Disfungsi EreksiWening Sari, dr., M.Kes.

Pendahuluan Disfungsi ereksi (DE): kegagalan penis berereksi yg memadai untk berhubungan seksualPasien impotenBedakan dg gangguan libido, gangguan ejakulasi, infertilitas (mandul) fatofisiologi beda terapi juga bedacontoh : tua dg masalah primer hipogonadisme libido

Fisiologi EreksiAnatomi Penis 2 corpus cavernosum (dorsal) terdiri atas jaringan yg saling berhubungan1 corpus spongiosum (ventral) mengelilingi uretraEreksi proses neurovaskuler yg dipengaruhi oleh faktor psikis & hormonalStimulus Seksual impuls saraf melepaskan neurotransmiter

The corpora cavernosa contain a network of smooth-muscle cells and endothelial cells surrounded by an expansible tunica albuginea. The sinusoid cavities are small in volume at rest as the smooth-muscle cells are tonically contracted With stimulation, smooth-muscle cells relax, which allows the sinusoids to engorge with blood and causes the penis to become tumescent. As the sinusoids expand, they compress the subtunical venous plexus, which causes an erection. If there is insufficient relaxation of smooth-muscle cells (e.g., from a lack of endogenous nitric oxide associated with endothelial disease) and decreased sinusoid compliance, an inadequate number of smooth-muscle cells (e.g., cell apoptosis from diabetes or neuropathy), or tunical degeneration (e.g., Peyronie's disease), then insufficient compression of the subtunical veins results in erectile dysfunction

Outflow from the parasympathetic nervous system leads to relaxation of the cavernous sinusoids in two ways, both of which increase the concentration of nitric oxide (NO) in smooth-muscle cells. First, nitric oxide is the neurotransmitter in nonadrenergic, noncholinergic (NANC) fibers; second, stimulation of endothelial nitric oxide synthase (eNOS) through cholinergic output causes increased production of nitric oxide. The nitric oxide produced in the endothelium then diffuses into the smooth-muscle cells. With the increase in nitric oxide content, the smooth-muscle cell decreases its intracellular calcium concentration through a pathway mediated by cyclic guanosine monophosphate (cGMP), which leads to relaxation. A separate mechanism that decreases the intracellular calcium level is mediated by cyclic adenosine monophosphate (cAMP). With increased cavernosal blood flow, as well as increased levels of vascular endothelial growth factor (VEGF), the endothelial release of nitric oxide is further sustained through the phosphatidylinositol 3 (PI3) kinase pathway. Active treatments (red boxes) include drugs that affect the cGMP pathway (phosphodiesterase [PDE] type 5 inhibitors and guanylyl cyclase agonists), the cAMP pathway (alprostadil), or both pathways (papaverine), along with neural-tone mediators (phentolamine)

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Androgen (1)Defisiensi androgen M ereksi nokturnal & libido, tp hipogonadisme dg adanya stimulus seksual scr visual respon ereksi + hipogonadisme androgen oral

Androgen (2)ES testosteron transdermal: iritasi kulit, dermatitis kontakKI : kanker prostat, hiperplasia prostat ok. Androgen memacu pertumbuhan prostatTerapi testosteron lama hematokrit, serum testosteron, lipid & prostate specific antigen harus dievaluasi setiap 6 bulanAndrogen oral: hepatotoksik (kolestasis, hepatitis)

Penghambat Fosfodiesterase-5 (PDE5)Penghambat selektif fosfodiesterase tipe 5 (PDE5); drug of choice utk sebag besar kasus disfungsi ereksiStimulasi seksual pelepasan nitrit oksida ke dlm otot polos penil penghambatan PDE5 oleh PDE5 inhibitor P kadar c-GMP di glans penis, corpus cavernosum & corpus spongiosus P relaksasi otot polos & ereksi yg lebih baikStimulasi seksual (-) kadar nitrit oksida & c-GMP PDE5 inhibitor tidak berefek

Guanilat siklaseStimulasi seksualSaraf nonadrenergik-nonkolinergik & endotelNitrit oksid / NOPDE5GTPGMP cGMPEreksi penis relaksasiOral PDE5 inhibitor

Fmkdinamik & Fmkinetika PDE5

Sildenafil (viagra)Vardenafil (Levitra)Tadalafil (Cialis)Hambat PDE5Hambat PDE6Hambat PDE11Kadar puncak plasma (jam)Absorbsi

Efek Samping PDE5 (1)ES inhibisi PDE5 nyeri kepala, fasial flushing, kongesti nasal, dispepsia, pusingES inhibisi PDE6 (sildenafil) gangguan visual: hipersensitif thdp cahaya,pandangan kabur, gangg dlm membedakan hijau-biru. Laporan gangg visual kronik (-) keamanan jangka lama (?). dg penykt retina hrs konsul dulu dg opthalmologis sebelum terapi sildenafil diberikanES visual jarang pd vardenafil (0,1%)ES inhibisi PDE11 (tadalafil) nyeri otot & pinggang (7-30% pasien)Sildenafil hambat PDE5 di platelet hati2 pasien terapi aspirin/ antiplatelet lain & pasien dg kecenderungan perdarahan

Efek Samping PDE5 (2)Sildenafil & vardenafil sistolik (8-10mmHg) & diastolik (5-6mmHg)Angka kejadian ES KV serius (angina & penykt arteri koroner) 4,1 per 100 /thn, infark miokard 1,7/100 /thnAktivitas seksual infark miokard 0,9% dr 858 ; angka kematian krn infark miokard/stroke pd dg rentang usia disfungsi ereksi biasa terjadi 170/1jt /mggu Sidenafil aman utk sebagian besar , namun ok sebag besar yg meninggal punya riwayat penykt KV status KV harus di evaluasi dg cermat sebelum terapi diberikan

Kematian terkait sildenafil Data FDA: maret Nov 1998 6 juta resep sildenafil 25-100mgPeriode yg sama 130 pasien mati terkait sildenafilUsia rata2 64th (29 87)Sildenafil & nitrat: hipotensi berat 16 pasien 44 pasien < 4 jam 27 pasien selama/segera setelah hubungan seksual

KI absolut Sildenafil : yg mendapat terapi nitrat

Penyebab kematianJumlahInfark miokard Cardiac arrestCardiac symptomPykt arteri koronerStroke KeracunanTdk diketahuiTotal 4127633248130

YohimbinAntagonis reseptor 2-adrenergik dr akar pohon yohimDiperkirakan bekerja di reseptor adrenergik saraf pusat yg terkait libido & ereksi penilPenelitian: 419 DE yohimbin lebih baik dr plaseboES: palpitasi, tremor, tekanan darah , ansietasTidak direkomendasikan utk organik DE efeknya marginal

FentolaminAntagonis nonkompetitif -adrenergik pro-erectogenic M< tonus adrenergik & m tonus kolinergik memperbaiki pengisian cavernosum Oral fentolamindpt perbaiki fungsi ereksiSering diberikan sbg injeksi intracavernosum, dikombinasi dg papaverin hindari monoterapi ok butuh dosis >> ES hipotensiUji klinik: 459 DE perbaikan fs ereksi: 37% (40mg), 45% (80mg), 16% (plasebo)ES:nyeri kepala, facial flushing, kongesti nasal, hipotensi (injeksi intracavernosum,terutama jk salah tempat suntik)Belum disetujui FDA USA

Apomorfin Obat pemacu muntah yg potenBekerja pada reseptor dopamin sentral (D1 / D2)Apomorfin SK menginduksi ereksi pd tikus & manusiaPenelitian 457 DE: 4 mg apomorfin vs plasebo 52% vs 35% apomorfin:16% muntah, 4% butuh antiemetikPenggunaannya terbatas krn ESnya:muntahBelum disetujui FDA USA

Trazodon Antagonis serotonin & reuptake inhibitor, digunakan sebagai sedatif & antidepresanSebabkan priapismus pd bbrp kasusEfeknya pd ereksi mungkin krn aktivitas serotonergik & -adrenolitikPd beberapa dpt memperbaiki fungsi ereksi, namun efeknya tidak signifikan pd penelitian multisenter

Alpostradil (1)Prostaglandin E1 stimulasi adenil siklase prod cAMP relaksasi otot polos arteri & sinusoid aliran & pengisian darah corpora >>Tersedia : injeksi intracavernosa & intrauretralSifat invasif, diberikan bila pasien gagal / tidak bisa dg terapi non invasif Cocok utk pasien DM terbiasa menyuntik sendiri & sensori nyeri

Alpostradil (2)Efektivitas: Inj. intracavernosa > intrauretraAlprostradil diinjeksikan hanya pada satu cavernosum, onset 5-15, durasi ereksi 1 jam (dosis 2,5-20mcg), dimetabolisme dg cepat oleh enzim lokal, obat yg terbawa sirkulasi sistemik diinaktifasi di paru, T 1Dosis 10-20mcg, max 60mcg > 60mcg: tdk hasilkan ereksi yg > baik, prolonge ereksi, atau hipotensi sistemik ES lokal: nyeri pd tempat injeksi / saat ereksi, priapismus, endapan darah hipoksia jaringan & fibrosis cavernosumES sistemik: jarang,hipotensi terkait dosis

PapaverinHambat cavernosal PDE metabolisme cAMP di jaringan cavernosum >: priapisme, fibrosis corporal, hipotensi dan hepatotoksikDosis >, aman: ES minimal Tunggal 7,5 60 mg, kombinasi 0,5-20mg, absorbsi sistemik , T 1 jam

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