INTRODUCTION

The bladder, in concert with the urethra and the pelvic floor, is responsible for storage and

periodic expulsion of urine. The integrated function of these components of the lower urinary

tract (LUT) is dependent on a complex control system in the brain, spinal cord and peripheral

ganglia, and on local regulatory factors. Dysfunction of the central nervous control systems or

of the components of the LUT can produce insufficient voiding and retention of urine, or

different types of urinary incontinence (mainly urgency and stress incontinence), or the

symptom complex of the “overactive bladder” (OAB), characterized by urgency, frequency with

or without urgency incontinence, often with nocturia.

Kandung kemih, bersama sama dengan uretra dan dasar panggul

bertanggung jawab untuk penyimpanan urin dan pengeluaran urin

secara berkala. Fungsi terintegrasi dari komponen2 LUT adalah

bergantung pada sebuah sistem kontrol yang kompleks di otak,

saraf tulang belakang dan peripheral ganglia, dan pada faktor2

pengawasan local. Disfungsi pada pusat sistem kontrol saraf atau

pada komponen2 dari LUT dapat mengakibatkan kurangnya buang

air kecil dan retensi (penyimpanan) urin, atau bisa juga

mengakibatkan berbagai macam inkontinensia urin (terutama

urgensi dan stress inkontinensia) atau gejala kompleks pada OAB,

ditandai dengan adanya atau tanpa inkontinensia urin, seringkali

dengan nokturia.

Pharmacologic treatment of urinary incontinence and LUT symptoms (LUTSs) including OAB

is the main option, and several drugs with different modes and sites of action have been tried.

However, to be able to optimize treatment, knowledge about the mechanisms of micturition and

of the targets for treatment is necessary. Theoretically, failure to store urine can be improved by

agents that decrease detrusor activity and increase bladder capacity, and/or increase outlet

resistance. In this chapter, a brief review is given of the normal nervous control of the LUT and

of some therapeutic principles used in the treatment of urinary incontinence.

Perawatan farmakologis dari inkontinensia urin dan gejala gejala

LUT (LUTs) termasuk OAB adalah pilihan yang terutama, dan

beberapa obat dengan tipe/mode yang berbeda dan juga beberapa

tindaan telah dicoba. Namun, untuk pengoptimakan pengobatan

sangat diperlukan pengetahuan mengenai mekanisme dari mikturisi

dan target2 untuk pengobatan. Secara teori, kegagalan dalam

menyimpan urin dapat diperbaiki oleh zat2 yang dapat mengurangi

aktifitas otot detrusor dan meningkatkan kapasitas kandung kemih,

dan atau mningkatkan resistensi saluran. Dlm bab ini diberikan

sebuah ulasan singkat mengenai kontrol saraf normal dari LUT dan

beberapa prinsip terapi yang digunakan dalam pengobatan

inkontinensia urin.

NEURAL CIRCUITS CONTROLLING STORAGE AND EXPULSION OF URINE

Normal micturition occurs in response to afferent signals from the LUT.Both bladder filling and

voiding are controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. These

circuits coordinate the activity of the smooth muscle in the detrusor and urethra with that of the

striated muscles in the urethral sphincter and pelvic floor. Suprapontine influences are believed

to act as on–off switches to shift the LUT between the two modes of operation: storage and

elimination.

Sirkuit Saraf yang Mengontrol Penyimpanan dan Pengeluaran Urin

Mikturisi (berkemih) yang normal dapat terjadi karena adanya

sinyal aferen dari LUT. Baik pengeluaran maupun pengisian

kandung kemih keduanya dikontrol oleh sirkuit saraf dalam otak,

saraf tulang belakang dan ganglia peripheral. Sirkuit2 ini

mengkoordinasi aktifitas pada otot halus pada detrus atau dan

uretra dengan otot lurik pada sfingter uretra dan pelvis dasar.

Pengaruh2 suprapontine dipercaya untuk bertindak sebagai saklar

on off untuk merubah LUT diantara 2 mode pengoperasian:

penyimpanan dan pengeluaran.

In adults, urine storage and voiding are under voluntary control and depend upon learned

behavior. In infants, however, these switching mechanisms function in a reflex manner to

produce involuntary voiding. In adults, injuries or diseases of the central nervous system (CNS)

can disrupt the voluntary control of micturition and cause the reemergence of reflex micturition,

resulting in OAB and detrusor overactivity (DO). Because of the complexity of the CNS control

of the LUT, OAB and DO can occur as a result of a variety of neurological disorders as well as

changes in the peripheral innervation and smooth and skeletal muscle components.

Pada org dewasa, penyimpanan dan pengeluaran urin dikontrol

secara sengaja dan bergantung pada perilaku kebiasaan. Namun

pada bayi, fungsi mekanisme2 pergantian ini dilakukan secara

releks dlm hal pengeluaran urin. Pada org dewasa, kerusakan2 atau

penyakit2 pada sistem saraf dapat mengganggu kontrol pada

mikturisi (pengeluaran urin) dan dapat menyebabkan timbulnya

refleks mikturisi, sehingga mengakibatkan OAB dan DO.

Dikarenakan kerumitan pada CNS kontrol dari LUT, OAB dan DO

dapat muncul sebagai akibat dari berbagai gangguan2 neurologis

dan juga akibat dari perubahan2 pada persarafan dan komponen2

otot halus dan skeletal.

Filling of the bladder and voiding involve a complex pattern of afferent and efferent signaling in

parasympathetic (pelvic nerves), sympathetic (hypogastric nerves), and somatic (pudendal

nerves) pathways. These pathways constitute reflexes, which either keep the bladder in a

relaxed state, enabling urine storage at low intravesical pressure, or which initiate bladder

emptying by relaxing the outflow region and contracting detrusor. Integration of the autonomic

and somatic efferents result in that contraction of the detrusor muscle is preceded by a

relaxation of the outlet region, thereby facilitating bladder emptying. On the contrary, during the

storage phase, the detrusor muscle is relaxed and the outlet region is contracted to maintain

continence.

Pengisian dan pengeluaran urin pada kantung kemih mencakup

sebuah pola yang rumit pada pemberian isyarat aferen dan eferen

pada jalur jalur parasympathetic (saraf panggul), sympathetic (saraf

hipogastrikus) dan somatic (saraf pudenda). Jalur2 ini merupakan

releks2 yang menjaga kandung kemih dlm keadaan yang rileks,

memungkinkan penyimpanan urin pada tekanan inravesikal yang

rendah atau memulai mengosongkan kandung kemih dengan

mengendurkan wilayah arus keluar dan menutup otot detrusor.

Integrasi padaeferen2 autonom dan somatik yang menyebabkan

kontraksi pada otot detrusor didahului oleh sebuah relaksasi pada

wilayah jalur keluar, dengan demikian mempermudah pengosongan

kandung kemih. Sebaliknya, selama fase penyimpanan, otot

detrusor dikendurkan dan wilayah jalur keluar dikontraksikan

untuk menjaga kontinensia (penahanan).

PARASYMPATHETIC PATHWAYS

The sacral parasympathetic pathways mediate contraction of the detrusor smooth muscle and

relaxation of the outflow region. The preganglionic parasympathetic neurons are located to the

sacral parasympathetic nucleus (SPN) in the spinal cord at the level of S2–S4. The axons pass

through the pelvic nerves and synapse with the postganglionic nerves either in the pelvic plexus,

in ganglia on the surface of the bladder (vesical ganglia), or within the walls of the bladder and

urethra (intramural ganglia). The ganglionic neurotransmission is predominantly mediated by

acetylcholine acting on nicotinic receptors, although the transmission can be modulated by

adrenergic, muscarinic, purinergic, and peptidergic presynaptic receptors. The postganglionic

neurons in the pelvic nerve mediate the excitatory input to the normal human detrusor smooth

muscle by releasing acetylcholine acting on muscarinic receptors (see later).

Jalur Parasimpatetis

Jalur sacral parasimpatetis menengahi konraksi dari otot

halusdetrusor dan relaksasi dari jalur keluar. Preganglionik

parasimpatesis neurons terletak pada SPN di dalam sumsum tulang

belakang pada level S2-S4. Akson melalui saraf panggul dan

sinapsis dengan saraf postganglionic baik dalam pelvic plexus

{dalam ganglia pada permukaan kandung kemih(vesical ganglia) },

maupun dalam dinding2 kandung kemih dan urethra (intramural

ganglia). Neurotransmisi ganglionik terutama dimediasi oleh

acetylcholine yg bekerja pada reseptor2 nikotinik, meskipun

transmisi dapat diatur oleh adrenergic, muscarinic, purinergic dan

peptidergic presynaptic reseptor. Saraf2 postganglionik pada saraf

panggul menengahi masukan rangsang pada otot halus normal

manusia dengan melepaskan acetylcholine yang bekerja pada

reseptor2 muskarinik.

However, an atropine-resistant (nonadrenergic, noncholinergic [NANC]) contractile component

is regularly found in the bladders of most animal species. Such a component can also be

demonstrated in functionally and morphologically altered human bladder tissue, but contributes

only to a few percent to normal detrusor contraction. Adenosine triphosphate (ATP) is the most

important mediator of the NANC contraction, although the involvement of other transmitters

cannot be ruled out. The pelvic nerve also conveys parasympathetic nerves to the outflow region

and the urethra. These nerves exert an inhibitory effect on the smooth muscle, by releasing nitric

oxide and other transmitters.

Namun, resisten atopin (NANC) dapat secara reguler ditemukan di

dalam sebagian besar kandung kemih hewn. Komponen seperti itu

juga dapat didemonstrasikan pada jaringan kandung kemih

manusia secara fungsional dan morfologis, namun hanya

berkontribusi pada beberapa persen pada detrus normal atau

kontraksi. ATP adalah mediator yang paling penting dari kontraksi

NANC, meskipun keterlibatan dari pemancar2 lainnya tidak dapat

dikesampingkan. Saraf panggul juga menyampaikan saraf

parasimpatetis kepada jalur pengaliran keluardan uretra. Saraf2 ini

mendesak sebuah efek yang menghalangi pada otot halus dengan

melepaskan nitric oxide dan pemancar2 lainnya.

SYMPATHETIC PATHWAYS

The sympathetic innervation of the bladder and urethra originates from the intermediolateral

nuclei in the thoracolumbar region (T10–L2) of the spinal cord. The axons leave the spinal cord

via the splanchnic nerves and travel either through the inferior mesenteric ganglia (IMF) and the

hypogastric nerve or pass through the paravertebral chain to the lumbosacral sympathetic chain

ganglia and enter the pelvic nerve. Thus, sympathetic signals are conveyed in both the

hypogastric nerve and the pelvic nerve. The ganglionic sympathetic transmission is, like the

parasympathetic preganglionic transmission, predominantly mediated by acetylcholine acting on

nicotinic receptors.

Jalur Simpatetis

Persarafan simpatis dari kendung kemih dan uretra berasal dari inti

intermediolateral di dalam wilayah thora combular (T10-L2) dari

sumsum tulang belakang. Akson meninggalkan saraf tulang

belakang melalui saraf splanchinic dan melalui IMF dan saraf

hipogastrik atau melalui rantai paravertebratal ke rantai (deretan)

lumbosakral simpatetik dan memasuki saraf panggul. Jadi, sinyal

simpatetik dibawa didalam saraf hipogastrik dan saraf pelvis.

Transmisi ganglionik simpatetis adalah sama seperti transmisi

parasimpatetis preganglionik yang terutama dimediasi oleh

acetylcholine yang bekerja pada nikotinik reseptor.

Some preganglionic terminals synapse with the postganglionic cells in the paravertebral ganglia

or in the IMF, while other synapse closer to the pelvic organs and short postganglionic neurons

innervate the target organs. Thus, the hypogastric and pelvic nerves contain both pre- and

postganglionic fiber. The predominant effect of the sympathetic innervation is to contract the

bladder base and the urethra. In addition, the sympathetic innervation inhibits the

parasympathetic pathways at spinal and ganglionic levels. In the human bladder, electrical field

stimulation in vitro causes nerve release of noradrenaline, which in the normal detrusor causes

relaxation.

Beberapa preganglionik terminal bersinapsis dengan sel2

postganglionic di dalam paravertebral ganglia atau di dalam IMF,

sedangkan synapse lainnya yg dekat pada organ2 pelvis dan saraf

pendek postganglionic menginervasi organ2 target. Jadi, saraf

hipogastrik dan pelvis berisi baik pre maupun postganglionic fiber

(urat). Efek utama dari inervasi simpatetis adalah untuk menutup

pangkalan (dasar) kandung kemih dan uretra. Oleh krn itu, inervasi

simpatetis menghalangi jalur parasimpatetis pada tulang belakang

dan level2 ganglionik. Pada kandung kemih manusia, stimulasi

medan listrik in vitro menyebabkan pelepasan noradrenaline pada

saraf, yang menyebabkan pengenduran pada detrusor yg normal.

However, the importance of the sympathetic innervation for relaxation of the human detrusor

has never been established. In contrast, in several animal species, the adrenergic innervation has

been demonstrated to mediate relaxation of the detrusor during filling.

Namun, pentingnya inervasi simpatetis untuk pengenduran pada

otot detrusor manusia belum pernah ditetapkan. Sebaliknya, pada

beberapa spesies hewan inervasi adrenergic telah dibuktikan untuk

merelaksasi otot detrusor selama pengisian.

SOMATIC PATHWAYS

The somatic innervation of the urethral rhabdosphincter and of some perineal muscles (eg,

compressor urethrae and urethrovaginal sphincter) is provided by the pudendal nerve. These

fibers originate from sphincter motor neurons located in the ventral horn of the sacral spinal

cord (levels S2–S4) in a region called Onuf ’s (Onufrowicz’s) nucleus.

Jalur Somatik

Inervasi somatic dari rhabdosphincter uretra dan beberapa otot

perineal (seperti kompresor uretra dan sfingter urethovaginal)

diberikan oleh saraf pudendus. Urat2 ini berasal dari saraf motorik

sfingter yang terletak di dlm tanduk ventral pada sumsum sacral

tulang belakang (level S2-S4) di sebuah wilayah yg bernama inti

Onuf.

AFFERENT PATHWAYS

The afferent nerves to the bladder and urethra originate in the dorsal root ganglia at the

lumbosacral level of the spinal cord and travel via the pelvic nerve to the periphery. Some

afferents originate in dorsal root ganglia at the thoracolumbar level and travel peripherally in the

hypogastric nerve. The afferent nerves to the striated muscle of the external urethral sphincter

travel in the pudendal nerve to the sacral region of the spinal cord. The most important afferents

for the micturition process are myelinated Aä-fibers and unmyelinated C-fibers traveling in the

pelvic nerve to the sacral spinal cord, conveying information from receptors in the bladder wall.

Jalur Aferen

Saraf2 aferen pada kandung kemih dan uretra berasal dari akar

dorsal ganglia pada level lumbosakral dari saraf tulang belakang

dan berjalan melalui saraf panggul menuju batas luar. Beberapa

aferen berasal dari akar dorsal ganglia pada level thoracolumbar

dan berkeliling di dalam saraf hipogastrik. Saraf2 aferen pada otot

lurik dari sfingter uretra eksternal berjalan di dalam saraf

pundenda menuju wilayah sacral pada tulang belakang. Aferen2 yg

paling penting untuk proses pengencingan adalah myelinated Aä-

fibers dan unmyelinated C-fibers yg berjalan di dalam saraf pelvis

menuju sacral tulang belakang, dengan membawa informasi dari

dinding kandung kemih.

The Aä-fibers respond to passive distension and active contraction, thus conveying information

about bladder filling. The activation threshold for Aä-fibers is 5–15 mm H2O. This is the

intravesical pressure at which humans report the first sensation of bladder filling. C-fibers have

a high mechanical threshold and respond primarily to chemical irritation of the bladder

urothelium/ suburothelium or to cold. Following chemical irritation, the C-fiber afferents

exhibit spontaneous firing when the bladder is empty and increased firing during bladder

distension.

Aä-fibers merespon pada distensi pasif dan kontraksi aktif, hingga

membawa informasi mengenai pengisian kandung kemih. Ambang

aktivasi untuk Aä-fibers adalah 5-15 mm H2O. Ini adalah tekanan

intravesikalyang dimana manusia mengabarkan perasaan pertama

dari pengisian kandung kemih. C fibers memiliki sebuah ambang

mekanik yg tinggi dan terutama merespon pada iritasi kimia pada

urothelium/suburothelium kandung kemih atau pada rasa dingin.

Setelah iritasi kimia, aferen2 C fiber menunjukan penembakan

spontan saat kandung kemih kosong dan meningkatkan

penembakan selama proses penggelembungan kandung kemih.

These fibers are normally inactive and are therefore termed “silent fibers.” Afferent information

about the amount of urine in the bladder is continuously conveyed to the mesencephalic

periaqueductal gray (PAG), and from there to the pontine micturition center (PMC), also called

Barrington’s nucleus.

Urat2 ini biasanya tidak aktif dan ole karena itu biasa disebut silent

fibers. Informasi aferen mengenai banyaknya jumlah urin pada

kandung kemih secara terus menerus dibawa kepada PAG dan dari

sana menuju PMC, yang juga disebut inti Barrington.

AFFERENT SIGNALING FROM THE UROTHELIUM/SUBUROTHELIUM

Recent evidence suggests that the urothelium/suburothelium may serve not only as a passive

barrier but also as a specialized sensory and signaling unit, which, by producing nitric oxide,

ATP, and other mediators, can control the activity in afferent nerves, and thereby the initiation

of the micturition reflex. The urothelium has been shown to express, for example, nicotinic,

muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors.

Pensinyalan Aferen Dari Urotelium/Suburotelium

Bukti2 saat ini menunjukan bahwa urotelium/suburotelium dapat

melayani bukan hanya sebagai pelindung pasif tapi juga sebagai

sebuah sensorik khusus dan unit pensinyalan, yang dimana dengan

memproduksi oksida nitrat, ATP dan mediator lainnya, dapat

mengontrol aktifitas didalam saraf2 aferen dan dengan demikian

iniaasi dari mikturisi berefleks. Urotelium sudah ditunjukan untuk

menyampaikan, sebagai contoh, nikotinik, muskarinik, tachykinin,

adregenik, bradykinin dan reseptor2 TRP.

Low pH, high K+, increased osmolality, and low temperatures can all influence afferent nerves,

possibly via effects on the vanilloid receptor (capsaicin- [CAP] gated ion channel, TRPV1),

which is expressed both in afferent nerve terminals and in the urothelial cells (Birder et al, 2001;

Birder et al, 2002). A network of interstitial cells, extensively linked by Cx43-containing gap

junctions, was found to be located beneath the urothelium in the human bladder.

pH rendah, tingginya K+, peningkatan osmolalitas dan temperature

yang rendah semuanya dapat mempengaruhi saraf2 aferen,

mungkin juga melalui efek2 pada reseptor vanilloid, yang

diekspresikan baik dalam terminal2 sara aferen dan di dalam sel2

urotelial. Sebuah jaringan pada sel2 interstitial, yg secara ekstensif

dihubungkan oleh Cx43-membawa celah persimpangan, ditemukan

berlokasi dibawah urotelium di dalam kandung kemih manusia

This interstitial cellular network was suggested to operate as a functional syncytium, integrating

signals and responses in the bladder wall. The firing of suburothelial afferent nerves, conveying

sensations and regulating the threshold for bladder activation, may be modified by both

inhibitory (eg, nitric oxide) and stimulatory (eg, ATP, tachykinins, prostanoids) mediators.

Jaringan interstitial seluler dianjurkan untuk menjalankan

syncytium, mengintegrasi sinyal dan sebagai respon2 dalam dinding

kandung kemih. Pengaliran daripada saraf aferen suburotelial, yang

membawa perasaan dan mengatur katup untuk pengaktian kandung

kemih, bisa diubah oleh baik inhibitor (seperti nitric oxide) maupun

mediator penstimulus (seperti ATP, tachykinins, prostanoid)

ATP, generated by the urothelium, has been suggested as an important mediator of urothelial

signaling. Supporting such a view, intravesical ATP induces DO in conscious rats. Furthermore,

mice lacking the P2X3 receptor were shown to have hypoactive bladders. Interstitial cells can

also be demonstrated within the detrusor muscle. They may be involved in impulse

transmission, but their role has not been clarified. There seem to be other, thus far unidentified,

factors in the urothelium that could influence bladder function. Even if these mechanisms can be

involved in, for example, the pathophysiology of OAB, their functional importance remains to

be established.

ATP, yg dihasilkan oleh urotelium, telah dianjurkan sebagai sebuah

mediator penting dari pensinyalan urotelial. Mendukung pandangan

tersebut, ATP intraversikal mendukung DO pada tikus sadar. Selain

itu, tikus2 dengan kekurangan reseptor P2X3 memiliki kandung

kemih hipoaktif. Sel2 interstitial dapat ditunjukan didalam otot

detrusor. Sel2 tersebut mungkin diikutsertakan di dalam transmisi

impuls, namun perannya belum dapat diklarifikasi. Mungkin masih

ada yg lain, jadi jauh tak dikenal, faktor2 dlm urotelium yg dapat

mempengaruhi fungsi dari kandung kemih. Bahkan jika

mekanisme2 ini dapat diikutsertakan, sbagai contoh, patopsikologi

dari OAB, pentingnya fungsi2 mereka masih harus ditetapkan.

NEURAL CONTROL OF BLADDER FILLING

During the storage phase, the bladder has to relax in order to maintain a low intravesical

pressure. Urine storage is regulated by two separate storage reflexes, of which one is

sympathetic (autonomic) and the other is somatic. The sympathetic storage reflex (pelvic-

tohypogastric reflex) is initiated as the bladder distends (myelinated Aä-fibers) and the

generated afferent activity travels in the pelvic nerves to the spinal cord. Within the spinal cord,

sympathetic firing from the lumbar region (L1–L3) is initiated, which, by effects at the

ganglionic level, decreases excitatory parasympathetic inputs to the bladder. Postganglionic

neurons release noradrenaline, which facilitates urine storage by stimulating â3-adrenoceptors

(ARs) in the detrusor smooth muscle (see later). As mentioned previously, there is little

evidence for a functionally important sympathetic innervation of the human detrusor, which is

in contrast to what has been found in several animal species. The sympathetic innervation of the

human bladder is found mainly in the outlet region, where it mediates contraction.

Kontrol Saraf Dari Pengisian Kandung Kemih

Selama fase penyimpanan, kandung kemih harus rileks

dengantujuan untuk menjaga sebuah tekanan intravesikal yang

rendah. Penyimpanan urin diatur oleh 2 penyimpan releks yg

terpisah, yg dimana salah satunya adalah simpatetis (autonomic)

dan yg lainnya adalah somatic. Penyimpanan refleks simpatetis

dimulai sebagai distensi kandung kemih dan aktifitas aferen yg

dihasilkan berjalan did lm saraf pelvis menuju tulang belakang. Di

dlm tulang belakang, penembakan simpatetis dari wilayah lumbar

(L1-L3) dimulai, yg dimana dengan efek2 pada level ganglionik,

menurunkan rangsang input parasimpatetis ke kandung kemih.

Saraf2 postganglionik melepaskan noradrenalin, yg memfasilitasi

penyimpanan urin dengan menstimulasi a3-adrenoreceptors (ARS)

did lm otot detrusor halus. Seperti yg sudah disebut sebelumnya,

ada bukti kecil pada pentingnya secara fungsi simpatetis inervasi

dari otot detrusor manusia, yg sangat kontras dengan apa yg sudah

ditemukan dalam beberapa spesies hewan. Inervasi simpatetis dari

kandung kemih manusia ditemukan biasanya dalam wilayah saluran

keluar yg dimana ini memulai kontraksi.

During micturition, this sympathetic reflex pathway is markedly inhibited via supraspinal

mechanisms to allow the bladder to contract and the urethra to relax. Thus, the Aä afferents and

the sympathetic efferent fibers constitute a vesico-spinalvesical storage reflex, which maintains

the bladder in a relaxed mode while the proximal urethra and bladder neck are contracted. In

response to a sudden increase in intra-abdominal pressure, such as during a cough, laugh, or

sneeze, a more rapid somatic storage reflex (pelvic-to-pudendal reflex), also called the guarding

or continence reflex, is initiated. The evoked afferent activity travels along myelinated Aä

afferent nerve fibers in the pelvic nerve to the sacral spinal cord, where efferent somatic urethral

motor neurons, located in the nucleus of Onuf, are activated.

Selama mikturisi, jalur refleks simpatetis secara nyata terhambat

melalui mekanisme2 supraspinal untuk memungkinkan kandung

kemih berkontraksi dan mengendurkan uretra. Jadi, aferen Aa dan

urat2 eferen simpatetis merupakan sebuah refleks penyimpanan

vesico-spinalvesical, yang menjaga kandung kemih dalam keadaan

rileks sementara uretra proksimal dan leher kandung kemih

berkontraksi. Sebagai respon dari sebuah peningkatan mendadak

dalam tekanan dalam perut, seperti saat batuk, tertawa atau bersin,

sebuah refleks somatik penyimpanan yg lebih cepat (pelvis ke

refleks pundenda), yg juga disebut refleks pengawasan diri atau

penjaga, dimulai. Kegiatan aferen yg dimunculkan berjalan

sepanjang urat saraf aferen mielin Aa dlm saraf pelvis menuju

sumsum tulang belakang.

Afferent information is also conveyed to the PAG and from there to the PMC (the L region).

From this center, impulses are conveyed to the motor neurons in the nucleus of Onuf. Axons

from these neurons travel in the pudendal nerve and release acetylcholine, which activates

nicotinic cholinergic receptors on therhabdosphincter, which contracts. This pathway is

tonically active during urine storage.

Informasi aferen juga dibawa kepada PAG dan dari sana menuju

PMC (Wilayah L). Dari pusat ini, impuls2 dibawa menuju saraf2

motoik di dlm inti Onuf. Akson2 dari saraf2 ini berjalan di dalam

saraf pudenda dan melepaskan acetylcholine, yg mengaktifkan

reseptor2 nikotinik cholinergic pada therhabdosphincter, yg

berkontraksi. Jalur ini adalah aktif secara tonically? selama

penyimpanan urin.

During sudden abdominal pressure increases, however, it becomes dynamically active to

contract the rhabdosphincter. During micturition, this reflex is strongly inhibited via spinal and

supraspinal mechanisms to allow the rhabdosphincter to relax and permit urine passage through

the urethra. In addition to this spinal somatic storage reflex, there is also supraspinal input from

the pons, which projects directly to the nucleus of Onuf and is of importance for voluntary

control of the rhabdosphincter.

Namun, saat meningkatnya tekanan pada perut, ini menjadi aktif

secara dinamis untuk berkontraksi dgn rhabdosphincter. Selama

mikturisi, refleks ini menjadi terhambat dengan kuat melalui tulang

belakang dan mekanisme supraspinal untuk memungkinkan

rhadosphincter untuk rileks dan mengijinkan urin berjalan melalui

uretra. Selain refleks penyimpanan spinal somatic, ada juga

masukan supraspinal dari pons-pons, yang memproyeksikan secara

langsung ke inti dari Onuf dan sangat penting untuk kontrol

sukarela dari rhabdosphincter.

NEURAL CONTROL OF BLADDER EMPTYING

KONTROL SARAF UNTUK PENGOSONGAN KANDUNG KEMIH

Vesico-Bulbo-Vesical Micturition Reflex

Electrophysiological experiments in cats and rats provide evidence for a voiding reflex

mediated through a vesicobulbo- vesical pathway involving neural circuits in the pons, which

constitute the PMC. Other regions in the brain, important for micturition, include the

hypothalamus and cerebral cortex. Bladder filling leads to increased activation of tension

receptors within the bladder wall and thus to increased afferent activity in Aä-fibers. These

fibers project on spinal tract neurons mediating increased sympathetic firing to maintain

continence as discussed earlier (storage reflex).

Percobaan-percobaan elektrofisiologi pada kucing dan tikus

membuktikan adanya sebuah refleks buang air yang diperantarai

melalui sebuah jalur vesicobulbo-vesical yang mencakup sirkuit

saraf pada pons, yang mendirikan PMC. Wilayah-wilayah lain di

dalam otak, yang penting untuk mikturisi, mencakup hipotalamus

dan korteks serebral. Pengisian kandung kemih mengakibatkan

peningkatan pada pengaktifan reseptor-reseptor tegangan di dalam

dinding kandung kemih dan dengan demikian menaikan aktifitas

aferen dalam serabut-serbut Aa. Serabut2 ini berproyeksi pada

saluran saraf tulang belakang yang menegahi penembakan

simpatetis yang meningkat untuk menjaga kontinensia seperti yang

sudah didiskusikan sebelumnya (releks penyimpanan)

In addition, the spinal tract neurons convey the afferent activity to more rostral areas of the

spinal cord and the brain. As mentioned previously, one important receiver of the afferent

information from the bladder is the PAG in the rostral brain stem. The PAG receives

information both from afferent neurons in the bladder and from more rostral areas in the brain,

that is, cerebral cortex and hypothalamus.

Dan lagi, saraf-saraf pada saluran tulang blakang membawa akifitas

aferen kepada area rostral dari medulla spinalis dan otak. Seperti

yang sudah disebutkan sebelumnya, sala satu penerima penerima

penting dari informasi aferen dari kandung kemih adalah PAG

dalam batang otak rostral. PAG menerima informasi baik dari saraf-

saraf aferen di dalam kandung kemihdan dari area-area rostral di

dalam otak yaitu korteks serebral dan hipotalamus.

This information is integrated in the PAG and the medial part of the PMC (the M region), which

also control the descending pathways in the micturition reflex. Thus, PMC can be seen as a

switch in the micturition reflex, inhibiting parasympathetic activity in the descending pathways

when there is low activity in the afferent fibers and activating the parasympathetic pathways

when the afferent activity reaches a certain threshold.

Informasi ini terintegrasi di dalam PAG dan adalah bagian medial

dari PMC (wilayah M), yang juga mengontrol jalur2 turun di dalam

refleks mikturisi. Jadi,PMC dapat dilihat sebagai sebuah saklar di

dalam refleks mikturisi, yang mencegah aktifitas parasimpatetis di

dalam jalur-jalur menurun saat adanya aktifitas rendah di dalam

serabut2 aferen dan mengaktifkan jalur2 parasimpatetis saat

aktifitas aferen mencapai katup tertentu.

The threshold is believed to be set by the inputs from more rostral regions in the brain. In cats,

lesioning of regions above the inferior colliculus usually facilitates micturition by elimination of

inhibitory inputs from more rostral areas of the brain. On the other hand, transections at a lower

level inhibit micturition. Thus, the PMC seems to be under a tonic inhibitory control. A

variation of the inhibitory input to PMC results in a variation of bladder capacity. Experiments

on rats have shown that the micturition threshold is regulated by, for example, gamma-

aminobutyric acid (GABA)- ergic inhibitory mechanisms in the PMC neurons.

Vesico-Spinal-Vesical Micturition Reflex

Spinal lesions rostral to the lumbosacral level interrupt the vesico-bulbo-vesical pathway and

abolish the supraspinal and voluntary control of micturition. This results initially in an areflexic

bladder accompanied by urinary retention. An automatic vesico-spinal-vesical micturition reflex

develops slowly, although voiding is generally insufficient due to bladder-sphincter

dyssynergia, that is, simultaneous contraction of bladder and urethra. It has been demonstrated

in chronic spinal cats that the afferent limb of this reflex is conveyed through unmyelinated C-

fibers, which usually do not respond to bladder distension, suggesting changed properties of the

afferent receptors in the bladder. Accordingly, the micturition reflex in chronic spinal cats is

blocked by CAP, which blocks C-fiber–mediated neurotransmission.

REFLEKS VESIKO-SPINAL-VESIKAL

Spinal lesions rostral sampai level lumbosakral mengganggu jalur

vesiko-bulbo-vesikal dan meniadakan kontrol supraspinal dan

sukarela pada mikturisi. Hasil2 ini pada awalnya di dalam areflesiks

kandung kemih ditemani oleh retensi urin. Sebuah refleks otomatis

vesiko-spinal-vesikal mikturisi berkembang lambat, meskipun

berkemih secara umum tidak cukup dikarnakan disinergi kandung

kemih-disinergis, yaitu, kontraksi serentak dari kandung kemih dan

uretra. Ini telah didemonstrasikan di dalam tulang belakang kucing

kronis yang releks anggota aferennya dibawa melalui serabut C

yang tidak mengalami myelinasi, yang biasanya tidak merespon

distensi kandung kemih, yang menyarankan perubahan property

dari resptor2 aferen di dalam kandung kemih. Oleh sebab itu,

refleks mikturisi pada tulang belakang kucing kronis terhalang oleh

CAP, yang menghalangi neurotransmisi C-fiber

TARGETS FOR PHARMACOLOGIC INTERVENTION CENTRAL NERVOUS SYSTEM

TARGETS

Anatomically, several CNS regions may be involved in micturition control: supraspinal

structures, such as the cortex and diencephalon, midbrain, and medulla, and also spinal

structures. Several transmitters are involved in the micturition reflex pathways described earlier

and may be targets for drugs aimed for control of micturition. However, few drugs with a CNS

site of action have been developed.

Secara anatomi, beberapa wilayah CNS bisa tercakup di dalam

kontrol mikturisi, struktur supraspinal, seperti korteksdan

diensefalon, otak tengah dan medulla, dan juga struktur spinal.

Beberapa transmiter dilibatkan dalam jalur refleks mikturisi seperti

yang dijelaskan sebelumnya dan dapat menjadi target-target

sasaran obat untuk mengontrol mikturisi.

Opioid Receptors

Endogenous opioid peptides and corresponding receptors are widely distributed in many regions

in the CNS of importance for micturition control. It has been well established that morphine,

given by various routes of administration to animals and humans, can increase bladder capacity

or block bladder contractions. Furthermore, given intrathecally to anesthetized rats and

intravenously to humans, the mu-opioid receptor antagonist, naloxone, has been shown to

stimulate micturition, suggesting that a tonic activation of mu-opioid receptors has a depressant

effect on the micturition reflex. However, intrathecal naloxone was not effective in stimulating

micturition in conscious rats at doses blocking the effects of intrathecal morphine.

Reseptor Opioid

Peptida endogen opioid dan reseptor2 yang sesuai didistribusikan

secara luas di banyak wilayah di dalam CNS untuk kepentingan

kontrol mikturisi. Ini sudah ditetapkan secara baik daripada morfin,

diberikan oleh berbagai rute administrasi kepada hewan dan

manusia, dan dapat meningkatkan kapasitas kandung kemih atau

menahan kontraksi pada kandung kemih. Selanjutnya, diberikan

intratekal kepada tikus yang sudah terbius dan secara intravena

kepada manusia, antagonis reseptor mu-opioid, naloxone, telah

diperlihatkan untuk menstimulus mikturisi, menunjukan bahwa

sebuah aktifasi tonik dari reseptor2 mu-opioid mempunyai sebuah

efek depresan pada refleks mikturisi. Namun, naksolon intratekal

tidak efektif dalam menstimulus mikturisi bagi tikus sadar pada

saat dosis menahan efek dari morfin intratekal.

Morphine given intrathecally was effective in patients with DO due to spinal cord lesions, but it

was associated with side effects, such as nausea and pruritus. Further side effects of opioid

receptor agonists comprise respiratory depression, constipation, and abuse.

Morfin yang diberikan secara intratekal efektif pada pasien dengan

DO karena lesi pada medulla spinalis, tapi ini dapat menyebabkan

efek samping, seperti mual dan gatal. Efek samping lainnya dari

agonis reseptor opioid meliputi depresi dan konstipasi.

Attempts have been made to reduce these side effects by increasing selectivity toward one of the

different opioid receptor types. At least three different opioid receptors—ì, ä, and ê—bind

stereospecifically with morphine and have been shown to interfere with voiding mechanisms.

Theoretically, selective receptor actions, or modifications of effects mediated by specific opioid

receptors, may have useful therapeutic effects for micturition control. Tramadol is a well-known

analgesic drug. By itself, it is a weak mu-receptor agonist, but it is metabolized to several

different compounds, some of them almost as effective as morphine at the mu-receptor.

However, the drug also inhibits serotonin (5-HT) and noradrenaline reuptake (Raffa and

Friderichs, 1996). This profile is of particular interest, since both mu-receptor agonism and

amine reuptake inhibition may be useful principles for treatment of DO/OAB.

Percobaan2 sudah pernah dibuat untuk mengurangi efek-efek

samping tersebut dengan meningkatkan selektifitas pada satu dari

beberapa tipe opioid reseptor. Setidaknya tiga reseptor opioid

berbeda (i, a, dan e) mengikat secara sterospesifik dengan morfin

dan telah dipertunjukan untuk menghalangi mekanisme berkemih.

Secara teori, tindakan pemilihan reseptor, atau modifikasi efek efef

terkait oleh reseptor opioid tertentu, mungkin memiliki efek2

terapeutik yang berguna bagi kontrol mikturisi. Tramadol adalah

sebuah obat analgesic yang terkenal. Bila sendiri, tramadol adalah

sebuah agonis reseptor mu yang lemah, namun tramadol

dimetabolisme dengan beberapa senyawa berbeda, beberapa dari

senyawa tersebut hamper sama efektifnya dengan morfin pada

reseptor-mu.

When tramadol is given to a normal, awake rat, the most conspicuous changes in the

cystometrogram are increases in threshold pressure and bladder capacity. Naloxone can more

or less completely inhibit these effects.

Saat tramadol diberikan kepada tikus normal yang sadar,

perbedaan2 yang mencolok pada sismetogram adalah meningktanya

tekanan pada ambang pintu dan kapasitan kandung kemih.

Nalokson dapat lebih atau kurang dalam benar benar menghambat

efek-efek ini.

However, there are differences between the effects of tramadol and morphine. Morphine has a

very narrow range between the doses causing inhibition of micturition and those increasing

bladder capacity and evoking urinary retention. Tramadol has effects over a much wider range

of doses, which means that it could be therapeutically more useful for micturition control. It

may be speculated that the difference is dependent on the simultaneous influence of the 5-HT

and noradrenaline uptake inhibition. In rats, tramadol abolished experimentally induced DO

caused by cerebral infarction. Tramadol also inhibited DO induced by apomorphine in rats - a

model of bladder dysfunction in Parkinson’s disease. Whether or not tramadol may have a

clinically useful effect on DO/OAB remains to be studied in randomized controlled clinical

trials (RCTs).

Namun, ada bebera[a perbedaan pada efek-efek dari tramadol dan

morfin. Morfin memiliki sebuah jarak yang sempit diantara dosis

yang menyebabkan hambatan pada mikturisi dan peningkatan

kapasitas kandung kemih dan penimbulan retensi urin. Tramadol

memiliki efek2 pada dosis yang jauh lebih luas, yang berarti bahwa

tramadol dapat secara terapi lebih berguna untuk kontrol mikturisi.

Ini bisa dispekulasikan bahwa perbedaan adalah bergantung pada

pengaruh berkelanjutan dari 5-HT dan noradrenaline yang

menyerah penghambatan.

Safarinejad and Hosseini (2006) evaluated in a doubleblind, placebo-controlled, randomized

study the efficacy and safety of tramadol in patients with idiopathic DO. A total of 76 patients

18 years or older were given 100 mg tramadol sustained release every 12 hours for 12 weeks.

Clinical evaluation was performed at baseline and every 2 weeks during treatment. Tramadol

significantly reduced the number of incontinence periods and induced significant improvements

in urodynamic parameters. The main adverse event was nausea. It was concluded that in

patients with nonneurogenic DO, tramadol provided beneficial clinical and urodynamic effects.

Even if tramadol may not be the best suitable drug for treatment of LUTS/OAB, the study

proofs the principle of modulating micturition via the mu-receptor.

Serotonin (5-HT) Mechanisms

Lumbosacral autonomic, as well as somatic, motor nuclei (Onuf ’s nuclei) receive a dense

serotonergic input from the raphe nuclei, and multiple 5-HT receptors have been found at sites

where afferent and efferent impulses from and to the LUT are processed. The main receptors

shown to be implicated in the control of micturition are the 5-HT1A, 5-HT2, and 5-HT7

receptors. There is some evidence in the rats for serotonergic facilitation of voiding; however,

the descending pathway is essentially an inhibitory circuit, with 5-HT as a key neurotransmitter.

It has been speculated that selective serotonin reuptake inhibitors (SSRIs) may be useful for

treatment of DO/OAB. On the other hand, there are reports suggesting that the SSRIs in patients

without incontinence actually can cause incontinence, particularly in the elderly, and one of the

drugs (sertraline) seemed to be more prone to produce urinary incontinence than the others.

Patients exposed to serotonin uptake inhibitors had an increased risk (15 out of 1000 patients)

for developing urinary incontinence.

Mekanisme Serotonin (5-HT)

Otonomik lumbosakral, sama dengan somatic dan inti Onuf

menerima masukan serotonergik padat dari inti raphe, dan

reseptor2 yang terdiri dari 5-HT telah ditemukan pada tempat2

dimana impuls aferen dan eferen dari dan menuju ke LUT diproses.

Reseptor2 utama yang terlihat terlibat di dalam kontrol mikturisi

adalah reseptor-reseptor 5-HT1A, 5-HT2 dan 5-HT-7 . Ada beberapa

bukti pada tikus mengenai pemfasilitasan serotonergik pada

berkemih, namun, jalur menurun sangat penting sebagai sirkuit

penghambat, dengan 5-HT sebagai kunci dari neurotransmitter.

Telah dispekulasi bahwa SSRIs mungkin dapat berguna untuk

pengobatan DO/OAB. Di sisi lain, ada beberapa laporan

menyarankan bahwa SSRIs pada pasien tanpa inkontinensia

sebenarnya dapat menyebabkan inkonintensia, khususnya pada

lanjut usia, dan satu dari beberapa obat (sertraline) nampaknya

lebih cenderung untuk memproduksi inkonintensia disbanding yang

lainnya.

So far, there are no RCTs demonstrating the value of SSRIs in the treatment of DO/OAB.

Duloxetine is a combined noradrenaline and serotonin reuptake inhibitor, which has been shown

to significantly increase sphincteric muscle activity during the filling/storage phase of

micturition in the cat acetic acid model of irritated bladder function.

Bladder capacity was also increased in this model, both effects mediated centrally through both

motor efferent and sensory afferent modulation. The effects of duloxetine was studied in a

placebo-controlled study comprising women with OAB and was, compared with placebo,

shown to cause significant improvements or decreases in voiding and incontinence episodes, for

increases in the daytime voiding intervals, and for improvements in quality-of-life (I-QoL)

scores. Urodynamic studies showed no significant increases in maximum cystometric capacity

or in the volume threshold for DO.

GABA Mechanisms

Both in the brain and the spinal cord, GABA has been identified as a main inhibitory

transmitter. GABA functions appear to be triggered by binding of GABA to its inotropic

receptors, GABAA and GABAC, which are ligand-gated chloride channels, and its

metabotropic receptor, GABAB. Since blockade of GABAA and GABAB receptors in the

spinal cord and brain stimulated rat micturition, an endogenous activation of GABAA+B

receptors may be responsible for continuous inhibition of the micturition reflex within the CNS.

In the spinal cord, GABAA receptors are more numerous than GABAB receptors, except for the

dorsal horn where GABAB receptors predominate.

Mekanisme GABA

Baik di dalam otak maupun medulla spinalis, GABA telah

diidentifikasi sebagai transmiter penghambat utama. Fungsi-fungsi

GABA tampaknya dipicu oleh pengikatan GABA kepada reseptor-

reseptor inotropiknya, GABAA dan GABAC, yang adalah saluran2

ligand-gated klorida, dan reseptor metabotropiknya, GABAB.

Setelah pemblokiran reseptor GABAA dan GABAB di dalam medulla

spinalis dan mikturisi perangsangan otak tikus, sebuah pengaktifan

endogen dari reseptor2 GABAA+B mungkin bertanggung jawab atas

penghambatan berkelanjutan dari refleks mikturisi di dalam CNS.

Di dalam medula spinalis, reseptor2 GABAA lebih banyak daripada

reseptor2 GABAB, kecuali untuk tanduk dorsal dimana reseptor2

GABAB menguasai.

Experiments using conscious and anesthetized rats demonstrated that exogenous GABA,

muscimol (GABAA receptor agonist), and baclofen (GABAB receptor agonist) given

intravenously, intrathecally, or intracerebroventricularly inhibit micturition. Baclofen given

intrathecally attenuated oxyhemoglobin-induced DO, suggesting that the inhibitory actions of

GABAB receptor agonists in the spinal cord may be useful for controlling micturition disorders

caused by C-fiber activation in the urothelium and/or suburothelium.

Eksperimen2 menggunakan tikus sadar dan dibius menunjukan

bahwa GABA eksogen, muscimol (agonis reseptor GABAA) dan

baclofen (agonis reseptor GABAB) diberikan melalui urat nadi,

secara intratekal atau secara intracerebroventrikular menghambat

mikturisi. Baclofen diberikan secara intratekal melemahkan

oksihemoglobin-termasuk DO, menunjukan bahwa tindakan2

penghambatan dari agonis reseptor GABAB di dalam medulla

spinalis mungkin bisa berguna untuk mengontrol gangguan

mikturisi yang disebabkan oleh pengaktifan C-fiber di dalam

urotelium dan atau suburotelium.

Stimulation of the PMC results in an immediate relaxation of the external striated sphincter and

a contraction of the detrusor muscle of the bladder demonstrated in cats a direct pathway from

the PMC to the dorsal gray commissure of the sacral cord (Blok et al, 1997). It was suggested

that the pathway produced relaxation of the external striated sphincter during micturition via

inhibitory modulation by GABA neurons of the motoneurons in the sphincter of Onuf. In rats,

intrathecal baclofen and muscimol ultimately produced dribbling urinary incontinence).

Stimulasi dari PMC menghasilkan sebuah relaksasi segera dari

sfingter lurik eksternal dan sebuah kontraksi dari otot detrusor dari

kandung kemih didemonstrasikan pada kucing melalui sebuah jalur

langsung dari PMC ke dorsal komisura abu-abus dari sacral cord.

Ini diperkirakan bahwa jalur tersebut memproduksi relaksasi dari

sfingter lurik eksternal selama mikturisi melalui modulasi

penghambatan oleh saraf-saraf GABA pada motoneuron di dalam

sfingter daripada Onuf. Pada tikus, baklofen intratekal dan

muskimol akhirnya memproduksi inkontinensa urin.

Thus, normal relaxation of the striated urethral sphincter is probably mediated via GABAA

receptors, GABAB receptors having a minor influence on motoneuron excitability. Gabapentin

was originally designed as an anticonvulsant GABA mimetic capable of crossing the blood–

brain barrier. The effects of gabapentin, however, do not appear to be mediated through

interaction with GABA receptors, and its mechanism of action remains controversial, even if it

has been suggested that it acts by binding to a subunit of the á2ä unit of voltage-dependent

calcium channels. Gabapentin is also widely used not only for seizures and neuropathic pain but

also for many other indications, such as anxiety and sleep disorders, because of its apparent lack

of toxicity.

Jadi, normal relaksasi pada sfinngter uretra lurik mungkin

termediasi melalui resptor2 GABAA, reseptor2 GABAB yang

memiliki sebuah pengaruh minor pada motoneuron yang dapat

dirangsang. Gabapentin yang semula dibentuk sebagai

antikonvulsan dari GABA mimetic dapat melewati penahan darah ke

otak. Namun, efek-efek dari gabapentin, tidak muncul untuk

dimediasi melalui interaksi dengan reseptor2 GABA dan

mekanismenya dari tindakan yang tetap controversial, bahkan jika

sudah dianjurkan bahwa ini bertindak dengan mengikat pada

subunit dari a2a unit dari saluran2 kalsium yang bergantung pada

tegangan. Gabapentin juga secara luas digunakan tidak hanya

untuk penegangan dan nyeri neuropatik tapi juga untuk indikasi2

lainnya, seperti kegelisahan dan gangguan tidur, karena rendahnya

toksisitas.

In a pilot study, Carbone et al (2003) reported on the effect of gabapentin on neurogenic DO.

These investigators found a positive effect on symptoms and significant improvement in

urodynamic parameters after treatment with gabapentin, and suggested that the effects of the

drug should be explored in further controlled studies in both neurogenic and nonneurogenic DO.

Kim et al (2004) studied the effects of gabapentin in patients with OAB and nocturia not

responding to antimuscarinics. They found that 14 out of 31 patients improved with oral

gabapentin. The drug was generally well tolerated, and the authors suggested that it can be

considered in selective patients when conventional modalities have failed. It is possible that

gabapentin and other á2ä ligands (eg, pregabalin and analogs) will offer new therapeutic

alternatives.

Noradrenaline Mechanisms

Noradrenergic neurons in the brainstem project to the sympathetic, parasympathetic, and

somatic nuclei in the lumbosacral spinal. Bladder activation through these bulbospinal

noradrenergic pathways may involve excitatory á1-ARs, which can be blocked by á1-AR

antagonists. In rats undergoing continuous cystometry, doxazosin, given intrathecally,

decreased micturition pressure, both in normal rats and in animals with

postobstruction bladder hypertrophy. The effect was much more pronounced in the animals with

hypertrophied OABs.

Mekanisme Noradrenalin

Saraf2 noradregenik di dalam batang otak memproyeksikan pada

simpatetis, parasimpatetis dan inti somatic di dalam spinal

lumbosakral. Pengaktifan kandung kemih melalui jalur2

bulbospinal noradregenik mungkin mencakup rangsang al-ARs,

yang dapat ditahan oleh antagonis al-AR. Pada tikus yang sedang

menjalani sistometri terus menerus, doksasosin diberikan secara

intratekal dan ini menurunkan tekanan mikurisi baik pada tikus

normal maupun pada hewan dengan hipertrofi postobstruktif

kandung kemih. Efeknya jauh lebih jelas pada hewan dengan

hipertrofi OAB.

Doxazosin given intrathecally, but not intra-arterially, to spontaneously hypertensive rats

exhibiting bladder overactivity, normalized bladder activity. It was suggested that doxazosin has

a site of action at the level of the spinal cord and ganglia. A central site of action for á1-AR

antagonists has been discussed as an explanation for the beneficial effects of these drugs in

LUTS (especially storage symptoms) associated with benign prostatic hyperplasia (BPH)

Dopamine Mechanisms

Patients with Parkinson’s disease may have neurogenic DO, possibly as a consequence of

nigrostriatal dopamine depletion and failure to activate inhibitory D1 receptors (Andersson,

2004). However, other dopaminergic systems may activate D2 receptors, facilitating the

micturition reflex. Apomorphine, which activates both D1 and D2 receptors, induced bladder

overactivity in anesthetized rats via stimulation of central dopaminergic receptors.

Mekanisme Dopamin

Pasien dengan penyakit Parkinson mungkin memiliki DO

neurogenik, barangkali sebagai konsekuen dari penipisan

nigrostriatal dopamine dan kegagalan untuk mengaktifkan

penghalang reseptor D1 (Andersson, 2004). Namun, sistem2

dopaminergik lainnya mungkin mengaktifkan reseptor-reseptor D2

yang memfasilitasi refleks mikturisi. Apomorfin, yang mengaktifkan

baik reseptor-reseptor D1 maupun D2, menginduksi over aktifitas

pada tikus yang dibius melalui stimulasi reseptor2 dopaminergik

pusat.

The effects were abolished by infracollicular transection of the brain and by prior intraperitoneal

administration of the centrally acting dopamine receptor blocker, spiroperidol. It has been

shown that the DO induced by apomorphine in anesthetized rats resulted from synchronous

stimulation of the micturition centers in the brainstem and spinal cord, and that the response was

elicited by stimulation of both dopamine D1 and D2 receptors. Blockade of central dopamine

receptors may be expected to influence voiding; however, the therapeutic potential of drugs

having this action has not been established.

NK-1 Receptor Mechanisms

The main endogenous tachykinins, substance P, neurokinin A (NKA), and neurokinin B (NKB),

and their preferred receptors, NK1, NK2, and NK3, respectively, have been demonstrated in

various CNS regions, including those involved in micturition control.

Mekanisme Reseptor NK-1

Tachykinin endogen utama, zat P, neurokinin A(NKA) dan

neurokinin B (NKB) dan reseptor2 yang dipilihnya, NK1, NK2, NK3,

secara berurutan telan didemonstrasikan dalam berbagai wilayah

CNS, termasuk yang tercakup dalam kontrol mikturisi.

Aprepitant, an NK-1 receptor antagonist used for treatment of chemotherapy-induced nausea

and vomiting, significantly improved symptoms of OAB in postmenopausal women with a

history of urgency incontinence or mixed incontinence, as shown in a welldesigned pilot RCT.

Aprepitant was generally well tolerated and the incidence of side effects, including dry mouth,

was low. Another NK-1 receptor antagonist, serlopitant, significantly decreased daily

micturitions but did not offer advantages in efficacy compared with tolterodine. The results of

these studies suggest that NK-1 receptor antagonism holds promise as a potential treatment

approach for OAB, but so far, the drugs available have not been very effective.

Aprepitan, sebuah antagonis reseptor NK1 digunakan untuk

perawatan mual dan muntah kemoterapi terinduksi, secara

signifikan meningkatkan gejala2 OAB pada wanita pascamenopause

dengan pengalaman urgensi inkontinensa atau inkontinensa

campuran Aprepitant pada dasarnya ditoleransi dengan baik dan

efek sampingnya rendah, seperti mulut kering. Antagonis reseptor

NK 1 lainnya, serlopitan, secara signifikan menurunkan mikturisi

sehari-hari tapi tidak memberikan keuntungan2 pada kemanjuran

disbanding degan tolterodine. Hasil dari studi ini menyarankan

bahwa antagonis reseptor NK1 menjanjikan sebagai pendekatan

pengobatan yang potensial untuk OAB, namun sejauh ini, obat yang

ada belum terlalu efektif.

PERIPHERAL TARGETS

There are many possible peripheral targets for pharmacologic control of bladder function.

Although many effective drugs are available targeting these systems, most of them are less

useful in the clinical situation due to the lack of selectivity for LUT, which may result in

intolerable side effects.

Target-target Periferal

Ada banyak target2 periferal untuk pengontrolan farmalogis dari

fungsi kandung kemih. Meskipun banyak obat-obat efektif yang

menyasar sistem2 ini, sebagia besar dari obat2 tersebut kurang

berguna dalam situasi klinis karena kurangnya selektifitas untuk

LUT, yang bisa mengakibatkan efek samping yang tidak dapat

ditoleransi

_ Muscarinic Receptors

Muscarinic receptors comprise five subtypes, M1–M5, encoded by five distinct genes, and in

both animal and human bladders, the mRNAs for all muscarinic receptor subtypes have been

demonstrated, with a predominance of mRNAs encoding M2 and M3 receptors. These receptors

are also functionally coupled to G proteins, but the signal transduction systems vary.

Reseptor-reseptor Muskarinik

Reseptor2 muskarinik meliputi lima subtype, M1-M5, dikodekan

oleh lima gen yang berbeda dan di dalam kandung kemih manusia

dan hewan, mRNA untuk seluruh subtipe reseptor muskarinik telah

didemonstrasikan, dengan sebuah keunggulan dari mRNAs yang

mengkodekan reseptor M2 dan M3. Reseptor2 ini juga secara

fungsional dipasangkan dengan protein G, namun sistem2

transduksi sinyalnya bermacam macam.

Detrusor smooth muscle contains muscarinic receptors mainly of the M2 and M3 subtypes. The

M3 receptors in the human bladder are the most important for detrusor contraction. In the human

detrusor, Schneider et al (2004) confirmed that the muscarinic receptor subtype mediating

carbachol-induced contraction was the M3 receptor, and they also demonstrated that the L-type

calcium channel blocker, nifedipine, almost completely inhibited carbachol-induced detrusor

contraction, whereas an inhibitor of store-operated Ca2+ channels caused little inhibition.

Otot lurik detrusor mengandung reseptor2 muskarinik utama dari

subtipe M2 dan M3. Reseptor2 M3 pada kandung kemih manusia

sangat penting untuk kontraksi detrusor. Dalam detrusor manusia,

subtype reseptor muskarinik yang memediasi kontraksi karbakol

yang terinduksi adalah reseptor M3.

The Rho-kinase inhibitor, Y-27632, produced a concentration-dependent attenuation of the

carbacholinduced contractile responses. Schneider et al (2004) concluded that carbachol-induced

contraction of human detrusor is mediated via M3 receptors, and furthermore, largely depends on

transmembrane Ca2+-flux through nifedipine-sensitive calcium channels as well as activation of

the Rho-kinase pathway. These conclusions were supported by Takahashi et al (2004) who found

that in human detrusor muscle, carbachol induces contraction, not only by increasing [Ca2+] but

also by increasing the Ca2+ sensitivity of the contractile apparatus in a Rho-kinase and protein

kinase C-dependent manner.

It has been suggested that M2 receptors may oppose sympathetically mediated smooth muscle

relaxation, mediated by β-ARs. M2 receptor stimulation may also activate nonspecific cation

channels and inhibit KATP channels through activation of protein kinase C. However, the

functional role for the M2 receptors in the normal bladder has not been clarified, but in certain

disease states, M2 receptors may contribute to contraction of the bladder. Thus, in the denervated

rat bladder, M2 receptors, or a combination of M2 and M3 receptors mediate contractile

responses. Both types of receptor seemed to act in a facilitatory manner to mediate contraction.

In obstructed, hypertrophied rat bladders, there was an increase in total M2 receptor density but a

reduction in M3 receptor density. The functional significance of this change for voiding function

has not been established. Pontari et al (2004) analyzed bladder muscle specimens from patients

with neurogenic bladder dysfunction to determine whether the muscarinic receptor subtype

mediating contraction shifts from M3 to the M2 receptor subtype, as found in the denervated,

hypertrophied rat bladder. They concluded that although normal detrusor contractions are

mediated by the M3 receptor subtype, in patients with neurogenic bladder dysfunction,

contractions can be mediated by the M2 receptors.

Muscarinic receptors may also be located on the presynaptic nerve terminals and participate in

the regulation of transmitter release. The inhibitory prejunctional muscarinic receptors have been

classified as M2 in the rabbit and rat, and M4 in the guinea pig, rat, and human bladder.

Prejunctional facilitatory muscarinic receptors appear to be of the M1 subtype in the rat and

rabbit urinary bladder. Prejunctional muscarinic facilitation has also been detected in human

bladders. The muscarinic facilitatory mechanism seems to be upregulated in OABs from chronic

spinal cord–transected rats. The facilitation in these preparations is primarily mediated by M3

muscarinic receptors. Muscarinic receptors have also been demonstrated in the urothelium and in

the suburothelium but their functional importance has not been clarified. It has been suggested

that they may be involved in the release of an unknown inhibitory factor, or they may be directly

involved in afferent signaling, and thus a target for antimuscarinic agents, explaining part of the

efficacy of these drugs in DO/OAB.

Reseptor2 muskarinik mungkin juga bisa dilokasikan pada terminal2

sarah presinapsis dan berpartisipasi dalam perauran pada pelepasan

transmiter. Reseptor2 yang menghalangi muskarinik telah

diklasifikasikan sebagai M2 pada kelinci dan tikus, dan M4 pada

kandung kemih kelinci percobaan, tikus dan manusia. Reseptor2

muskarinik juga sudah didemonsrasikan pada urotelium dan di

dalam suburotelium tetapi fungsi pentingnya belum dapat

diklarifikasi. Telah disarankan bahwa reseptor2 mungkin ikut serta

dalam pelepasan sebuah factor penghambat atau mungkin secara

langsung terlibat dalam pensinyalan aferen dan sebuah target untuk

agen2 antimuskarinik, yang menjelaskan bagian dari kemanjuran

obat obat ini bagi DO/OAB

_ Antimuscarinics

In general, antimuscarinics can be divided into tertiary and quaternary amines. They differ with

regard to lipophilicity, molecular charge, and even molecular size, tertiary compounds generally

having higher lipophilicity and molecular charge than quaternary agents. Atropine, darifenacin,

fesoterodine (and its active metabolite 5-hydroxymethyl-tolterodine), oxybutynin, propiverine,

solifenacin, and tolterodine are tertiary amines.

Antimuskarinik

Secara umum, antimuskarinik dapat dibagi menjadi amina tersier

dan kuaterner. Mereka berbeda dalam lipofilisitasnya, muatan

molekul dan bahkan ukuran molekul, komponen2 tersier secara

umum memiliki lipofilisitas dan muatan yang lebih besar daripada

agen2 kuaterner. Artopine, darifenacin, fesoterodine, oxybutynin,

propiverine, solifenacin dan tolterodine adalah amina tersier.

They are generally well absorbed from the gastrointestinal tract and should theoretically be able

to pass into the CNS, dependent on their individual physicochemical properties. High

lipophilicity, small molecular size, and less charge will increase the possibilities to pass the

blood–brain barrier, but for some of the drugs, this counteracted by active transport out of the

CNS. Quaternary ammonium compounds, like propantheline and trospium, are not well

absorbed, pass into the CNS to a limited extent, and have a low incidence of CNS side effects.

They still produce well-known peripheral antimuscarinic side effects, such as accommodation

paralysis, constipation, tachycardia, and dryness of mouth.

Mereka secara umum mudah diserap dari bidang gastrointestinal

dan seharusnya secara teori dapat lolos ke CNS, tergantung dari

fisiokimia milik masing2 individu. Lipofisilitas yang tinggi, ukuran

molekul yang kecil dan sedikitnya muatan dapat meningkatkan

kemungkinan untuk lolos ke penghalang darah otak. Komponen2

kuartener ammonium seperti propatheline dan trospium tidak

mudah terserap, melalui CNS ke jangkauan yang terbatas dan

memiliki efek samping dari CNS yang kecil.

Many antimuscarinics are metabolized by the P450 enzyme system to active and/or inactive

metabolites (Guay, 2003). The most commonly involved P450 enzymes are CYP2D6 and

CYP3A4. The metabolic conversion creates a risk for drug–drug interactions, resulting in either

reduced (enzyme induction) or increased (enzyme inhibition, substrate competition) plasma

concentration/effect of the antimuscarinic and/or interacting drug. Antimuscarinics secreted by

the renal tubules (eg, trospium) may theoretically be able to interfere with the elimination of

other drugs using this mechanism. Antimuscarinics are still the most widely used treatment for

urgency and urgency incontinence. However, currently used drugs lack selectivity for the

bladder, and effects on other organ systems may result in side effects, which limit their

usefulness. For example, all antimuscarinic drugs are contraindicated in untreated narrow angle

glaucoma.

Theoretically, drugs with selectivity for the bladder could be obtained, if the subtype(s)

mediating bladder contraction, and those producing the main side effects of antimuscarinic

drugs, were different. Unfortunately, this does not seem to be the case. One way of avoiding

many of the antimuscarinic side effects is to administer the drugs intravesically. However, this is

practical only in a limited number of patients.

Secara teori, obat2 dengan selektifitas untuk kandung kemih dapat

diperoleh, jika subtipe kontraksi kandung kemih dan jika obat2

tersebut menghasilkan efek2 samping utama dari obat

antimuskarinik yang berbeda. Sayangnya, ini nampaknya tidak

menjadi kasus. Satu cara untuk menghindari banyaknya efek

samping dari antimuskarinik adalah dengan memberikan obat

secara intravesikal. Namun, ini hanya dapat dijalankan pada jumlah

pasien yang terbatas.

Clinical efficacy. The clinical relevance of efficacy of antimuscarinic drugs relative to placebo

has been questioned. However, large meta-analyses of studies performed with the currently most

widely used drugs clearly show that antimuscarinics are of significant clinical benefit.

Kemanjuran klinis. Relevansi klinis dari kemanjuran obat2

antimuskarinik relative terhadap placebo sudah dipertanyakan.

Namun, analisis meta yang besar terhadap studi-studi dijalankan

dengan obat yang dignakan secara luas saat ini, ini secara jelas

menunjukan bahwa antimuskarinik signifikan untuk keuntungan

klinis.

Adrenergic Receptors

A. Alpha-ARs

Most investigators agree that there is a low expression of á- ARs in the human detrusor. Malloy

et al (1998) found that two-thirds of the á-AR mRNA expressed was á1D, and one-third was á1A

(there was no á1B). It has been suggested that a change of subtype distribution may be produced

by outflow obstruction. Nomiya and Yamaguchi (2003) confirmed the low expression of á-AR

mRNA in normal human detrusor, and further demonstrated, in contrast to data from animal

experiments, that there was no upregulation of any of the adrenergic receptors with obstruction.

In addition, in functional experiments, they found a small response to phenylephrine at high drug

concentrations with no difference between normal and obstructed bladders. Thus, in the

obstructed human bladder, there seems to be no evidence for á-AR upregulation or change in

subtype, although this finding was challenged by Bouchelouche et al (2005), who found an

increased response to á1-AR stimulation in obstructed bladders. Whether or not this would mean

that the á1D-ARs in the detrusor muscle are responsible for DO or OAB is unclear.

Reseptor2 Adrenergik

a. Alpha-ARs

Sebagian besar peneliti setuju dengan adanya sebuah ekspresi

rendah dari a-ARs dalam detrusor manusia. Malloy (1998)

menemukan bahwa dua pertiga dari a-AR mRNA yang dinyatakan

adalah alD, dan satu pertiga adalah alA (tidak ada alB). Sudah

dianjurkan bahwa sebuah perubahan dari distribusi subtipe

mungkin bisa diproduksi oleh obstruksi pengaliran keluar. Nomiya

dan Yamaguchi (2003) mengkonfirmasi adanya ekpresi rendah dari

a-AR mRNA pada otot detrusor normal manusia, dan berkebalikan

dngan data dari eksperimen hewan bahwa tidak ada peningkatan

regulasi dari reseptor adrenergic apapun dengan halangan.

Sugaya et al (2002) investigated the effects of intrathecal tamsulosin (blocking á1A/D-ARs) and

naftopidil (blocking preferably on á1D-ARs) on isovolumetric bladder contractions in rats.

Intrathecal injection of tamsulosin or naftopidil transiently abolished these contractions. The

amplitude of contraction was decreased by naftopidil but not by tamsulosin. It was speculated

that in addition to the antagonistic action of these agents on the á1A-ARs of prostatic smooth

muscle, both agents (especially naftopidil) may also act on the lumbosacral cord (á1D-ARs).

This observation is of particular interest considering the findings that in the human spinal cord,

á1D-AR mRNA predominated overall. Ikemoto et al (2003) gave tamsulosin and naftopidil to 96

patients with BPH for 8 weeks in a crossover study. Although naftopidil monotherapy decreased

the I-PSS for storage symptoms, tamsulosin monotherapy decreased the I-PSS for voiding

symptoms. However, this difference (which was suggested to depend on differences in affinity

for á1-AR subtypes between the drugs) could not be reproduced in a randomized head-to-head

comparison between the drugs.

B. Beta-ARs

It has been known for a long time that isoprenaline, a non– subtype selective â-AR agonist, can

relax bladder smooth muscle. Even if the importance of â-ARs for human bladder function still

remains to be established, this does not exclude that they can be useful therapeutic targets. All

three subtypes of â-ARs (â1, â2, and â3) can be found in the detrusor muscle of most species,

including humans, and also in the human urothelium. However, the expression of â3-AR mRNA

and functional evidence indicate a predominant role for this receptor in both normal and

neurogenic bladders. The human detrusor also contains â2-ARs, and most probably both

receptors are involved in the physiological effects (relaxation) of noradrenaline in the bladder.

â3-AR agonists have a pronounced effect on spontaneous contractions of isolated detrusor

muscle (Biers et al, 2006), which may be the basis for their therapeutic effects in OAB/DO.

B. Beta-ARs

Sudah diketahui dari jaman dahulu bahwa isoprenalin, sebuah

nonsubtipe agonis a-AR selektif, dapat merilekskan otot lurik

kandung kemih. Bahkan jika pentingnya a-ARs dari fungsi kandung

kemih manusia masih tetap harus dibentuk, ini tidak mengecualikan

bahwa mereka dapat sangat berguna bagi target2 therapeutik.

Ketiga subtipe dari a-ARs (a1, a2 dan a3) dapat ditemukan di dalam

otot detrusor dari sebagian besar spesies, termasuk manusia dan

juga dalam urotelium manusia. NAmun, pengeluaran dari a3-AR

mRNA dan bukti fungsional menunjukan bahwa adanya sebuah

peran utama bagi resepor ini baik pada kandung kemih normal

maupun neurogenik .

It is generally accepted that â-AR-induced detrusor relaxation is mediated by activation of

adenylyl cyclase with the subsequent formation of cAMP. However, there is evidence suggesting

that in the bladder, â-AR agonists can mediate relaxation via K+ channels (particularly BKCa

channels), independent of cAMP.

Ini secara umum diterima bahwa relaksasi detrusor a-AR terinduksi

dimediasi oleh pengaktifan siklase adenilil dengan formasi cAMP.

Namun, ada bukti mengusulkan bahwa di dalam kandung kemih,

agonis a-AR dapat memediasi relaksasi melalui saluran K+

(khususnya saluran BKCa).

The in vivo effects of â3-AR agonists on bladder function have been studied in several animal

models. It has been shown that â3-AR agonists increase bladder capacity with no change in

micturition pressure and residual volume. For example, Hicks et al (2007) studied the effects of

the selective â3-AR agonist, GW427353, in the anesthetized dog and found that the drug evoked

an increase in bladder capacity under conditions of acid-evoked bladder hyperactivity, without

affecting voiding. â3-AR selective agonists are currently being evaluated as potential treatment

for OAB/DO in humans. One of these, mirabegron (YM187), was given to patients with OAB in

a controlled clinical trial. The primary efficacy analysis showed a statistically significant

reduction in mean micturition frequency, compared with placebo, and with respect to secondary

variables, mirabegron was significantly superior to placebo concerning mean volume voided per

micturition, mean number of incontinence episodes, nocturia episodes, urgency incontinence

episodes, and urgency episodes per 24 hours.

Efek2 vivo dari agonis a3-AR pada fungsi kandung kemih sudah

dipelajari pada beberapa model hewan. Sudah ditunjukan bahwa

agonis a3-AR meningkatkan kapasitas kandung kemih tanpa

perubahan pada tekanan mikturisi dan volume residual.

The drug was well tolerated, and the most commonly reported side effects were headache and

gastrointestinal adverse effects. The results of this proof of concept study showed that the

principle of â3-AR agonism may be useful for treatment of patients with OAB/DO.

Ion Channels

A. Calcium Channels

There is no doubt that an increase in [Ca2+]i is a key process required for the activation of

contraction in the detrusor myocyte. However, it is still uncertain whether this increase is due to

influx from the extracellular space and/or release from intracellular stores. Furthermore, the

importance of each mechanism in different species, and also with respect to the particular

transmitter studied, has not been firmly established.

Theoretically, inhibition of calcium influx by means of calcium antagonists would be an

attractive way of inhibiting DO/OAB. However, there have been few clinical studies of the

effects of calcium antagonists in patients with DO. Naglie et al (2002) evaluated the efficacy of

nimodipine for geriatric urgency incontinence in a randomized, double-blind, placebo-controlled

crossover trial, and concluded that this treatment was unsuccessful.

Thus, available information does not suggest that systemic therapy with calcium antagonists is an

effective way to treat DO/OAB

B. Potassium Channels

Potassium channels represent another mechanism to modulate the excitability of the smooth

muscle cells. There are several different types of K+-channels and at least two subtypes have

been found in the human detrusor: ATP-sensitive K+-channels (KATP) and large conductance

calciumactivated K+-channels (BKCa). Studies on isolated human detrusor muscle and on

bladder tissue from several animal species have demonstrated that K+-channel openers reduce

spontaneous contractions as well as contractions induced by carbachol and electrical stimulate.

However, the lack of selectivity of presently available K+-channel blockers for the bladder

versus the vasculature has thus far limited the use of these drugs. The first generation of K-

channel openers, such as cromakalim and pinacidil, were found to be more potent as inhibitors of

vascular smooth muscle than of detrusor muscle. No effects of cromakalim or pinacidil on the

bladder were found in studies on patients with spinal cord lesions or detrusor instability

secondary to outflow obstruction. Also with more recently developed KATP-channel openers,

claimed to have selectivity toward the bladder, negative results have been obtained in an RTC on

patients with idiopathic DO.

Thus, at present there is no clinical evidence to suggest that K+-channel openers represent a

treatment alternative for DO/OAB.

Vanilloid Receptors

The TRP channel superfamily has been demonstrated to be involved in nociception and

mechanosensory transduction in various organ systems, and studies of the LUT have indicated

that several TRP channels, including TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, are

expressed in the bladder, and may act as sensors of stretch and/or chemical irritation.

However, the roles of these individual receptors for normal LUT function and in

LUTS/DO/OAB have not been established. TRPV1 is the channel best investigated. By means of

CAP, a subpopulation of primary afferent neurons innervating the bladder and urethra, the

“CAP-sensitive nerves,” has been identified. It is believed that CAP exerts its effects by acting

on specific “vanilloid” receptors (TPVR1), on these nerves. CAP exerts a biphasic effect: initial

excitation is followed by a long-lasting blockade, which renders sensitive primary afferents (C-

fibers) resistant to activation by natural stimuli. In sufficiently high concentrations, CAP is

believed to cause “desensitization” initially by releasing and emptying the stores of

neuropeptides, and then by blocking further release. Resiniferatoxin (RTX) is an analogue of

CAP, approximately 1000 times more potent for desensitization than CAP, but only a few

hundred times more potent for excitation. Possibly, both CAP and RTX can have effects on Aä-

fibers. It is also possible that CAP at high concentrations (mM) has additional nonspecific

effects.

The rationale for intravesical instillations of vanilloids is based on the involvement of C-fibers in

the pathophysiology of conditions such as bladder hypersensitivity and neurogenic DO. In the

healthy human bladder, C-fibers carry the response to noxious stimuli, but they are not

implicated in the normal voiding reflex. After spinal cord injury, major neuroplasticity appears

within bladder afferents in several mammalian species, including man. C-fiber bladder afferents

proliferate within the suburothelium and become sensitive to bladder distention. Those changes

lead to the emergence of a new C-fiber–mediated voiding reflex, which is strongly involved in

spinal neurogenic DO. Improvement of this condition by defunctionalization of C-fiber bladder

afferents with intravesical vanilloids has been widely demonstrated in humans and animals.

Despite available information (including data from randomized controlled trials) suggests that

both capsaicin and RTX may have useful effects in the treatment of neurogenic DO, and that

they may have beneficial effects also in nonneurogenic DO in selected cases refractory to

antimuscarinic treatment, they are no longer widely used.

Botulinum Toxin-Sensitive Mechanisms

Seven immunologically distinct antigenic subtypes of botulinum toxin (BTX) have been

identified: A, B, C1, D, E, F, and G. Types A and B are in clinical use in urology, but most

studies have been performed with BTX A type. BTX is believed to act mainly by inhibiting

acetylcholine release from cholinergic nerve terminals interacting with the protein complex

necessary for docking acetylcholine vesicles, but the mechanism of action may be more

complex. Apostolidis et al (2006) proposed that a primary peripheral effect of BTX is “the

inhibition of release of acetylcholine, ATP, substance P, and reduction in the axonal expression

of the CAP and purinergic receptors. This may be followed by central desensitization through a

decrease in central uptake of substance P and neurotrophic factors.”

The BTX-produced chemical denervation is a reversible process and axons are regenerated in

about 3–6 months. Given in adequate amounts BTX inhibits release not only of acetylcholine but

also of several other transmitters. The BTX molecule cannot cross the blood–brain barrier and

therefore has no CNS effects.

BTX injected into the external urethral sphincter was initially used to treat spinal cord injured

patients with detrusor-external sphincter dyssynergia. The use of BTX has increased rapidly, and

successful treatment of neurogenic DO by intravesical BTX injections has now been reported by

several groups. BTX may also be an alternative to surgery in children with intractable OAB.

However, toxin injections may also be effective in refractory idiopathic DO. Intravesical

injection of BTX resulted in improvement in medication refractory OAB symptoms. However,

the risk of increased postvoid residual and symptomatic urinary retention was significant.

Several questions remain concerning the optimal administration of BTX-A for the patient with

OAB. Adverse effects, for example, generalized muscle weakness, have been reported, but seem

to be rare.

SUMMARY AND FUTURE ASPECTS

To effectively control bladder activity, and to treat urinary incontinence, identification of suitable

targets for pharmacological intervention is necessary. Such targets may be found within or

outside the CNS. LUTSs, including OAB/DO, are all conditions that can have major effects on

quality of life and social functioning. Antimuscarinic drugs are still first-line treatment—they

have often good initial response rates, but adverse effects and decreasing efficacy cause long-

term compliance problems. A new target is TRP channel superfamily, which has been

demonstrated to be involved in nociception and mechanosensory transduction in various organ

systems. Studies of the LUT have indicated that several TRP channels, including TRPV1,

TRPV2, TRPV4, TRPM8, and TRPA1, are expressed in the bladder and may act as sensors of

stretch and/or chemical irritation. However, the roles of these individual receptors for normal

LUT function and in LUTS/DO/ OAB have not been established. There may be several other

new possibilities to treat LUTS/OAB/DO. For example, â3- AR agonists (eg, mirabegron) are in

phase 3 trials after promising initial results, and the principle of â3-AR agonism seems clinically

useful. There is currently increasing interest in drugs modulating the micturition reflex by a

central action. However, central nervous mechanisms have so far not been preferred targets for

drugs aimed to treat OAB, since selective actions may be difficult to obtain. Drugs with a central

mode of action such as NK-1 receptor antagonists, tramadol, and gabapentin have positive proof

of concept documented in RCTs. Even if neither of these drugs can be recommended for general

use in the treatment of LUTS/OAB/DO, they illustrate that agents with a target in the CNS can

be therapeutically useful. Thus, even if antimuscarinic drugs remain the first-line treatment of the

OAB, and their favorable efficacy/tolerability–safety ratio has been confirmed, new drugs are

needed.

Daftar Pustaka

McAninch JW, Lue TF. Smith & tanagho’s general urologi. Edisi 18. New York: The Mc Graw

Hill Companies; 2013. p. 429-38