Adverse reactionsIntracavemosal injection（海绵窦内注射） penile pain (50%), prolonged erections (5%), priapism
17、 (1%,阴茎异常勃起), and fibrosis (2%) Intraurethral administration（经尿道给药） local pain (2941%), dizziness (1.914%), and urethral bleeding (5%),Drugs treating PE,Drugs treating PE,Premature ejaculation (PE) is ejaculation occurring, without control, on or shortly after penetration and before the person wishe
18、s it, causing marked distress or interpersonal difficulty.Although timing of intravaginal ejaculatory latency time (IELT) (i.e. time from penetration to ejaculation) is not included in this definition, an IELT of less than 2 minutes, or ejaculation occurring before penetration, has been considered c
19、onsistent with PE.,Drugs treating PE,Drugs treating PE Topical preparations: lidocaine 利多卡因TCA: clomipramine 氯丙咪嗪SSRIs: fluoxetine 氟西汀, sertraline 舍曲林, paroxetine 帕罗西丁, dapoxetine 达泊西汀,Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation EUROPEAN UROLOGY 5 7 ( 2 0 1
20、0) 8 0 4 8 1 4,2009 European Association of Urology (EAU) guidelines,Drugs treating PE,Topical preparationsLidocaine（利多卡因）,Lidocaine 利多卡因,Drugs treating PE,Lidocaine - aerosol, cream, sprayLidocaine is topically applied 2030 min before sexual intercourse. Prolonged application of a topical anestheti
21、c agent (3045 min) may result in loss of erection due to numbness of the penis. A condom is required to avoid diffusion of the topical anesthetic agent into the vaginal wall, causing numbness in the partner.,Drugs treating PE,Tricyclic antidepressants (TCA)Clomipramine氯丙咪嗪,Drugs treating PE,Clomipra
22、mine Greater effect on intravaginal ejaculatory latency time (IELT) than daily use of the SSRIs fluoxetine or sertraline, but with a greater side effect profile (P 0.05).Daily clomipramine significantly increased IELT from 81 s to 202 s at 25mg/day and 419 s at 50mg/day (P 0.01). Sexual satisfaction
23、 increased for both partners, especially at the higher dose. Side effects including dry mouth, constipation, feeling “different”, nausea, sleep disturbances, fatigue, dizziness and hot flushes.,Drugs treating PE,Selective serotonin reuptake inhibitors (SSRIs)Fluoxetine (氟西汀) Sertraline (舍曲林) Paroxet
24、ine (帕罗西丁) Dapoxetine (达泊西汀),SSRIs block serotonin transporters at the synaptic cleft, resulting in increased serotonin within the CNS and spinal cord. Serotonin is a potent vasoconstrictor with an inhibitory effect on ejaculation.,Drugs treating PE,Paroxetine (2040 mg/d) Sertraline (25200 mg/d) Flu
25、oxetine (1060 mg/d) slow onset of action (5 h) and long t1/2 (13 days)SSRIs increase the mean IELT by 2.6-fold to 13.2-fold. Paroxetine is superior to fluoxetine, clomipramine, and sertraline.,Drugs treating PE,Ejaculation delay may start a few days after drug intake, but it is more evident after 12
26、 wk and may be maintained for several years. Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry mouth, diarrhea, and perspiration; they are usually mild.,Drugs treating PE,Dapoxetine is the first SSRI developed specifically for PE. It is rapidly absorbed to give peak plasma concentrations within 13 h, has a relatively short t1/2 of 1.5 h and a terminal t1/2 of 18 h, and can be taken as needed. Studies have confirmed a 50% increase in IELT with 60mg dapoxetine taken “as needed” compared with placebo.,Drugs treating PE,
