LATIHAN DI RUMAH (KM) Buku pegangan : Siswandono; Bambang Soekardjo.
Catatan: Hanya untuk latihan di rumah (jika ditemukan dlm ruangan mendapat nilai mak. D) Obat yang dibuat sintetik mahal, sehingga diisolasi dari bahan alam adalah…. 1. Kuinin Kuinin 2. Insuli Insulin n 3. Atrop Atropin in 4. Diuret Diuretika ika 2. Kimia medisinal biasa disebut dgn nama lain yaitu .... 1. Kimia Kimia !armasi !armasi 2. !armakoki !armakokimia mia 3. Kimia Kimia terapi terapi 4. !armakote !armakoterapi rapi 3. Obat dgn struktur kimia berbeda tetapi akti"itas akti"itas biologisnya sama adalah .... 1. #ter 2. $alotan 3. %iopenta %iopenta 4. &iklopropan 4. &i'at kimia 'isika obat berperan penting untuk men(elaskan akti"itas akti"itas biologis obat, )A). )A). *engangkutan obat untuk men+apai reseptor ditentukan oleh si'at kimia 'isikanya. . %u(uan %u(uan akhir dari dari ran+angan obat adalah..... adalah..... 1. #'ek #'ek samping ringan 2. )eker(a selekti' 3. -yaman 4. #konomis . /angkah penting harus harus diketahui dalam dalam pengembangan obat obat adalah….1.0en+ari adalah….1.0en+ari senyaa penuntun 2. *engembangan senyaa senyaa penuntun 3. *rosedur pengembangan pengembangan 4. an+angan obat rasional . Dalam u(i klinik 'ase III, III, dimana hasil yang diinginkan adalah…A. adalah…A. Keamanan ). %oksisitas . &tabilitas D. #'ikasi #. #'ikasi multi5+enter. 6. Obat yang aal digunakan untuk memperpan(ang ker(a penisilin, tetapi sekarang sekarang digunakan sebagai urikosurik adalah .... A. Allopurinol ). eserpin . *robenesid D. *ergilin #. Ipronia7id Ipronia7 id 8. *ra5obat Imipramin untuk men(adi metabolit akti', maka harus melalui proses metabolisme se+ara.. A. Kon(ugasi ). eduksi . -5Asetilasi -5Asetilasi D. -5Demetilasi -5Demetilasi #. Dehidratasi. Dehidratasi. 19. ontoh senyaa kimia akti' yangditemukan se+ara tidak senga(a adalah ...1. Antikoagulan5 Antikoagulan5 kumarol 2. Antipiretik5Asetanilid Antipiretik5Asetanilid 3. Adrenergik5 #'edrin 4. Diuretik5Klorotia7id Diuretik5Klorotia7id 11. Asetomino'en diisolasi dan diidenti'ikasi diidenti'ikasi dari metabolit.... metabolit.... 1. !enasetin !enasetin 2. Ars'enamin 3. Asetanilid 4. Asetosal 12. Obat yang dibuat untuk sukar diabsorpsi dalam saluran +erna adalah.... 1. *talilsul'atia7ol *talilsul'atia7ol 2. *talissul'amera7ol *talissul'amera7ol 3. &uksinilsul'atia7ol &uksinilsul'atia7ol 4. *talilsul'adia7ol *talilsul'adia7ol 13. Obsorpsi obat melalui paru5paru tergantung pada ...1.Kadar obat dalam al"eoli 2. Koe'isien partisi 3. Ke+epatan aliran darah paru 4. :kuran partikel obat 14. !ase yang menentukan ter(adinya akti"itas biologis obat adalah 'ase... 1. !armakodinamika !armakodinamika 2. !armakokinetika !armakokinetika 3. !armasetika 4. )io'armasi. 1. $ampir semua obat mengalami proses kon(ugasi Asam glukuronat, )A) D5glukuronat dalam tubuh +ukup banyak 1. $ampir semua obat mengalami proses kon(ugasi Asam glukuronat, )A) D5glukuronat dalam dalam tubuh +ukup banyak A; 1. %u(uan metabolisme metabolisme obat se+ara umum adalah mengubah obat men(adi. . . . . 1.)ioinaktivasi 2. Detoksifikasi Detoksifikas i 3. Hydrofil . !li"inasi#ekskresi !li"inasi#ekskr esi 16. Anal$esik derivat %ara&a"inofenol y$ "en$ala"i "eta'olis"e "en(adi aseto"inofen adala).... *. Asetanilid Asetanilid 2. Asetosaldan Asetosaldan 3. +enasetin +enasetin . Hidroksilain. Hidroksilain. 18. ,en-r-nan kee%atan "eta'olis"e "eta'olis"e akan "enye'a'kan.... *. "enin$katkan intensitas o'at 2. "asa ker(a o'at di%er%an(an$ 3.ke"-n$kinan toksisitas ditin$katkan . /'at tidak efektif. 20. ,e""'erian dosis INH %ada oran$ 1e%an$ dan !ski"o )ar-s 'esar !4A4 Mereka ter"as-k asetilator la"'at 2*. 5onto) de%o %enyi"%anan yan$ akan "ele%askan o'at keairan dara) adala) ..... *.1arin$an le"ak 2. Hati 3. 6inal . /tot. 22. enya7a a$onis adala) senya7a senya7a yan$ da%at "enetralisir res%on 'iolo$is senya7a a$onis !4A4 Anti)ista"in 'eker(a den$an "e"'lokir te"%at aksi )ista"in endo$en.
B. URAIAN .
*. 1elaskan seara ske"atis -r-tan keadian dala" %roses %en$e"'an$an o'at seara rasional "-lai dari %en$enalan "asala sa"%ai %e"asaran dan %ro"osi8 2. 1elaskan seara ke"a %en$e"'an$an o'at 'ar- dan taa%&taa% -i klinik8 (* 3. 1elaskan lan$ka&lan$ka dala" ranan$an 0'at 8**&*2 . 1elaskan lan$ka&lan$ka dala" "enari senya7a %en-nt-n8 *9&*:. 9. 1elaskan 3 onto %en$e"'an$an senya7a %en-nt-n seara s-'tit-si -nt-k "enda%atkan senya7a yan$ le'i %oten s%esifik a"an dan efek sa"%in$ "ini"al8 (20) ;. 1elaskan -r-tan %rosed-r %en$e"'an$an o'at "en-r-t Aries8 22&29 <. 1elaskan "etode yan$ di$-nakan -nt-k "eranan$ o'at rasional 8 2;&2< =. 1elaskan onto o'at y$ dikete"-kan "elal-i ranan$an rasional 8 2< :. 1elaskan fase&fase -nt-k -nt-k "enent-kan teradinya aktivitas aktivitas 'iolo$is o'at 2:&30 *0. 1elaskan ke"-n$kinan yan$ teradi setela o'at 'e'as "as-k ke%eredaran dara 30 **. 1elaskan 'e'era%a f-n$si dari ikatan ko"%leks o'at&%rotein 8 ;. *2. 1elaskan kee%atan dan 'esarnya distri'-si o'at dala" t-'-8
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PENDAHULUAN Batasan kimia medisinal menurut Burger 189) adalah < Ilmu pengetahuan yang merupakan +abang dari ilmu kimia dan biologi, dan digunakan untuk memahami dan men(elaskan mekanisme ker(a obat. &ebagai dasar adalah men+oba menetapkan hubungan struktur kimia dan akti"itas biologis obat, serta menghubungkan perilaku biodinamik melalui si'at5si'at 'isik dan kereakti'an kimia senyaa obat. Kimia medisinal melibatkan isolasi, karakte karakteris risasi asi,, dan sintes sintesis is senya senyaa5s a5senya enyaa a yang yang diguna digunakan kan dalam dalam bidang bidang kedokte kedokteran ran,, untuk untuk men+egah dan mengobati penyakit serta memelihara kesehatan. Batasan kimia medisinal menurut IUPAC 184; adalah < Ilmu pengetahuan yang mempela(ari penemuan, pengembangan, identi'ikasi, dan interpretasi +ara ker(a senyaa biologis akti' obat; pada tingkat molekul. Kimia medisinal (uga melibatkan study, identi'ikasi, dan sintesis produk metabolisme obat dan senyaa yang berhubungan.
Batasan kimia medisinal menurut Taylor dan Kennewall 1861; adalah < &tudyk &tudykimi imiai ai senya senyaaa atau atau obat yang yang dapat dapat member memberika ikan n e'ek e'ek mengunt menguntungk ungkan an dalam dalam siste sistem m kehidupan, dan melibatkan study hubungan struktur kimia senyaa dengan akti"itas biologis serta mekanisme mekanisme +ara ker(a senyaa senyaa pada sistem sistem biologis, biologis, dalam usaha mendapatkan mendapatkan e'ek pengobatan yang maksimal dan memperke+il e'ek samping yang tidak menguntugkan. uang lingku! "idang kimia medisinal menurut Burger 1869; adalah < 1. Isol Isolas asii dan dan ident dentii'ikas ikasii seny senya aaa akt akti' dalam dalam tana tanama man n yang yang se+a se+ara ra empi empirrik telah elah digunakan untuk pengobatan. 2. &int &intes esiis str strukt uktur anal analog og dar dari bent bentuk uk dasa dasarr seny senya aaa yang yang mem mempuny punyai ai akt akti"it "itas pengobatan potensial. 3. 0en+ 0en+ari ari stru strukt ktur ur indu induk k baru baru deng dengan an +ar +araa sint sintes esia ia seny senya aaa organ organik ik,, deng dengan an ata ataupu upun n tanpa berhubunga dengan 7at akti' alamiah. 4. 0eng 0enghu hubu bung ngka kan n str struk uktu turr kim kimia ia obat obat deng dengan an +ara +ara ker( ker(an anya ya.. . 0engembangkan ran+angan obat. . 0eng 0engem emba bang ngka kan n hubu hubung ngan an struk struktu turr kimi kimiaa deng dengan an akti" akti"it itas as biol biolog ogis is mela melalu luii si'a si'att kimia 'isika dengan bantuan statistik.
Kimia medisinal Medicinal Chemistry; Chemistry; sering pula disebut dengan nama yang lain seperti kimia Pharmaceutical Chemistry;, Chemistry;, #armakokimia Farmacochemie, Farmacochemie, Pharmacochemistry;, Pharmacochemistry;, dan #armasi #armasi Pharmaceutical Chimie Therapeutique;. Therapeutique;. kimia tera!i Chimie $ubungan kimia medisinal dengan +abang ilmu lain dapat dilihat pada diagram berikut < Kimia Analisis Kimia Organik Kimia !isik )iokimia
Kimia medisinal
!armasetika )io'armasi
Kedokteran Klinik
!armakologi
)iologi 0ikrobiologi !isiologi
%oksikologi *atologi
)eberapa abad yang lalu, pada periode perkembangan bahan obat organik, telah bnayak perhatian diberikan untuk men+ari kemungkinan adanya hubungan antara struktur kimia, si'at5si'at kimia 'isika 'isika dan akti"itas biologis biologis senyaa senyaa akti' atau obat. *ada abad ke 18, bahan alamiah alamiah yang se+ara
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)erdasarkan sumbernya obat yang ada deasa ini digolongkan men(adi tiga yaitu < 1.Obat alamiah, obat yang terdapat di alam, yaitu pada tanaman, +ontoh < kuinin dan atropin, pada hean, +ontoh < minyak ikan dan hormon, serta mineral, +ontoh < belerang &; dan kalium bromida K)r;. 2.Obat semisintetik, obat hasil sintesis yang bahan dasarnya berasal dari obat yang terdapat di alam, +ontoh < mor'in men(adi kodein dan diosgenin men(adi progesteron. 3.Obat sintetik murni, obat yang bahan dasarnya tidak berkhasiat, setelah disintesis akan didapatkan senyaa dengan khasiat 'armakologis tertentu, +ontoh < obat5obat golongan analgetik5antipiretik, antihistamin dan diuretika. Obat yang berasal dari alam sudah banyak yang dibuat se+ara sintetik, seperti metilsalisilat, kam'er, mentol, dan asam amino. Ada pula beberapa senyaa alamiah yang digunakan sebagai obat, yang tidak dapat dibuat se+ara sintetik atau biaya produksinya terlalu mahal sehingga diproduksi dengan +ara isolasi dari sumber alam, +ontoh < glikosida (antung, kuinin, atropin, dan insulin.
Deasa ini diperkirakan lebih dari (uta senyaa kimia yang sudah diidenti'ikasi, dan (umlah tersebut tersebut bertambah bertambah terus dengan dengan 199.999 senyaa senyaa kimia baru baru setiap tahun. tahun. Dari (umlah (umlah diatas 3.999 3.999 senyaa senyaa telah telah digunaka digunakan n se+ara umum, umum, diantara diantaranya nya 4.999 4.999 sebagai sebagai obat 4.999 4.999 sebagai sebagai bahan tambahan makanan dan 1.99 sebagai sebag ai pestisida. Dari 22 obat pada da'tar obat esensial yang dikeluarkan oleh =$O 186;, sumber5sumber obat dapat dibagi sebagai berikut < 1. &intetis kimia 2. &emisintetik 3. 0ikroorganisme 4. ?aksin . &era . 0ineral . %umbuh5tumbuhan 6. $ean
46,8 >; 8, >; ,4 >; 4,3 >; 2 >; 8,1 >; 11,1 >; 6, >;
@olongan 1 sampai , yaitu sekitar 69 > obat, dipela(ari dalam bidang kimia medisinal, sedang sisanya 29 > 56; ditekankan pada bidang 'armakognosi. &etelah ilmu pengetahuan makin berkembang, didapatkan baha struktur kimia obat ternyata dapat men(elaskan si'at5si'at obat dan terlihat baha unit5unit steruktur atau gugus5gugus molekul obat berkaitan dengan akti"itas biologisnya. :ntuk men+ari hubungan antara struktur kimia dan akti"itas biologis dapat dilakukan terutama dengan mengaitkan gugus 'ungsional tertentu dengan respons biologis yang tertentu pula. $al ini kadang5kadang mengalami kegagalan karena terbukti baha senya senyaaa dengan dengan unit unit strukt struktur ur kimia kimia sama sama belum belum tentu tentu menun( menun(ukka ukkan n akti"i akti"itas tas biolog biologis is sama, sama, sebaliknya akti"itas biologis yang sama sering diperlihatkan oleh senyaa5senyaa dengan struktur kimia yang berbeda. ontoh senyaa dengan gugus gug us 'ungsional sama dan mempunyai akti"itas biologis sama < 1.%urunan 'enol, +ontoh < 'enol, kresol, eugenol, dan timol, mengandung gugus 'ungsi hidroksil 'enol dan berkhasiat sebagai antibakteri. :0:& 2.%urunan sul'onamida, +ontoh < sul'anilamid, sul'asetamid, sul'aguanidin, dan sul'ametoksasol, mengandung gugus 'ungsi sul'onamida dan berkhasiat sebagai antibakteri. :0:& ontoh senyaa dengan struktur kimia berbeda tetapi akti"itas biologisnya sama < 1.Obat anestesi sitemik, +ontoh < eter,siklopropan, halotan, dan tiopental. :0:&
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diuretik hidroklorotia7id;, antilepra dapson;, antimalaria sul'adoksin;, urikosurik probenesid; dan antidiabetes karbutamid;. :0:& %urunan senyaa dengan gugud 'ungsi sama dapat memberikan respons biologis yang sama oleh karena beker(a pada reseptor yang sama atau mempengaruhi proses biokimia yang sama pula. &ebagai +ontoh pada turunan turunan 'enol, 'enol, gugus 'ungsi hidroksi 'enol dapat menyebabkan menyebabkan koagulasi dan denaturasi protein sel bakteri, sedang pada turunan sul'onamida, gugus 'ungsi sul'onamida dapat beker(a se+ara penghambatan bersaing dengan asam p5aminoben7oat, suaru senyaa yang diperlukan untuk pembentukan asam dihidropteroat, yang sangat diperlukan untuk pertumbuhan bakteri. %urunan senyaa dengan struktur kimia yang berbeda dapat memberikan respons biologis yang sama oleh karena akti"itas turunan tersebut tidak tergantung pada sutuktur kimia yang spesi'ik, tetapi lebih tergantung pada si'at kimia 'isik, seperti kelarutan dan akti"itas termodinamika. $al ini ter(adi pada senyaa yang berstruktur tidak spesi'ik, seperti pada +ontoh obat anestesi sistemik.
:ntuk obat diuretik dapat menghasilkan respons 'armakologis yang sama karena masing5 masing masing turunan turunan mempengaruhi mempengaruhi proses biokimia interaksi dengan reseptor; reseptor; yang berbeda, berbeda, (adi mekanisme mekanisme ker(anya berbeda, tapi e'ek biologis biologis yang ditimbulkan ditimbulkan sama, yaitu diuresis. !enomena ini menun(ang pengertian baha mekanisme ker(a obat pada tingkat molekul dapat melalui beberapa (alan, dan ini memberi pen(elasan mengapa obat dengan tipe struktur berbeda dapat menun(ukkan respons 'armakologis yang sama. &enyaa dengan unit stuktur sama tetapi dapat memberikan akti"itas biologis berma+am5 ma+am ma+am oleh oleh karena karena unit unit strukt struktur ur terseb tersebut, ut, dengan dengan sediki sedikitt perubah perubahan an strukt struktur ur,, ternya ternyata ta dapat dapat berinteraksi dengan reseptor yang berbeda sehingga menimbulkan respons 'armakologis yang berbeda pula, seperti pada +ontoh obat turunan sul'onamida. %idak semua senyaa obat dapat di(elaskan hubungan struktur dan akti"itasnya. &ering kegagal kegagalan an untuk untuk mendapa mendapatka tkan n hubunga hubungan n antar antar strukt struktur ur kimia, kimia, si'at si'at kimia kimia 'isika 'isika,, dan akti"i akti"itas tas biologis disebabkan oleh si'at sistem biologis tubuh yang sangat kompleks dan banyaknya 'aktor yang yang mempen mempengar garuhi uhi akti"i akti"itas tas obat. obat. Adanya Adanya persam persamaan aan ataupu ataupun n perbeda perbedaan an akti"i akti"itas tas biologi biologiss senya senyaa a orga organi nik, k, baik baik yang yang memp mempun unyai yai hubun hubungan gan stru strukt ktur ur maupu maupun n tidak tidak,, tern ternyat yataa sang sangat at dipengaruhi oleh si'at5si'at 'isika kimia. &i'at5si'at tersebut ditentukan oleh (umlah, ma+am, dan susunan atau molekul obat. &i'at5si'a &i'at5si'att kimia 'isika merupakan dasar yang sangat penting untuk men(elaskan men(elaskan akti"itas biologis obat, oleh karena < 1. &i' &i'at kimia kimia 'isi 'isika ka memeg memegan ang g pera perana nan n pent pentiing dalam dalam penga pengang ngku kuttan obat obat untu untuk k men+apai men+apai reseptor reseptor.. &ebelum &ebelum men+apai men+apai reseptor, reseptor, molekul obat harus melalui berma+am5 berma+am5 ma+am saar membran, berinteraksi dengan senyaa5senyaa dalam +airan luar dan dalam sel serta biopolimer. Disini si'at kimia 'isika berperang dalam proses absorpsi dan distribusi obat, sehingga kadar obat pada aktu men+apai reseptor +ukup besar. besar. 2. $anya $anya obat obat yang yang mem mempu puny nyai ai str strukt uktur ur den denga gan n kekha kekhasa san n tingg tinggii sa(a sa(a dap dapat at ber berin inte tera raks ksii dengan reseptor biologis. biologis. Oleh karena itu si'at kimia 'isika 'isika obat harus menun(ang menun(ang orientasi orientasi khas molekul pada permukaan reseptor. &i'at kimia 'isika penting yang berhubungan dengan akti"itas biologis antara lain adalah kelarutan, koe'isien koe'isien partisi, partisi, adsorbsi, adsorbsi, akti"itas akti"itas permukaan, permukaan, dera(at dera(at ionisasi, ionisasi, isosteri isosterisme, sme, ikatan kimia, kimia, seperti seperti ikatan5ikatan ko"alen, ion, hidrogen, dipol5dipol, "an der =alls dan hidro'ob, (arak antar atom dari gugus5gugus 'ungsional potensial redoks, pembentukan kelat dan kon'igurasi molekul dalam ruang isomer;. Dalam keadaan tertentu si'at5si'at tersebut dikaitkan dengan 'ungsi kimia yang khas, seperti tetapan disosiasi pKa;, atau kadang5kadang dikaitkan dengan si'at molekul keseluruhan, seperti kelarutan dalam lemakair log *;. *ada proses distribusi obat, penembusan membran biologis teruta terutama ma dipenga dipengaruh ruhii oleh oleh si'at si'at lipo'i lipo'ill molekul molekul obat, obat, sepert sepertii kelaru kelarutan tan dalam dalam lemak lemakair air,, si'at si'at elektronik obat, seperti dera(at ionisasi, dan suasana p$. *roses interaksi obat dengan reseptor khas dipengaruhi dipengaruhi oleh tipe ikata kimia, kimia, interaksi interaksi hidro'ob, kerapatan elektron, elektron, ukuran molekul obat dan
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struktur struktur5akti 5akti"itas "itas B $K&A atau Quatitative Structure-Activity Structure-Activity Relationships B C&A;. $ubungan kuan kuanti tita tati ti'' stru strukt ktur ur5a 5akt kti" i"it itas as meru merupa paka kan n bagi bagian an penti penting ng dari dari kimi kimiaa medi medisi sinal nal dala dalam m usaha usaha mendapatkan suatu obat baru dengan akti"itas yang dikehendaki dan biaya yang lebih ekonomis. *enge *engeta tahu huan an tent tentan ang g pros proses es meta metabol bolis isme me seny senya aaa obat obat di dalam dalam tubu tubuh h (uga (uga sang sangat at dibutuhkan dibutuhkan dalam kimia medisinal medisinal oleh karena banyak senyaa yang diberikan diberikan dalam bentuk pra5 obat obat dan kemudi kemudian an dalam dalam tubuh tubuh mengal mengalami ami metabol metabolism ismee menghas menghasilk ilkna na senyaa senyaa akti'. akti'. *roses *roses metabolisme (uga berperan untuk menilai dan memprediksi e'ikasi dan keamanan obat, dan sebagai dasar pen(elasan ter(adinya e'ek samping dan toksisitas senyaa obat. 0etode 0etode pengemb pengembanga angan n obat melalu melaluii modi'i modi'ikas kasii molekul molekul dengan dengan optimi optimisas sasii senya senyaaa penuntun lead compound ; dan ran+angan obat yang rasional (uga merupakan tahap penting dalam usaha men+ari dan menemukans senyaa baru yang lebih akti', lebih selekti' dengan e'ek samping dan toksisitas yang rendah.
)A) II *#-@#0)A-@A*#-@#0)A-@ A- O)A% O)A%
,ada a7al %erke"'en$an o'at -saa %ene"-an o'at 'ar- %ada -"-"nya 'ersifat o'a& o'a (trial and error) sein$$a sein$$a 'iaya %en$e"'an$an %en$e"'an$an o'at 'ar- san$at "aal. Unt-k sat enis o'at sa"%ai da%at di%asarkan di'-t-kan 'iaya le' k-ran$ R%. * trily-n. Hal ini da%at di%aa"i "en$in$at dari =00 sa"%ai *0.000 senya7a 'ar- yan$ disintesis atayan$ yan$ dida%a dida%att dari dari s-"'er s-"'er ala" ala" setela setela "elal"elal-ii 'er'a$ 'er'a$ai ai -i ki"ia ki"ia fisika fisika aktivi aktivitas tas toksis toksisita itas s far"ak far"akoki okinet netik ik far"ak far"akodi odina" na"ika ika dan -i klinik klinik ke"-n$k ke"-n$kina inan n anya anya satsatsenya7a yan$ seara klinik da%at di$-nakan se'a$ai o'at ( 6a"'ar * ). >akt- yan$ di'-t-kan "-lai dari %roses sintesis ata- ekstraksi %ena%isan far"akolo$i sa"%ai eval-si klinik dan %erset--an %endaftaran "e"akan 7akt- le'i k-ran$ *0 ta-n. Hal terse'-t -$a dise'a'kan dise'a'kan ole ketatnya ketatnya %erat-ran&% %erat-ran&%erat-r erat-ran an tentan$ tentan$ o'at 'ar- -nt-k diiinkan da%at di%asarkan. Ini 'erarti a$ar 'a7a %en$e"'an$an o'at 'ar- teta% layak seara seara ekono" ekono"ii %erl%erl- tero'os tero'osan an %e"iki %e"ikiran ran yan$ "endasa "endasarr 'a$ai"a 'a$ai"ana na "elak-k "elak-kan an %eneli %enelititian an den$an den$an se-"l se-"la a keil keil senya7a senya7a yan$ yan$ ter%il ter%ili i dan 'a$ai" 'a$ai"ana ana "erana "eranan$ n$ senya7a den$an le'i 'aik. Iatila ?o'at? tidak anya "eli%-ti senya7a yan$ di$-nakan -nt-k %en$o'atan %enyakit dan dan 'aan aan dia$n ia$nos osttik saa aa teta eta%i "eli eli%-t %-ti se" se"-a seny senya7 a7a a ki" ki"ia yan$ yan$ da%at a%at "e"%en "e"%en$ar $ar-i -i ataata- "eni"' "eni"'-lk -lkan an efek efek %ada %ada siste" siste" 'iolo$ 'iolo$is is ter"as ter"as-k -k insekt insektisi isida da f-n$isida er'isida flavoran odoran %enarik dan %en$-sir seran$$a serta senya7a& senya7a yan$ di$-nakan -nt-k -i far"akolo$i dan fisiolo$is. Da-l- %en$e"'an$an o'at 'ar- le'i 'anyak dilak-kan di -niversitas (90 @) sedan$ saat ini %en$e"'an$an o'at 'ar- le'i 'anyak dilak-kan ole ind-stri (:0 @) -niversitas anya : @ sedan$ le"'a$a riset %e"erinta * @. ,roses %en$e"'an$an o'at 'ar- da%at di'-at 'a$an se%erti yan$ terliat %ada 6a"'ar 2. Lan$ka %erta"a dala" %en$e"'an$an o'at adala "elak-kan %en$enalan "asala. *ada pengenalan masalah dilakukan studi riset dasar yaitu tentang proses 6999519999 *er+obaan kimia pertama *enapisan 'armakolgi :(i toksisitas akut &tudi per+obaan 'armakologis yang lebih luas
299 299 9 9
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Gambar Gambar 1. ,en$e"'an$an o'at 'ar- den$an ara o'a&o'a (trial and error). Dari rata&
rata :000 senya7a ki"ia yan$ diselidiki setela "elal-i 'er'a$ai %ena%isan anya satyan$ di$-nakan se'a$ai %en$o'atan. (disad-r dari Koroklovas A, !ssentials of Mediinal 5e"istri 2nd. Ne7 ork 5iester 4ris'ane Toronto in$a%-re B 1on 7iley C ons *:== al.;* den$an "odifikasi)
,enyakit %enyakit yan$ dise'a'kan ole "ikroor$anis"e f-n$si siste" nor"al t-'- dan %er%er-'a 'aan an sist siste" e" aki' aki'at at %enya %enyaki kit t dan dan -$a -$a dila dilakk-kan kan st-d st-dii dasa dasar& r&das dasar ar ki"i ki"ia a dan dan 'ioki"ia. Lan$ka selan-tnya adala "enari senya7a aktif 'ar- den$an ara isolasi ata- ekstraksi dari 'aan ala" yan$ seara e"%iris di$-nakan se'a$ai o'at tradisional ata- dari %ena%isan %rod-k sintesis sintesis senya7a senya7a or$anik. or$anik. 5ara ini %ada -"-"nya -"-"nya 'ersifat 'ersifat o'a&o'a (trial and error) dan "e"'-t-kan 'iaya yan$ 'esar. 5ara yan$ le'i rasional adala "elak-kan %endekatan den$an "elal-i ranan$an o'at. Ranan$an o'at adala -saa -nt-k "en$e"'an$kan o'at yan$ tela ada yan$ s-da diketa-i str-kt-r "olek-l dan aktivitas 'iolo$isnya atas dasar %enalaran yan$ siste"atik dan rasional den$an "en$-ran$i faktor o'a&o'a se"ini"al "-n$kin. T--an dari ranan$an o'at %ada a7alnya adala "enda%atkan o'at 'ar- den$an aktivitas yan$ le'i 'aik den$an 'iaya yan$ layak seara ekono"i ke"-dian 'erke"'an$ -nt-k "end%atkan o'at dena$n efek sa"%in$ yan$ "ini"al (a"an di$-nakan) 'ekera le'i selektif "asa kera yan$ le'i la"a dan "enin$katkan kenya"anan %e"akaian o'at. Rana Ranan$ n$an an o'at o'at seri serin$ n$ di$a di$a"' "'ar arka kan n se'a se'a$a $aii %ros %roses es ela' ela'or oras asii sist siste" e"at atik ik -nt-nt-kk "en$e"'a$kan le'i lan-t o'at yan$ s-da ada den$an t--an "enda%atkan o'at 'arden$an efek 'iolo$is yan$ diin$inkan diin$inkan dan "en$-ran$i "en$-ran$i ata- "en$ilan$kan "en$ilan$kan efek sa"%in$ yan$ ada "elal-i "ani%-lasi "olek-l. Lan$ka&lan$ka ranan$an o'at dielaskan se'a$ai 'erik-t B Menar arii senya senya7a 7a %en%en-nt nt-n -n (lead compound) yait- senya senya7a 7a yan$ yan$ di$di$-na nakan kan 1. Men compound) yait se'a$ai %an$kal tolak "odifikasi "olek-l. enya7a %en-nt-n adala senya7a yan$ da%at da%at "eni"' "eni"'-lk -lkan an aktivi aktivitas tas 'iolo$is 'iolo$is se%ert se%ertii aksi aksi tera%et tera%etik ik aksi toksik toksik re$-la re$-lasi si fisio fisiolo lo$i $is s or" or"on on dan dan fero fero"o "on n sert serta a senya senya7a 7a yan$ yan$ terl terli' i'at at ataata- 'er% 'er%en$ en$ar ar- - terada% %roses 'ioki"ia dan %atolo$i %ada e7an ata- t-"'-&t-"'-an. ,ada -"-" -"-"ny nya a seny senya7 a7a a yan$ yan$ akan akan dike dike"' "'an an$k $kan an "e"% "e"%-n -nya yaii sifa sifatt yan$ yan$ k-ra k-ran$ n$ "en$-nt-n$kan se%erti aktivitasnya yan$ le"a k-ran$ s%esifik efek sa"%ai ''esar k-ran$ k-ran$ sta'il sta'il "asa "asa kera kera sin$kat sin$kat ataata- "e"%-ny "e"%-nyai ai 'a- dan rasa rasa yan$ k-ran"$ k-ran"$ "enyenan$kan.
Pengenalan Pertimbangan Pelaksanaan riset
Rancangan Kimia
Rancangan Biologis Pencarian Literatur Penggabungan Program
Pengembangan metode intesis
intesa en$a%a Analog
Pengembangan dan Penelitian !eknik"teknik U#i
Pena&isan A%al
Perlindungan Paten U#i"u#i $ang lebi' ter&erinci
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'tudi si#at Kimia (isik
Pembuatan kala Kecil
Produksi kala Industri
Kont Kontro roll Anal Analiitik tik dan dan )arm )armak akol olog ogii Kli Klinik nik Pengembangan )armasetika tudi +armakonetika
Percobaan Klinik ang lebi' meluas
Pemasaran dan Promosi In+ormasi *edis Gambar -. 4an$-n -r-tan keadian dala" %roses %en$e"'an$an o'at seara rasional. Korokl klov ovas as A, !ssent (dis (disad ad-r -r dari dari Koro !ssential ialss of Medii Mediinal nal 5e"is 5e"istri tri 2nd. Ne7 ork 5iester 5iester
4ris'ane Toronto Toronto in$a%-re B 1on 7iley C ons *:== al.;* den$an den$ an "odifikasi)
2. Mani%-lasi "olek-l ("odifikasi "olek-l ata- "odifikasi str-kt-r) yait- ensintesi
se-"l se-"la a t-r-nan t-r-nan senya7a senya7a %en-nt%en-nt-n n "elak-k "elak-kan an identi identifik fikasi asi str-kr str-krt-r t-r dan "en$- "en$-ii aktivitas 'iolo$isnya. 6-$-s ata- s-'stit-en yan$ dis-'sit-sikan da%at di%ili den$an "en$ "en$$-n $-nak akan an "eto "etode de To%li o%liss ss "eto "etode de %ena %enari rian an +i'o +i'ona na ii "eto "etode de ran$k ran$kaia aian n o%ti"isasi si"%leks ata- analisis klaster. 1-"la senya7a yan$ disntesis ter$ant-n$ dari "etode yan$ di$-nakan. 3. "er-"-skan -'-n$an k-antitatif se"entara antara strkt-r&aktivitas 'iolo$is dari senya7a yan$ -"lanya ter'atas den$an "en$$-nakan statistik analisis re$resi. ,ada taa% ini -"-"nya di$-nakan "odel L+!R Hans ("odel ekstrater"odina"ik) ata"odel de novo +ree&>ilson. ,ara"eter sifat ki"ia fisika yan$ di$-nakan dala" HKA "ode "odell Hans Hans adal adala a %ara %ara"e "ete terr li%of li%ofililik ik se%er se%ertiti lo$ lo$ , f dan dan R" R" %ara %ara"e "eter ter elektronik se%erti %Ka E Ei EF + + dan R serta %ara"eter % ara"eter sterik se%erti MR (,) !s L dan 4*&49. ,ara"eter&% ,ara"eter&%ara"et ara"eter er terse'-t terse'-t da%at ditent-kan "elal-i %ero'aan ata- %eit-n$an %eit-n$an teoritis ata- dia"'il dari data asil %ero'aan terda-l- yan$ 'anyak terant-" dala" '-k-&'-k- ki"ia "edisinal. ,erit-n$an ,erit-n$an teoritis %ara"eter %ara"eter sifat ki"ia fisika antara lain adala %erit-n$an nilai lo$ , den$an "en$$-nakan teta%an dari Han Han& & +-i +-ita ta tet teta% a%an an fra$ fra$"e "ent ntas asii f Han&Leo dan teta%an fra$"entasi f Rekker& Mannold. . Has Hasil ana analisi lisiss re$r re$res esii ke"ke"-di dian an diev dieval al-a -asi si dan dan "eran erana an$ n$ see seeni nisn snya ya -nt -nt-k "en$e"'an$kan "en$e"'an$kan dan "enye"%-rnak "enye"%-rnakan an -'-n$an -'-n$an terse'-t. terse'-t. ,eneliti ar-s s-da yankin 'a7a senya7a seenis yan$ akan disintesis "er-%akan %ilian ?ter'aik? sera i%otesis. Dari %roses di atas dida%atkan dida%atkan senya7a&senya senya7a&senya7a 7a ter%ili ter%ili -nt-k diadikan diadikan alon o'at dan selan-tnya di%atenkan. ,roses ini "e"erl-kan 7aklt- le'i k-ran$ 2&3 ta-n. 4eri 4erikk-tn tnya ya dila dilakk-ka kan n enel enelititia ian n le'i le'i "end "endal ala" a" ter terad ada% a% senya senya7a 7a ter% ter%ilili i den$ den$an an "elak-kan %ero'aan far"akolo$i le'i lan-t %ada 'e'era%a s%esies e7an se%erti tik-s anin$ dan %ei"ata yait- -i toksisitas s-'ak-t st-di terato$enik dan "-ta$enik selain it- dilak-kan -$a st-di far"akokinetik %ada e7an dan -i dosis yan$ "eni"'-kan
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efektivitas dari %en$at-ran dosis. elan-tnya dilak-kan -i klinik fasa II terada% %enderita ata- %asien dala" -"la ter'atas (90&300 oran$) -nt-k "eliat efek dan kea"anan o'at. ,ada saat yan$ sa"a -$a diranan$ %en$$-naaan 'ent-k sediaan o'at yan$ ses-ai yait- %en$e"'an$an for"-lasi se%erti -i sta'ilitas 'ent-k sediaan o'at dan %rod-ksi dala" skala keil. ,roses ini "e"erl-kan 7akt- antara 3 sa"%ai ; ta-n. Taa% 'erik-tnya dilak-kan -i klinik fasa III %ada "an-sia den$an skala yan$ le'i l-as ('e'era%a ri'- oran$) yait- %ero'aan klinis %ada vol-nter yan$ seat dan %asien den$an "odel '-ta ran$ka% (double blind) dieval-asi efikasi dan toleransi o'at serta di"onitor efek sa"%in$ ter-ta"a ter-ta"a yan$ aran$ teradi. teradi. 4ersa"aan den$an al ini dilak-kan -i o'a %rod-ksi dala" skala 'esar. Ke%-t-san akir -nt-k "e"%erkenalkan o'at 'ar- -nt-k da%at di$-nakan dala" kalan$an kedokteran di'-at atas dasar asil yan$ dida%at dari eval-asi tera%etik dala" klinik. !val-asi o'at 'ar- %ada %asien ata- vol-nter ar-s selaldilen$ka%i den$an k-"%-lan data yan$ selen$ka% "-n$kin se%erti data %roses a'sor'si ekskresi %e"'ent-kan "eta'olit kadar o'at dala" %las"a dosis "aksi"al dan dosis s-'toksik. !val-asi -$a dilak-kan terada% toksisitas ak-t dan kronik efek sa"%in$ efek karsino$enik dan efek terato$enik. !val-asi klinik dilak-kan %ada te"%at tertent- den$an %en$ontrolan yan$ ketat. 4ila eval-a eval-asi si klinik klinik "e"en- "e"en-ii %ersya %ersyarat ratan an "aka "aka taa% taa% yan$ yan$ etrak etrakir ir adala adala %en$a%en$a-an an %eriinan ke le"'a$a yan$ 'er7enan$ (de%arte"en Keseatan) den$an "enyertakan 'erkas&'erkas asil %en$-ian di atas. etela diiinkan o'at 'ar- da%at diedarkan atadi%asarkan den$an disertai %e"'erian infor"asi "edis. ,roses ini "e"erl-kan 7aktantara 3 sa"%ai 9 ta-n. es-da o'at 'eredar "asi di%erl-kan -i klinik fasa IG -nt-k "e"astikan kea"anan o'at dan "e"anta- resiko&resiko yan$ "-n$kin teradi aki'at %en$$-naan o'at. ,roses %en$e"'an$an o'at 'ar- 'eserta fasa&fasa -i klinik da%at di'-at seara ske"atis se%erti yan$ terliat %ada 6a"'ar 3. Dalam pengembangan obat ada empat langkah penting yang harus diketahui, yaitu men+ari senyaa penuntun, pengembangan senyaa penuntun, prosedur pengembangan obat, dan ran+angan obat rasional. A&ENCAI A&EN CAI 'EN*A+ 'EN*A+A PENUNTUN PENUN TUN )eberapa pendekatan dalam men+ari dan menemukan senyaa penuntun (lead penuntun (lead compound, parent compound antara compound antara lain adalah penapisan a+ak senyaa produk alam, penemuan se+ara kebetulan, hasil u(i metabolit obat, studi biomolekul dan endokrinologi, studi perbandingan biokimia, analisis akti"itas senyaa multi poten, e'ek samping obat, dan penapisan hasil sintesis sintesis kimia.
,ena%isan +ar"akolo$is
Ui ta'ilitas t-di +ar"akokinetik %ada He7an
Ui +ar"akolo$is Lan-tan
Ui Toksisitas Aktif
Ui Toksisitas -'ak-t Ui Terato$enisitas dan M-ta$enisitas
Ui klinik +ase I
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A%likasi /'at 4ar-
,e"asaran /'at 'ar-
Ui Klinik +asa IG (etela /'at 4eredar) Gambar
1. Pena!isan A,ak 'enyawa Produk Alam *ada abad ini telah banyak digunakan ekstrak dari sumber tanaman atau organ biatang untuk pengobatan berbagai ma+am penyakit. Karena menghasilkan e'ek yang +ukup baik, maka penelitian tentang obat tradisional sampai sekarang masih terus dikembangkan. )eberapa obat yang digunakan pada aktu ini, terutama antibiotik, "itamin dan hormon, (uga dihasilkan dari pemurnian atau isolasi berbagai ektrak sumber alam. %urunan penisilin dan tetrasiklin dianggap termasuk senyaa antibiotik yang berasal dari produk alam Diseluruh dunia terdapat lebbih kurang 99.999 (enis tumbuh5tumbuhan, lebih kurang 499.999 diantaranya merupakan tanaman tinggi, tetapi baru sekitar 19 > diantaranya telah diteliti se+ara kimia dan 'armakologi. &umber yang masih potensial ini diharapkan sebagai lapangan peelitian dalam usaha men+ari dan menemukan obat baru. *enemuan senyaa produk alam pada umumnya dilakukan karena penapisan se+ara masal dari bahan alam, diisolasi dan dimurnikan senyaa yang terkandung, ditentukan struktur kimianya, diu(idengan sistem u(i biologis dengan metode yang sesuai ( in vitro, in situ dan in vivo sehingga vivo sehingga disapatkan senyaa penuntun. ontoh penemuan obat yang dikembangkan dari senyaa produk alam < a. *enemuan antikoagulan dikumarol. $ean $ean sapi sapi yang makan makan tanama tanaman n s!eet clover hay,apabila hay,apabila mengalami perdarahan akan mati penyak yakit s!eet clover ;. %anama anaman n ters terseb ebut utkem kemud udian ian diis diisol olas asii seny senya aaa akti akti'n 'nya ya dan dan diidenti'ikasi struktur molekulnya, ternyata mengandung dikumarol bishidroksi kumarin;. Dari hasl hasl u(i biologi biologiss terhada terhadap p dikuma dikumarol rol ternyat ternyataa senya senyaaa terseb tersebut ut dapat dapat mengham menghambat bat sintes sintesis is protrombin danproses pembekuan darah. b. *enemuan kokain dari tanaman erythro"ylon coca# +. *enemuan senyaa mor'in dara Papaver dara Papaver somni$erum ontoh senyaa akti' lain yangdidapatdari sumber tanaman alam dapat dilihat pada %abel 1. -& 'enyawa Kimia Akti# dari Ke.adian se,ara Tidak 'enga.a atau Ke"etulan )eberapa obat kadang5kadang diketemukan kebetulan dalam laboratorium atau klink olehahli
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%ubokurarin *apa"erin, teo'ilin eserpin Digoksin Kuinin Kuinidin Kumarin Antrokuinon ?inblastin, ?inblastin, "inkristin,podo'ilotoksin,elipt "inkristin,podo'ilotoksin,eliptisin isin #metin &antonin
*elemas otot ?asodilator Antihipertensi Kardiotonik Antimalaria Antiaritmia Antikoagulan *urgati' Antikanker Antiamuba Antihelmentiuk
(leming 1828;, menemukan e'ek antibakteri dari penesilin se+ara kebetulan karena adanya pengotoran (amur pada media bakteri. (o2 182;, dalam suatu u(i senyaa antituberkulosis i!ronia3id , mendapatkan baha senyaa tersebut mempunyai e'ek antidepresi. '!ragu e dan Beyer 186;, men+oba mensin tesis 5kloro52,4 disul'amoilanilin dengan +ara 'ormil 'ormilasi asi turunan turunan amino amino dari dari diklor diklor'en 'enami amid, d, tetapi tetapi tidak tidak berhas berhasil il dan (ustru (ustru menghas menghasil ilkan kan produk yang tidak terduga yaitu klorotia3id , senyaa penghambat en7im karbonik anhidrase yang poten, dan berkhasiat sebagai diuretik. Dikl Diklor orodi odi'e 'eni nilt ltri rikl klor oroet oetan an DD% DD%;; yang yang tela telah h disi disint ntes esis is pada pada tahu tahun n 16, 16, teta tetapi pi akti" akti"it itas as insektisidalnya baru diketahui tahun 1849, pada aktu mengembangkan e'ek insektisida turunan alkana terklorinasi. Kadang5kadang' pada pengembangan obat baru untuk digunakan melaan suatu penyakit, se+ara tak terduga didapatkan baha senyaa tersebut (uga berguna untuk pengobatan penyakit yang lain. ontoh < eser!in , a. obat antihiperten antihipertensi, si, didapatkan didapatkan (uga mempunyai akti"itas akti"itas tranEuili7ar tranEuili7ar dan sedati' yang +ukup poten. Pargilin , b. obat antidepre'si, didapatkan (uga mempunyai akti"itas hipotensi'. +. Pro"enesid , digunakan digunakan untuk memperpan(an memperpan(an g masa "er(a penisilin penisilin karena dapat menghambat menghambat se+a7ra se+a7ra kompetiti' sekresi akti' penisilin di tubulus gin(al. &enyaa didapatka (uga men ghambat transpor transpor tubular dan reab sorpsi asam urat sehingga sehingga &emarang banyak digunakamn digunakamn sebagai urikosurik. Alo!urinol , d. penghambat en7im Fantin oFidase yang poten, digunakan untuk menghambat inakti"asi 5 merk merkap apto topu puri rin n men( men(ad adii asam asam 5ti 5tiour ourat at,, sehi sehing ngga ga ter( ter(ad adii e'ek e'ek pote poten n Isas Isasii deng dengan an 5 merk merkap apto topu puri rin n pada pada pengo pengobat batan an leu+e leu+emi mia.a a.alo lopu puri rinol nol didap didapat atkan kan (uga (uga meng mengham hambat bat perubahan Fantin dan hipoFantin men(adi asam urat, sehingga sekara'ng lebih banyak diigunakan seb agai urikosurik urikosurik antigout;. 3. U.i eta"olit 4"at yang ungkin em"erikan Akti5itas& Kadang5kadang ada obat yang menimbulkan akti"itas setelah mengalami proses metabolisme pra5obatpro5drug;. $asil metabolit akti' tersebut dapat digunakan langsung sebagai obat atau
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pengembangan senyaa antagonis spesi'ik, seeperti antimetabolit, anti"itamin dan senyaa litik. Ta"el -& *ra5obat,metabolit akti' dn akti"itas biologis *ra5obat A7atiopren Klorproma7in Kortison *rednison Dia7epam Digotoksin *rokainamid Kuinidin *ropanolol *roguanil G50etil dopa 0etil'enobarbital Imipramin Kloralhidrat
*roses 0etabolime 0etabolit akti' Kon(ugasi glutation 50erkaptopurin $idroksilasi aromatik 5 $idroksiklorproma7in $idroksiklorproma7in eduksi keton $idrokortison eduksi keton *rednisolon 35$idroksilasi Ok7a7epam $idroksilasi alisiklik Digoksin -5Asetilasi -5Asetilasi -5Asetilprokainamid -5Asetilprokainamid $idroksilasi alilik 35$idroksikuinidin $idroksilasi aromatik 45$idroksipropanolol Oksidasi siklisasi &ikloguanil Dekarboksilasi 50etilnorepine'rin -5Dekarboksilasi -5Dekarboksilasi !enobarbital -5Demetilasi -5Demetilasi Desmetilimipramin Dehidratasi,reduksi %rikloretanol
Akti"itas )iologis Antikanker Antipsikotik Antiradang Antiradang &edati' Kardiotonik Antiaritmia Anntiaritmia H5)loker Antimalaria -eurotransmiter -eurotransmiter &edati' Antidepresi $ipnotik
4erke" 4erke"'an 'an$ny $nya a ,en$et ,en$etaa-an an tentan tentan$ $ %eran %eran Re%lik Re%likasi asi kro"os kro"oso" o" dan "-lti% "-lti%lik likasi asi 'io% 'io%ol oli" i"er er "e"' "e"'-k -ka a la%a la%an$ n$an an 'ar'ar- -nt-nt-kk "ene "ene""-ka kan n senya senya7a 7a %en-nt %en-nt-n% -n%ada ada ranan$an o'at. Re%likasiADN transkri%si infor"asi $enetik dari ADN ke mesengger ARN dan translasi %rotein %ada ri'oso" "e"erl-kan %eratin yan$ k--s karena 'anya 'anyakk senya senya7a 7a akti aktiff yan$ yan$ da%a da%att "e"% "e"%en en$ar $ar- -ii taa% taa%&t &ta aa% a% %enti %entin$ n$ %ros %roses es 'iosintesis %rotein terse'-t. 5onto B 'ekera a se'$ai se'$ai antika antikanker nker den$an den$an "en$a" "en$a"'at 'at %roses %roses a. Anti'iotik mitomisin mitomisin / 'eker re%likasi ADN "elal-i reaksi alkilasi 'ekera a se'a$ai se'a$ai antika antikanker nker den$an den$an "en$a" "en$a"'at 'at %roses %roses b. 0okso 0oksorub rubis isin in 'eker re%likasi re%likasi dan trans&kri% trans&kri%si si ADN "elal-i "elal-i interaksi interaksi interkalasi interkalasi den$an %asan$an %asan$an 'asa %ada do'el eliks ADN. . tudi Perbandingan Biokimia
,roses ,roses 'ioki" 'ioki"ii 'ersif 'ersifat at -niver -niversal sal sein$ sein$$a $a senya7 senya7a a anti"e anti"eta' ta'oli olitt dan antivi antivita" ta"in in -"-" "en-n-kkn aktivitas yan$ -$a -niversal yait- 'ekera %ada s%esies yan$ l-as "-lai dari "ikroor$anis"e "a"alia dan "an-sia. Dala" al inist-di %er'andin$an %rose %rosess 'iok 'ioki" i"ia ia san$ san$at at %ent %entin in$ $ kare karena na da%at da%at "e"' "e"'ant ant- -nt-k -nt-k "eli "eliat at adanya adanya %er'edaan %roses 'ioki"ia antar s%esies. Aksi yan$ selektif %ada s%esies tertent"-n$kin dida%at den$an "en$e"'an$kan %en$a"'at "eta'olik antara lain den$an "e"%en$ar-i %roses 'ioki"ia yan$ %entin$ %ada sat- s%esies (%arasit) teta%i tidak %entin$ ata- tidak ada %ada s%esies yan$ lain (ost). 5onto B T-r-nan &enisilin a%at a%at "e"%en "e"%en$ar $ar-i -i sintes sintesis is "-ko%o "-ko%oli% li%e%t e%tida ida yan$ yan$ a. di%erl-kan -nt-k %e"'ent-kan dindin$ sel 'akteri dan al terse'-t tidak teradi %ada e7an ata- "an-sia. T-r-nan sul+onamida da%at "en$a"'at "en$a"'at seara 'ersain$ den$an asa" %& b.
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!fek !fek sa"%in sa"%in$ $ "e"%-ny "e"%-nyai ai "ekani "ekanis"e s"e aksi yan$ ter%is ter%isa. a. ,ada 'anyak o'at efek sa"%i sa"%in$ n$ di%an di%anda dan$ n$ se'a se'a$ai $ai efek efek yan$ yan$ tida tidakk diin diin$i $ink nkan an karen karena a "e"% "e"%en$ en$ar ar- -ii keseatan individ-. Meski%-n de"ikian efek sa"%in$ da%at dike"'an$kan "enadi o'at (senya7a %en-nt-n) den$an efek yan$ diin$inkan dan da%at 'er$-na seara tera%e-tik. 5onto Antiista"in yan$ "eni"'-ilkan efek sa"%in$ sedatif k-at se%erti %ro"etain da%at dike"'an$kan le'i lan-t "elal-i ranan$an o'at "enadi senya7a tran-ilier yan$ %oten se%erti klor&roma6in. 7& U.i Hasil Antara Proses 'intesis 4"at
enya7a antar (inter"ediate) adala senya7a lain disa"%in$ %rod-k yan$ teradi %ada reaksi sintesis. A 4 5 (senya7a antara) D (%rod-k akir) ⃗
5iri&iri senya7a antara adala "en$and-n$ $-$-s tertent- yan$ sa"a den$an %rod-k akir dan "e"%-nyai aktivitas 'iolo$is yan$ "iri%. enya7a antara di atas da%at dike"'an$kan se'a$ai senya7a %en-nt-n.
5onto B ,ada sintesis sulmeti6ol dite"-kan senya7a antra t-r-nan tiosemikarba6on yan$ di-i 'iolo$is 'iolo$is ternyata ternyata 'erkasiat se'a$ai antit-'erk-los antit-'erk-losis. is. Ui 'iolo$is 'iolo$is dari isonia6id (INH) yan$ di$-nakan di$-nakan %ada sintesis sintesis tiosi"ikar'a tiosi"ikar'aon on tenyata tenyata %rek-sor "e"%-nyai "e"%-nyai efek efek antitantit-'er 'erk-l k-losi osis. s. ,en$e" ,en$e"'n$ 'n$n n le'i le'i lan-t lan-t dari dari INH dida%a dida%akn kn i&ronia6id yan$ %ada %ada -i -i le'i le'i lan lan-t -t dida dida%t %tka kan n "e"% "e"%-n -nya yaii efek efek anti antide de%r %res esan an kare karena na da%a da%att "en$a"'at kera eni" "onoa"in oksidase. 8& eran,ang 'truktur Kimia Baru dan Peneta!an Akti5itas Biologis
Dasar Dasar %en$e" %en$e"'an 'an$an $an ini adala adala "elak"elak-kan kan sintes sintesis is senya7 senya7a a seara seara ki"ia ki"ia "-rni "-rni ke"-dia ke"-dian n dilak-k dilak-kan an %ena%i %ena%isan san aktivi aktivitas tas 'iolo$i 'iolo$isny snya a seara seara aak aak len$ka len$ka% % den$an den$an ara% ara%an an 'e'er 'e'era% a%a a dian dianta tara rany nya a "-n$k "-n$kin in "en"en-n n-k -kka kan n akti aktivi vita tass yan$ yan$ 'er$ 'er$-n -na. a. enya enya7a 7a yan$ yan$ "en"en-n n-k -kka kan n akti aktivi vita tass tert terten entt- dike" dike"'a 'an$a n$an n "en "enadi adi senya senya7a 7a %en-nt-n dan selan-tnya diranan$ ti%e "olek-l 'ar- dala" -saa "enda%atkan o'at den$an aktivitas yan$ diin$inkan. 5ara ini 'ersifat o'a&o'a (trial and error) dan
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,en$e" n$e"'a 'an n$an $an a"f a"fea"in "enadi metam+etamin yan$ yan$ 'erk 'erkas asia iatt %eran$san$ siste" saraf yan$ le'i %oten. b. ,en$ ,en$e" e"'a 'an$ n$an an s-lf s-lfon onilila" a"id ida a (ant (anti' i'ak akte teri ri to%i to%ika kal) l) "en "enad adii t-rt-r-nn nn s-lfonila" s-lfonila"ida ida yan$ 'erkasiat 'erkasiat anti'akter anti'akterii siste"ik siste"ik (sul+adi6in,sul+ametaksa6ol) ata- anti'akteri %ada sal-ran erna (sul+aguanidin, &talisul+ati6ol7 +. ,en$e"'an$an asa" salisilat (anal$esik) yan$ "e"%-nyai efek sa"%in$ iritasi la"'-n$ "enadi t-r-nan yan$ tidak "en$iritasi la"'-n$se%erti difl-nisal dan kar'atilsalisilat. 2. ,en$-'aan s%ektr-"aktivitas 5onto B a. Men$-'a senya7a a$onis "enadi anta$onis s%esifik. Hasil %rod-k ini adala adala anta$onis anta$onis s%esifik dari %rod-k ala"i se%erti senya7a anti& "eta'olit antivita"in antior"on antikoliner$ik dan snya7a %e"'lok adrener$ik. '. Me"isa Me"isakan kan ko"%onen ko"%onen -ta"a -ta"a dari dari s%ektrs%ektr-" " aktivitas aktivitas ke dala" dala" "olek-l "olek-l yan$ 'er'eda sein$$a dida%atkan senya7a den$n s%ektr-" yan$ 'ar-. ster steroi oid d anab anabol olik ik,, 5onto B %en$e"'an$an senya7a se%erti dan etilestrenol, dari dari seny senya7 a7a a ster steroi oid d oksimetolon,stano6ol nadrolon, da andro$enikse%erti metiltesteron. . Ko"'inasi aktivitas dari o'at yan$ 'er'eda 5onto B Ko"'inasi Ko"'inasi anestesi sete"%at lidokain den$an adrenalin (vasokontriktor) den$an t--an a$r lidokai yan$ tertaal la"a %ada rese%tor sein$$a aktivitas o'at "enadi le'i 'aik. a.
d. Me"%erkeil efek sa"%in$ o'at
Modifikasi dit--kan -nt-k "en$asilkan senya7a den$an s%ektr-" aktivitas 'aryan$ yan$ le'i le'i s%es s%esififik ik dan dan "e"% "e"%-n -nya yaii indek indekss tera tera%i %i 'esar 'esar ataata- efek efek sa"%i sa"%in$ n$ "ini"al. 5onto B "en$ilan$kan efek mineralokortikoid (retensi $ara") %ada "odifikasi str-kt-r t-r-nan glukortikoid (Ta'el 3) Dari ta'el 3 terliat 'a7a den$an "odifikasi "olek-l da%at diasilkan senya7a yan$ tidak tidak "eni"' "eni"'-lka -lkan n efek efek "inera "ineralko lkort rtikoi ikoid d (reten (retensi si $ara" $ara" ) den$an den$an efek efek $l-kokortikoid yan$ le'i 'esar. e. elektif terada% s%esies ata- or$an tertent elektivitas terada% s%esies ata- or$an tertent- da%at dike"'an$kan den$an "enari %er'edaan %roses 'ioki"ia dari s%esies yan$ terli'at . 4iasanya ada %er'edaan keil dari eteroisoeni" %ada s%esies ata- or$an yan$ 'er'eda. Den$an "en$$-nakan "en$$-nakan eni" asa" diidrofolat diidrofolat red-ktase red-ktase yan$ 'er'eda asalnya asalnya yait- dari Proteus vulgaris dan tik-s 8itc'ing 'erasil "en$e"'an$kan senya7a
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'. Mod-lasi -'-n$n 7akt-&kadar 7akt-&kadaryaityait- den$an "e"'-at sedian de%o ata- sediaan le%as le%as la"'at la"'at 'ila 'ila diin$i diin$inka nkan n efek efek o'at o'at yan$ yan$ le'i le'i la"aa la"aatata- di'-at di'-at sediaa sediaan n intravena 'ila diin$inkan efek o'at yan$ e%at. 5ontoB *.!s *.!ste terr dari dari or"on or"on ster steroi oid d yan$ yan$ san$a san$att li%of li%ofililiise% se%er ertiti idrok idroksi si &rogesteron ka&roat dan medroksi &rogesteron asetat o'at kontrase%si yan$ 'ila di'erikan seara intra"-sk-larefektif intra"-sk-larefektif sela"a le'i k-ran$ ti$a '-lan. 2. 4ent-k 4ent-k $ara" sodi-" dari deksametason da%at di'-at sediaan intrvenaya intrvenayan$ n$ di$-nakan 'ila diin$inkan efek o'at seara e%at. . Mod-la Mod-lasi si distri'distri'-si si o'at %ada %ada 'er'a$a 'er'a$aii ko"%ar ko"%arte" te"en. en.Mis Misaln alnya ya o'at di'-at di'-at idrofilik k-at sein$$a tidak da%at "ene"'-s "e"'ran 'iolo$is tertent- dan efek %ada %ada ko"% ko"%ar arte te"e "en n tert terten entt-.. 5ont 5onto oBB sul diran nan$ an$ dala dala" " 'ent 'ent-k -k sul+ati +atias asol ol dira e"i%talil(&talilsul+atiasol7 ata- e"is-ksinil a"ida(suksisnilsul+atiasol) yan$ s-kar dia'sorsi dala" sal-ran ernasein$$a efektif -nt-k %oen$o'atan infeksi sal-ran erna.
C& P4'EDU PEN%EBAN%AN 4BAT
Ariens "e"'a$i %rosed-r %en$e"'an$an o'at 'erdasarkan %er-'aan st-kt-r dan s-fat
ki"ia fisika se'a$ai 'erik-tB *. ,e"'-atan sediaan o"olo$. -at- senya7a o"olo$ o"olo$ da%at di'-at den$an "e"%er%anan "e"%er%anan$ $ rantai rantai idrokar'on idrokar'on.. ,er%a ,er%an nan an$a $an n rant rantai ai ato" ato" 5 akan akan "en$"en$-'a 'a sifa sifatt ki"i ki"ia a fisi fisika ka seny senya7 a7a a dan dan al al terse'-t terse'-t da%at "e"%en$ar-i "e"%en$ar-i aktivitas aktivitas 'iolo$isnya. 'iolo$isnya. 5onto B seri o"olo$ n"ali+atik alkool dan n" alkil resorsinol se'a$ai anti'akteri. 2. Men$-'a enis ata- ked-d-kan s-'tit-en %ada rantai sa"%in$. si&rominsenya7 5onto B tranil si&romin senya7a a %en$a %en$a"'a "'att "onoa" "onoa"in in oksida oksidase se (MA/) (MA/) yan$ yan$ %rot %rotei ein n di-' di-'a a "en "enadi adi am+etaminsenya7 senya7a a %eran$s %eran$san$ an$ siste" siste" saraf saraf %-sat %-sat yan$ yan$ %otenden$an aktivitas %en$a"'at MA/ se%er li"a ri'- dari aktivitas tranilsi%ro"in 3. Men$$anti 'a$ian yan$ k-ran$ %entin$ dan "e"%ertaankan $-$-s f-n$si yan$ ada
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$-$-s %en$$anti terse'-t %ada -"-"nya "e"%-nyai sifat sterik ata- elektronik yan$ sa"a. Ta'el . Aktivitas dan O&adrener$ik dari t-r-nan katekola"in tr-kt-r -"-" B :0:&
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5onto B %en$$antian $-$-s ester (5//) %ada "olek-l &rokain senya7a anestesi &rokai aina nami mid d yan$ sete"%a sete"%at t den$an den$an $-$-s $-$-s a"ida a"ida (5/NH) (5/NH) akan "en$a "en$asil silkan kan &rok 'erkasiat antiarit"ia. Me"isakan a"%-ran iso"er Mesk eski%-n '-kan kan "odifikas kasi "olek-l -l %e"isaan an iso"er se%ert erti %ada stereoiso"er-k-% %entin$ karena ked-a iso"er ke"-n$kinan 'er'eda s%ektr-" ataata- intens intensita itass aktivi aktivitas tasnya nya.. ,e"isa ,e"isaan an iso"er iso"er 'ert- 'ert--an -an -nt-k -nt-k "enda% "enda%atk atkan an senya7a den$anaktivitas yan$ le'i tin$$i ata- le'i selektif. 5onto B ()&, ()&,ro% ro%oks oksife ifen n 'erka 'erkasia siatt anal$e anal$esik sik sedan$ sedan$ iso"er iso"er (&)&,ro (&)&,ro%oks %oksife ifen n a. 'erksiat anti'at-k. b. Dari e"%at 'ent-k iso"er klora"fenikol yan$ 'erkasiat se'a$ai anti'akteri anya 'ent-k iso"er D(&) treo&klora"feniko
,e"'ent-kan senya7a ke"'ar enya7a ke"'ar adal d-a "olek-l o'at di$a'-n$ "enadi sat- "elel-i ikatan kovalen a. Ko"' Ko"'in inasi asi dari dari d-a d-a "ole "olekk-ll o'at o'at yan$ yan$ sa"a sa"a (ke" (ke"'a 'arr iden identitik) k) ataata- 'er' 'er'eda eda (ke"'ar tidak identik) "elal-i ikatan kovalen 5onto ke"'ar identik B salisil salisilat (d-a "olek-l asa" salisilat) dan meta6id ( d-a "olek-l isoniaid di$a'-n$kan "elal-i e"'atan "etilen ). RUMU 5onto ke"'ar tidak identik B asetaminosalol (asa" salisilat dan aseta"inofen)
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I"%ian I"%ian ali ki"ia "adisinal dan far"ako$i far"ako$i adala da%at "e"'-at "e"'-at o'at yan$ aktif seara far"akolo$is dan 'ekera san$at selektif "elal-i ranan$an rasional yan$ 'enar. a"%ai sekaran$ %ene"-an o'at 'ar- "elal-i ranan$an seara rasional relatif "asi sedikit teta%i %ros%ek %en$e"'an$annya -k-% 'esar. Ran Rann$ n$an an o'at o'at adal adal s-at s-at- seri seri %ro$ %ro$ra ra" " yan$ yan$ dila dilakk-ka kan n den$ den$an an "aks "aks-d -d -nt-nt-kk "ene"-kan senya7a ki"ia 'ar- yan$ 'er$-na -nt-k keseatan yait- -nt-k "en$o'ati dan "ene$a %enyakit tertent- ata- -nt-k "e"%erole ke"'ali keseatan "ental dan fisik. Ranan$an o'at asional adala s-at- rann$an -nt-k "ene"-kan o'at 'ar- seara lo$is dan da%at dia'arkan seara teoritis. ,ada kenyataannya tidak "-n$kin "e"'-at s-atranan$an o'at den$an lo$ika dan teoritis "-rni karena 'anyaknya faktor&faktor yan$ da%at "e"%en$ar-i "e"%en$ar-i aktivitas aktivitas dan keselektifa keselektifan n o'at. Meski%-n de"ikian al ini se"akin 'erke" 'erke"'an$ 'an$ %ada %ada 'e'era 'e'era%a %a ta-n ta-n teraki terakirr ini dan den$an den$an 'erke" 'erke"'an 'an$nya $nya teknol teknolo$i o$i ko"%-ter ranan$an o'at rasional "e"%-nyai %ros%ek yan$ era dala" %enarian o'at 'ar- %ada "asa "endatan$. Meran Meranan$ an$ o'at o'at seara seara rasion rasional al 'er-' 'er-'-n$ -n$an an den$an den$an %en$et %en$etaa-an an tentan tentan$ $ al&a al&all 'erik-t B a. Mekanis"e kera dan sisi kera o'at %da tin$kat "olek-l dan tin$kat elektronik. b. H-'-n$an k-alitatif dan k-antitatif str-kt-r str-kt-r ki"ia dan aktivitas aktivitas 'iolo$is +. Rese%tor o'at dan to%o$rafi ti$a di"ensi d. Model interaksi o'at rese%tor e. !fek far"akolo$is dari $-$-s yan$ s%esifik H-'-n$an an %ara"e %ara"eter ter sifat sifat ki"ia ki"ia fisika( fisika(id idrof rofo' o' elektr elektroni onikk dan sterik sterik)) den$an den$an '. H-'-n$ aktivitas 'iolo$is
g. Mekanis"e reaksi ki"ia dan 'ioki"ia h. 4iosintesis "eta'olit dan konstit-en lain dala" or$anis"e id-% i. ,er'edaan sitolo$i dan 'ioko"ia antara "an-sia dan %arasit 0etode yang digunakan dalam ran+anga oba rasional antara lain adalah < a.
Ranan$an o'at den$an 'ant-an ko"%-ter (Computer assited Drug Design 5ADD)S ter-ta"a 'er-'-n$an den$an %ara"eter ki"ia fisika yan$ terli'at dala" aktivitas o'at-'-n$an k-antitatif str-kt-r&aktivitas dan "odel ki"ia k-ant-" ata- %erit-n$an or'it "olek-l ,ro$ra" ko"%-ter -nt-k ranan$an o'at rasionalantara lain B
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,ro$ra" ko"%-ter -nt-k ranan$an sintesis or$anik !5 B Simulation of Chemical Synthesis 'a$ian dari %ro$ra" UM! 1; -nt-k "enent-ka al-r sintesis "olek-l tar$et dan el-sidasi str-kt-r '. 6rafik "olek-l ter-ta"a -nt-k "en$eta-i 'ent-k konfor"asi dan "odel "olek-l senya7a se'a$ai %et-n-k dala" ranan$an analo$. ,ro$ra"ko"%-ter yan$ di$-nakan antara lain a. 3D&56 (' Dimensional Computer &raphics) . b. LHAA B 6rafik str-kt-r interaktif-nt-k sintesis or$anik +. /55 $rafik str-kt-r interaktif-nt-k sintesi or$anik ,R/,H!T B Model 'an$-nan ti$a di"ensita'-lasi$ra%is dan analisis d. statistik data far"akolo$is M/L,AT -nt-k " e. '. enari %ola far"akoforik +. ,en$enalan %ola (,attern reo$nition) -nt-k seleksi senys7a&senya7a yan$ diin$inkan.
,ro$ra" ko"%-ter yan$ di$-nakanB ADA,T d. Keses-aian Keses-aian rese%tor( rese%tor(eseptor -nt-k karakt karakteri erisas sasii rese%t rese%tor or far"ak far"akolo olo$is $is dan eseptor fit) -nt-k "eliat "odel interaksi o'at&rese%tor ata- s-'strat&eni" serta ikatan&ikatan ki"ia yan$ terli'at dala" interaksi o'at&rese%tor. 5onto o'at yan$ dikete"-kan "el-i ranan$an rasional antara lain 1. Pralidoksin senya7a reaktivator kolinesterasedi$-nakan se'a$ai o'at %en-nan$ atro%in %ada %en$o'atan kera-nan ole senya7a or$anofosfat. 2. Asiklovir senya7a antivir-s yan$ efektif terada% er%es da%at "en$ikat seara k-at dan s%esifik eni" ti"idikinase %ada vir-s er%es
3. Bro Brokres kresiin, %en$ %en$a a"' "'at at ist istid idin in dekar dekar'ok 'oksi sila lase se eni" eni" yan$ yan$ 'er%e 'er%era ran n %ada %ada
'iosintesis ista"in sein$$a da%at 'ekera se'a$ai antiista"in yan$ %oten
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,erte"-an III
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Biologis
Keterangan =
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m" > mem"ran "iologis "iologis 4 > 4"at > ese!tor P > Protein <4) <4) > kom! kom!le leks ks o"at o"at1r 1res es!t !tor or <4P) > Kom!leks o"at !rotein
%am"ar 9= Proses a"sor"si dan distri"usi o"at&
Tiga #ase yang menentukan ter.adinya akti5itas "iologis o"at adala/= 1. (ase #armasetik0 yang meliputi proses pabrikasi, pengaturan dosis, 'ormulasi, bentuk sediaan, peme+ahan bentuk sediaan dan terlarutnya obat akti'. !ase ini berperan dalam ketersediaan obat untuk dapat diabsorbsi ke tubuh. 2. (ase #armakokinetik #armakokinetik00 yang meliputi bproses absorbsi, distribusi, metabolisme dan ekskresi obat AD0#;. !ase ini berperan dalam ketersediaan obat untuk men+apai (aringan sasaran target; atau reseptor sehingga dapat menimbulkan respons biologis. (ase #armakodinamik0 #armakodinamik0 yaitu 'ase ter(adinya interaksi obat5reseptor dalam (aringan 3. sasaran. !ase ini berperan dalam dalam timbulnya respons biologis obat.
$ubungan 'ase5'ase di atas di(elaskan dalam bentuk bagan seperti yang terlihat pada gambar 4.
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peme+ahan bentuk sediaan dan terlarut obat akti';
*enyerapan Ketersediaan hayati;
*eredaran *eredar an darah
*er i.m.
Jaringan Depo;
!ase farna*o*ineti*a ("DE)
per i.".
5 'ase 'armakodinamik
Obat bebas *rotein plasma
eseptor
eseptor biologis
bioakati"asi
)ioinakti"asi #kskresi
0etabolisme
%am"ar 6. (ase"+ase &enting dalam ker#a obat, $aitu +ase +armasetis, +armakokinetik dan +armakodinamik.
Distri'-si o'at %ada rese%tor dan sisi keilan$an ter$ant-n$ dari sisi ki"ia fisika "olek-l
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bentuk sediaan terutama berpengaruh terhadap ke+epatan absorbsi obat, yang se+ara tidak langsung dapat mempengaruhi intensitas respons biologis obat. )entuk sediaan pil, tablet, kapsul, suspensi, emulsi, serbuk dan larutan, proses absorbsi obat memerlukan memerlukan aktu yang berbeda5beda berbeda5beda dn (umlah ketersediaan ketersediaan hayati kemungkinan kemungkinan (uga berlainan. :kuran :kuran partik partikel el bentuk bentuk sediaa sediaan n (uga (uga mempen mempengar garuhi uhi absorb absorbsi si obat. obat. 0akink 0akinke+il e+il ukuran ukuran partikel, luas permukaan yang bersinggungan dengan pelarut semakin besar sehingga keepatan melarut obat semakin besar. Adanya bahan5bahan tambahan atau bahan5bahan bahan5bahan pembantu, seperti bahan pengisi, pengisi, peli+in, peli+in, penghan+ur, pembasah dan emulgator, dapat mempengaruhi aktu han+ur dan melarut obat, yang akhirnya berpengaruh terhadap ke+epatan absorpsi obat.
b. &i'at Kimia !isika Obat )ent )entuk uk asam asam,, basa, basa, este esterr, garam garam,, kompl komplek ekss atau atau hidr hidrat at dari dari baha bahan n obat obat dapa dapatt mempengaruhi kelarutan dan absorbsi obat. &elain itu bentuk kristal atau polimor', kelarutan dalam lemakair dan dera(at ionisasi (uga mempengaruhi absorpsi obat. ontoh< 1. *enisilin ? dalam bentuk garam K lebih mudah melarut dibanding penisilin ? untuk basa. 2. -o"obiosin btk amor' lebih +epat melarut dibanding btk kristal.
,& )aktor Biologis !aktor5'aktor biologis yang berpengaruh terhadap proses absorbsi obat antara lain adalah "ariasi keasaman p$; saluran +erna, sekresi +airan lambung, gerakan saluran +erna, luas permukaan saluran +erna, aktu pengosongan lambung dan aktu transit dalam usus, serta banyaknya buluh darah pada tempat absorpsi.
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/emak Ar5-$2
*lasma p$ B ,49; Ar5-$2
/ambung p$ B 153; Ar5-$3 Ar5-$3 Ar5-$2
:sus p$ B 56;
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A"ino%irin K-inin 4enalkoni-" klorida
90 = &
& & 0
& *= 0
2* : 0
92 9 0
!abel 2. Hubungan koefisien partisi korofor"#air 9P7 dan %rosen a'sor%si 'ent-k
tak terionisasi 'e'era%a senya7a asa" dan 'asa. -ama Obat Tio%ental Anilin Asetanilid Asetosal Asa" 'ar'it-rat Manitol
*; *00 2; <; 20 000= X 0002
*ersen *enyerapan ;< 9 3 2* 9 X2
t-di t-di tentan tentan$ $ "asala "asala yan$ yan$ 'er-' 'er-'-n$ -n$an an den$an den$an a'sor' a'sor'si si t-r-nan t-r-nan a"onia"oni-" " k-artener %ada sal-ran erna kadan$&kadan$ san$at ko"%leks. 5ontoB 1. ,e"'er ,e"'erian ian seara seara oral oral antel antel"en "entik tik t-r-na t-r-nan n a"onia"oni-" " k-arten k-artener er yan$ yan$ 'ersifat 'asa k-at se%erti &irvinium &amoat (%avon) dan ditiaanin iodida ternyata
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'esar "aka a'sor%si "elal-i '-l- dara %ar- 'eralan den$an e%at. e%at. A'sor%si o'at "elal-i %ar- ter$ant-n$ %ada B a. kadar o'at dala" alveoli. Koefisien %artisi $as#dara. b. +. Kee%atan aliran dara %ar-. d. Uk-ran %artikel o'at. Hanya o'at den$an $aris ten$a le'i keil dari *0 Y" yan$ da%aat "as-k %eredaran alairan %ar-.
Absor&si obat melalui kulit 4. *enggunaan obat pada kulit pada umumnya ditu(ukan untuk memperoleh e'ek setempat. *ada aktu ini sedang dikembangkan bentuk sediaan obat yang digunakan melalui kulit dengan dengan tu(uan tu(uan untuk untuk mendap mendapatka atkan n e'ek e'ek siste sistemik mik.. Absorp Absorpsi si obat obat melalu melaluii kulit kulit sangat sangat tergant tergantung ung pada pada kelaru kelarutan tan obat alam alam lemak lemak karena karena epider epidermis mis kulit kulit ber'un ber'ungsi gsi sebaga sebagaii membran lemak biologis. 8UBUNGAN !RUK!UR, I)A! I)A! KI*IA )IIKA 04NGAN PR54 0I!RIBUI 5BA! 5BA!
).
etela "as-k ke %eredaran siste"ik "olek-l o'at seara serentak didistri'-sikan
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4erdas 4erdasark arkan an sifat sifat ke%ola ke%olaran rannya nya la%isa la%isan n 'io"ol 'io"olekek-ll di'a$i di'a$i "enad "enadii d-a 'a$ian yait- 'a$ian non %olar terdiri dari rantai oidrokar'on dan 'a$ian %olar %olar yan$ yan$ terdir terdirii dari dari $-$-s $-$-s idrok idroksil sil kolest kolestero eroll dan $-$-s $-$-s $liser $liserilf ilfosf osfat at fosfoli%id. ,rotein 2; 3; 4ent-k %rotein 'ervariasi ada yan$ 'esar 'esar 'erat "olek-lnya Z 300.000 dan ada %-la yan$ san$at kil. ,rotein 'ersifat a"%ifil karena "en$and-n$ $-$-s idrofil dan idrofo'. 4; M-ko%olisakarida 1-"la "-ko%olisakarida %ada "e"'ran 'iolo$is keil dan str-kt-rnya tidak dala"keadaan dala"keadaan 'e'as teta%i teta%i dala" 'ent-k ko"'inasi den$an le"ak se%erti $likol $likoli%i i%id d ataata- den$an den$an %rotei %rotein n se%ert se%ertii $liko%r $liko%rote otein. in. M-ko%o M-ko%olis lisaka akarid rida a ini 'er%eran -nt-k %en$enalan sel dan interaksi anti$en&anti'odi. Me"' Me"'ra ran n sel "e"% "e"%-n -nyai yai %ori %ori yan$ yan$ 'er$ 'er$ar aris is ten$ ten$a a anta antara ra 39& 39& 2 2 [ "er-%akan sal-ran yan$ 'erisi air dan dikelilin$i ole rantai sa"%in$ "olek-l %rotein yan$ 'ersifat %olar. \at terlar-t da%at "ele7ati %ori ini seara dif-si karena kek-atan tekanan dara.
*odel membran sel Dari 'er'a$ai "odel str-kt-r "e"'ran sel. Ada ti$a "odel yan$ %entin$ -nt-k diketa-i yait- "odel 0avson"0anielli "odel "odel Robertson dan "odel inger dan
b.
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Proses difusi dibagi men+adi dua yaitu difusi pasif dan difusi a*tif. a.
Difusi pasif %ene"'-san "e"'ran 'iolo$is seara dif-si %asif di'edakaan "enadi ti$a yaitdif-si %asif "elal-i %ori (ara %enyarin$an) dif-si %asif den$an ara "elar-t dala" le"ak %eny-s-n "e"'ran dan dif-si %asif den$an fasilitas. 1;
Difusi pasif melalui pori
Me"'ran sel "e"%-nyai %ori den$an $aris ten$a sekitar [ dan da%at dile7ati seara dif-si ole "olek-l yan$ 'ersifat idrofil "olek-l den$an $aris ten$an yan$ le'i keil dari [ dan "olek-l den$an -"la ato" 5 le'i keil dari 3 ata- 'erat "olek-l le'i keil dari *90. kee%atan dif-si o'at ter$ant-n$ %ada -k-ran %ori -k-ran "olek-l o'at dan %er'edaan kadar antar "e"'ran. sel $lo"erol-s ka%s-la 4o7"an $inal "e"%-nyai "e"'ran karakteristik den$an %ori yan$ le'i 'esar di'andin$ %ori "e"'ran 'iolo$is lain. %orinya da%at dile7ati ole "olek-l o'at den$an $aris ten$a Z 0 [ dan "olek-l "olek-l %rotein den$an 'erat "olek-l sa"%ai 9000. se'a$ian 'esar "olek-l o'at "e"%-nyai $aris ten$a le'i 'esar [ sein$$a ara %enyarin$an ini k-ran$ %entin$ dala" "ekanis"e %en$an$k-tan o'at. 2; Difusi Pasif dengan Cara Melarut pada Lemak Penyusun Membran. 5verton (*:0*) "en$e"-kakan s-at- konse% 'a7a kelar-tan senya7a or$anik
dala" le"ak 'er-'-n$an den$an "-da ata- tidaknya %ene"'-san "e"'ran sel. %ol 'ersif 'ersifat at "-da "-da lar-t lar-t dal le"ak le"ak yai ar
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/'at "odern se'a$ian 'esar 'ersifat elektrolit le"a yait- asa" ata- 'asa le"a dan deraat ionisasinya ditent-kan ole nilai nilai %Ka dan s-asana %H. H-'H-'-n$ n$an an anta antara ra %Ka %Ka den$ den$an an frak fraksi si o'at o'at teri terion onis isas asii dan dan yan$ yan$ tida tidakk terionisasi dari o'at yan$ 'ersifat asa" dan 'asa le"a da%at dinyatakan "elal-i %ersa"aan Henderson&Hassel'al se'a$ai 'erik-t
Untuk asam lema/ =
%Ka %H lo$ 5 -#5i
5- +raksi asa" yan$ tdk terionisasi 5i +raksi +r aksi asa" yan$ terionisasi
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1;
Sistem Pengangkutan Aktif
siste" %en$an$k-tan aktif ata- trans%or aktif "iri% den$an %roses dif-si %asif den$an fasilitas yait- sa"a&sa"a 'erdasarkan teori %e"'a7a "e"'ran. ,er'edaannya adala B %en$ank-ta -tan n o'at da%at 'eral 'eralan an dari dari daera daera yan$ 'erkada 'erkadarr renda renda ke a. %en$ank daera yan$ 'erkadar yan$ le'i tin$$i adi tidak ter$ant-n$ %ada %er'edaan kadar antar "e"'ran. b. %en$an$ %en$an$k-t k-tan an terse' terse'-t -t "e"erl "e"erl-kan -kan ener$i ener$i yan$ yan$ 'erasa 'erasall dari dari adenosi adenosin n trifosfat (AT,) +. Reaksi "e"'ent-k ko"%leks o'at %e"'a7a "e"erl-kan afinitas. /onto' &engangkutan akti+
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dala" dala" dara dara selalselal- 'erkai 'erkaitan tan den$an den$an kadar kadar o'at yan$ terika terikatt %ada %ada %rotei %rotein n %las"a. K-ran$ K-ran$ le'i le'i ;9@ ;9@ ko"%os ko"%osisi isi dara dara adala adala %rotei %rotein n dan Z90@ Z90@ dari dari %rotei %rotein n ters terse' e'-t -t adala adala al'-" al'-"in in yan$ yan$ "e"% "e"%-ny -nyai ai %eran %eran %ent %entin in$ $ dala dala" " %ros %roses es %en$ikatan o'at. Al'-"in "e"%-nyai 'erat "olek-l Z;:.000 'ersifat a"foter a"foter "e"%-n "e"%-nyai yai %H isoele isoelektr ktrik ik yan$ yan$ le'i le'i renda renda di'and di'andin$ in$ %H fisiol fisiolo$i o$iss (<) (<) sein$$a dala" dara akan 'er"-atan ne$atif. Karena "en$and-n$ ion \7itter al'-" al'-"in in da%a da%att 'eri 'erint nter erak aksi si 'aik 'aik dala dala" " kati kation on "a-% "a-%-n -n anio anion n o'at o'at.. ela elain in al'-"in %rotein yan$ serin$ "en$ikat o'at adala &globuin 4ila %rotein %las"a tela en- o'at 'e'as dala" airan dara 'erinteraksi den$an rese%tor dan "eni"'-lkan res%ons 'iolo$is. 4ila kadar o'at 'e'as
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detoksifikasi kera-nan lo$a" 'erat%ada kera-nan H$ H$ diikat seara k-at ole $-$-s H %rotein sein$$a efek toksiknya d%at dinetralkan. Menin$k Menin$katk atkan an a'sor's a'sor'sii o'at o'at onto onto B dik-"a dik-"arol rol dia'so dia'sor%s r%sii c. den$an 'aik ole -s-s karena dala" dara o'at dia'sor%si seara k-at ole %rotein %las"a. d. Me"%en$ar-i siste" distri'-si o'at yait- den$an "e"'atasi interaksi o'at dn$an rese%tor kas "en$a"'at "eta'olis"e dan ekskresi o'at sein$$a "e"%er%anan$ "asa kera o'at. 5ontoB suramin, o'at antitri%anoso"a 'ila di'erikan dala" dosis t-n$$al seara intravena da%at "ene$a seran$an %enyakit tid-r sela"a 'e'era%a '-lan. Hal ini dise'a'kan ikatan ko"%leks s-ra"in&%rotein b.
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K#0
Dara 1arin$an Dara 1arin$an /'at A /'at 4 6a"'ar *3. Kadar i%otetik o'at A da' 4 dala" dara dan arin$an. Dari $a"'ar *3 disi"%-lkan al&al se'a$i 'erik-t B Kadar total o'at A dala" dara le'i 'esar di'andin$ kadar total o'at a. 4.
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%ada %ada kee%at kee%atan an "eta'o "eta'olis lis"e "e ataata- ekskres ekskresiny inya a teta%i teta%i le'i le'i ter$ant ter$ant-n$ -n$ %ada %ada kee%atan distri'-sinya. !stela 3 a" %e"'erian kadar tio%ental dala" de%o le"ak *0 kali le'i 'esar di'andin$ kadar o'at dala" %las"a.
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b.
#ntera*si -has
Interaksi kas adala interaksi yan$ "enye'a'kan %e-'aan str-kt-r "akro"olek-l
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