男性性功能调节药物

1. 男性性功能调节药物 Drugs modulating male sexual dysfunction

2. Sexual function sexual 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.

6. Illustration of the anatomical relationship between the prostate and the neurovascular bundles (NVBs)

7. Neurobiogenesis of ejaculation nPGi = nucleus paragigantocellularis

10. Drugs regulating male sexual dysfunction • Sexual disorders in men are categorized according totheir occurrence in the cycle of sexual response intodisorders ofdesire,arousal (erectile dysfunction), ororgasm(premature or delayed ejaculation, or anorgasmia),albeit with considerable potential for overlap andconcurrence between these disorder groups.

11. Drugs regulating male sexual dysfunction • In addition to functionalsexual disorders, sexual dysfunction may or may not be associatedwith organic pathology, disorders of sexual development,gender identity, sexual preference (paraphilia)and sexual behaviour can occur in men.

12. Drugs regulating male sexual dysfunction • Infertility（不育） • Abnormal sexual desire（性欲望异常） • Homosexuality（同性恋）Loss of libido（ 性欲丧失） • Abnormal sexual arousal（性唤起异常） • Erectile dysfunction（ED, 勃起功能障碍，阳痿） • Abnormal sexualorgasm（性高潮异常） • Premature ejaculation（PE, 早泄） • Delayed ejaculation（延迟射精）or anorgasmia（性快感缺失）

13. Drugs regulating male sexual dysfunction • Drugs treating ED • 2 receptor antagonist: yohimbine • PDE5 inhibitors: sildenafil, vardenafil, tadalafil • Prostaglandin E1 • Drugs treating PE • Topical preparations: lidocaine • TCA: clomipramine • SSRIs:fluoxetine, sertraline, paroxetine, dapoxetine • Drugs treating hypogonadism(性腺功能不全) • Testosterone

14. Drugs treating ED

15. Drugs treating ED • Erectile dysfunction (ED) is a common male sexual disorder. • ED is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance.

16. Secondary ED

17. Drugs treating ED Age-dependent ED

18. 2009 European Association of Urology (EAU) guidelines Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation EUROPEAN UROLOGY 5 7 ( 2 0 1 0) 8 0 4 – 8 1 4

20. Recommendations for ED treatment

21. Drugs treating ED • Drugs treating ED • 2 receptor antagonist:yohimbine（育亨宾） • PDE5 inhibitors:sildenafil（西地那非, Viagra, 伟哥）, vardenafil（伐地那非）, tadalafil, mirodenafil, udenafil • Prostaglandin E1：intracavemosal injection（海绵窦内注射），transurethral（尿道内给药） First-line Second-line

22. Drugs treating ED • Phosphodiesterase 5(PDE5) inhibitors • Sildenafil（西地那非, Viagra, 伟哥） • Vardenafil（伐地那非） • Tadalafil; Mirodenafil; Udenafil Sildenafil Vardenafil

23. Milestones in the development of sildenafil for erectile dysfunction and pulmonary arterial hypertension

24. Drugs treating ED Pharmacological effects Selectively inhibiting PDE5, resulting in cGMP-dependent responses: Penile erection Reduction of pulmonary arterial resistance & pressure Cardiac vasodilation Increasing cerebral blood flow Neuroprotection

25. Drugs treating ED PDE5

27. eNOS nNOS Mechanisms of pharmacological effects of sildenafil

28. Possible actions of PDE5 inhibitors on various organ systems

30. Drugs treating ED Pharmacokinetics

31. Drugs treating ED Clinical uses 1) ED Sildenafil:first-lineoral therapy;effective at 30–60 min; improved erections: 56%, 77%, and 84% of men taking 25, 50, and 100 mg; last for up to 12 h. 2) Pulmonary arterial hypertension (PAH) Sildenafil:effective first-lineoral therapy; symptomatic PAHwho do not have indications for treatment with intravenousprostacyclin; useful in numerous case reports of PAH from a varietyof causes. 3) OthersNeurogenesis; memory enhancement; neuroprotection; pain; multiple sclerosis; CVS disorders

32. Efficacy of sildenafil vs placebo for ED patients

33. Vardenafil vs placebo

34. Drugs treating ED Adverse reactions headache(10–16%), flushing (5–12%), dyspepsia (4–12%), nasal congestion (1–10%), dizziness (2–3%), visual abnormalities (<2%), 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.

36. Drugs treating ED • Prostaglandin E1 (PGE1, Alprostadil) Pharmacological effects Activating adenylate cyclase  cAMP  activating PKA  Ca2+i  smooth muscle relaxation (+) Alprostadil

37. Drugs treating ED Clinical Uses Second-line therapy for ED Intracavemosal injection（海绵窦内注射） 5-40 mg, erection appears after 5–15 min. Efficacy rates are about 70%, with reported sexual activity after 94% of injections and satisfaction rates of 87–93.5% in patients and 86–90.3% in partners. Intraurethral administration（尿道内给药） A semisolid pellet (125–1000 mg), about 70% of patients aresatisfied orvery satisfied with treatment.

38. Drugs treating ED Adverse reactions Intracavemosal injection（海绵窦内注射） penile pain (50%), prolonged erections (5%), priapism (1%,阴茎异常勃起), and fibrosis (2%) Intraurethral administration（经尿道给药） local pain (29–41%), dizziness (1.9–14%), and urethral bleeding (5%)

39. Drugs treating PE

40. Drugs treating PE Premature ejaculation (PE) is ejaculation occurring, without control, on or shortly after penetration and before the person wishes 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 consistent with PE.

41. 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

42. 2009 European Association of Urology (EAU) guidelines Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation EUROPEAN UROLOGY 5 7 ( 2 0 1 0) 8 0 4 – 8 1 4

44. Drugs treating PE • Topical preparations • Lidocaine（利多卡因） Lidocaine 利多卡因

45. Drugs treating PE • Lidocaine -- aerosol, cream, spray • Lidocaine is topically applied 20–30 min before sexual intercourse. • Prolonged application of a topical anesthetic agent (30–45 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.

46. Drugs treating PE • Tricyclic antidepressants (TCA) • Clomipramine氯丙咪嗪

47. Drugs treating PE • Clomipramine • 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 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.

48. Drugs treating PE • Selective serotonin reuptake inhibitors (SSRIs) • Fluoxetine (氟西汀) Sertraline(舍曲林) • Paroxetine(帕罗西丁) Dapoxetine(达泊西汀)

49. Drugs treating PE • SSRIs block serotonin transportersat the synaptic cleft, resulting in increased serotonin within the CNS and spinal cord. • Serotonin is a potentvasoconstrictor with an inhibitory effect on ejaculation.

50. Drugs treating PE • Paroxetine(20–40 mg/d) • Sertraline(25–200 mg/d) • Fluoxetine(10–60 mg/d) • slow onset of action (5h) and long t1/2 (1–3 days) • SSRIs increase the mean IELT by 2.6-fold to 13.2-fold. • Paroxetineis superior to fluoxetine, clomipramine, andsertraline.