Vincristine

From Wikipedia, the free encyclopedia Jump to: navigation, search Vincristine

Systematic (IUPAC) name

(3aR,3a1R, R,!",!aR,1#$R%&methyl &aceto'y&3a&ethyl&(&((!",)",("%&!& ethyl&!&hydro'y&(&(metho'ycar$onyl%&*, ,!,+,),,,(,1#&octahydro&1-&3,)& methano.1/a0acycloundecino.!, &$/indol&(&yl%&+&formyl&!&hydro'y&,& metho'y&3a,3a1, ,!,!a,+,11,1*&octahydro&1-&indoli0ino.,,1&cd/car$a0ole& !&car$o'ylate

Clinical data AHFS/Drugs.com monograph MedlinePlus a+,*,** Pregnancy cat. 1 (23% 1 (3"% 4rescription only egal status !outes "#clusi$ely intravenous P%armaco&inetic data 'ioa$aila(ility n5a Protein (inding 6)!7 Meta(olism -epatic Hal)*li)e 1( to 1!! hours "#cretion 8ostly $iliary, 1#7 in urine Identi)iers CAS num(er !)&**&) A+C code 9#1:2#* Pu(C%em :;1 !(), Drug'an& 1<##! 1 C%emS,ider !)!, U-II !J (=+<)#F ."// 1#,+)( C%"'I :-><;:*, ! C%"M' :->8<93#3!+# C%emical data Formula C +H!+- 01#

Mol. mass ,* ?(!, g5mol "8;9>".sho@/ ;n:h;.sho@/ (1%at is t%is2) ($eri)y) Vincristine ($rand name, Ancovin%, formally kno@n as leurocristine, sometimes a$$reviated BV:RB, is a vinca alkaloid from the Catharanthus roseus (8adagascar peri@inkle%, formerly Vinca rosea and hence its name? ;t is a mitotic inhi$itor, and is used in cancer chemotherapy? Vincristine is created $y the coupling of indole alkaloids vindoline and catharanthine in the vinca plant?.1/

Contents

1 8echanism * 3ses 3 "ide&effects -istory ! "uppliers + "ee also ) References , >'ternal links

Mec%anism
Cu$ulin is a structural protein that polymeri0es to microtu$ules? Che cell cytoskeleton and mitotic spindle, among other things, are made of microtu$ules? Vincristine $inds to tu$ulin dimers, inhi$iting assem$ly of microtu$ule structures? 1isruption of the microtu$ules arrests mitosis in metaphase? Cherefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, $ut also those of intestinal epithelium and $one marro@?

Uses
Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens? ;ts main uses are in non&-odgkinDs lymphoma as part of the chemotherapy regimen :-A4, -odgkinDs lymphoma as part of 8A44, :A44, <>2:A44, or the less popular "tanford V chemotherapy regimen, in acute lympho$lastic leukemia, and in treatment for nephro$lastoma (Wilms tumor, a kidney tumor most common in young children%? ;t is also used to induce remission in A @ith 1e'amethasone and 9& 2sparaginase? Vincristine is occasionally used as an immunosuppressant, for e'ample, in treating throm$otic throm$ocytopenic purpura (CC4% or chronic idiopathic throm$ocytopenic purpura (;C4%? ;t is used in com$ination @ith prednisone to treat childhood leukemia?

Side*e))ects
Che main side&effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss? 4eripheral neuropathy can $e severe, and hence a reason to avoid, reduce, or stop the use of vincristine? Ane of the first symptoms of peripheral neuropathy is foot drop: 2 person @ith a family history of foot drop and5or :harcot&8arie&Cooth disease (:8C% may $enefit from genetic testing for :8C $efore taking vincristine?.*/ 2ccidental inEection of vinca alkaloids into the spinal canal (intrathecal administration% is highly dangerous, @ith a mortality rate approaching 1## percent? Che medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied $y intracta$le pain, almost uniformly leading to deathF a handful of survivors @ere left @ith devastating neurological damage @ith no hope of recovery? Rescue treatments consist of @ashout of the cere$rospinal fluid and administration of protective medications?.3/ 2 significant series of inadvertent intrathecal vincristine administration occurred in :hina in *##) @hen $atches of cytara$ine and methotre'ate ($oth often used intrathecally% manufactured $y the company "hanghai -ualian @ere found to $e contaminated @ith vincristine?. /

History
-aving $een used as a folk remedy for centuries, studies in the 1(!#s revealed that C. roseus contained )# alkaloids, many of @hich are $iologically active? While initial studies for its use in dia$etes mellitus @ere disappointing, the discovery that it caused myelosuppression (decreased activity of the $one marro@% led to its study in mice @ith leukemia, @hose lifespan @as prolonged $y the use of a vinca preparation? Creatment of the ground plant @ith "kelly&< defatting agent and an acid $en0ene e'tract led to a fraction termed Bfraction 2B? Chis fraction @as further treated @ith aluminium o'ide, chromatography, trichloromethane, $en0&dichloromethane, and separation $y p- to yield vincristine?.!/ Vincristine @as approved $y the 3nited "tates Food and 1rug 2dministration (F12% in July 1(+3 as Ancovin? Che drug @as initially discovered $y a team led $y 1r? J?G? 2rmstrong, then marketed $y >li 9illy and :ompany?

Su,,liers
Chree generic drug makers supply vincristine in the 3nited "tates & 244, 8ayne, and "icor (Ceva%?

Vin(lastine
From Wikipedia, the free encyclopedia Jump to: navigation, search

Vin$lastine

Systematic (IUPAC) name

dimethyl (*H,3H, H,!I,1*H,1(I%& 1!&.(!S,(S%& !&ethyl& !&hydro'y& (& (metho'ycar$onyl%

Clinical data AHFS/Drugs.com monograph MedlinePlus a+,*, , Pregnancy cat. 1 (23% 1 (3"% 4A8 (3J% &only (3"% egal status !outes "#clusi$ely intravenous P%armaco&inetic data 'ioa$aila(ility n5a Meta(olism -epatic (:K432 &mediated% Hal)*li)e * ?, hours (terminal% "#cretion <iliary and renal Identi)iers CAS num(er ,+!&*1& A+C code 9#1:2#1 Pu(C%em :;1 * 1(#3 Drug'an& 1<##!)# C%emS,ider *11 + U-II !V(J9L! :K ."// 1#,+)! C%"'I :-><;:*)3)! C%"M' :->8<91!( -IAID C%emD' ##*+)3 Synonyms vincaleuko$lastine C%emical data Formula C +H!,- 0( Mol. mass ,1#?()! g5mol "8;9>".sho@/ ;n:h;.sho@/ (1%at is t%is2) ($eri)y)

Vin(lastine is an antimicrotu$ule drug used to treat certain kinds of cancer, including -odgkinDs lymphoma, non&small cell lung cancer, $reast cancer, head and neck cancer, and testicular cancer? ;t is also used to treat 9angerhans cell histiocytosis? Vin$lastine @as traditionally o$tained from Catharanthus roseus, also kno@n as Vinca rosea, a 8adagascar 4eri@inkle? ;t is generated in the plant $y the Eoining of t@o alkaloids catharanthine and vindoline?.1/

Contents

1 -istory * 4harmacology 3 8echanism of 2ction ;solation and "ynthesis ! ;ndications + "ee also ) Footnotes

History
Vin$lastine @as first isolated $y Ro$ert Mo$le and :harles Chomas <eer at the 3niversity of Western Antario from the 8adagascar peri@inkle plant? Vin$lastineDs utility as a chemotherapeutic agent @as first suggested $y its effect on the $ody @hen the plant @as consumed in a tea? 1rinking the tea led to a decreased num$er of @hite $lood cells, so it @as hypothesi0ed that vin$lastine might $e effective against cancers of the @hite $lood cells such as lymphoma?

P%armacology
Vin$lastine is a vinca alkaloid and a chemical analogue of vincristine? ;t $inds tu$ulin, there$y inhi$iting the assem$ly of microtu$ules? ;t is 8 phase cell cycle specific since microtu$ules are a component of the mitotic spindle and the kinetochore @hich are necessary for the separation of chromosomes during anaphase of mitosis? Co'icities include $one marro@ suppression (@hich is dose&limiting%, gastrointestinal to'icity, potent vesicant ($lister&forming% activity, and e'travasation inEury (forms deep ulcers%? Vin$lastine paracrystals may $e composed of tightly&packed unpolymeri0ed tu$ulin or microtu$ules?.*/ Vin$lastine is reported to $e an effective component of certain chemotherapy regimens, particularly @hen used @ith $leomycin, and methotre'ate in V<8 chemotherapy for "tage ;2 or ;;2 -odgkin lymphomas? Che inclusion of vin$lastine allo@s for lo@er doses of $leomycin and reduced overall to'icity @ith larger resting periods $et@een chemotherapy cycles?.3/

Mec%anism o) Action

Che comple' of tu$lin and vin$lastine? Vin$lastine is sho@ed as yello@ stick? 8icrotu$ule disruptive drugs like vin$lastine, colcemid, nocoda0ole have $een reported to act $y t@o mechanisms?. / 2t very lo@ concentrations they suppress microtu$ule dynamics and at higher concentrations they reduce microtu$ule polymer mass? Recent findings indicate that they also produce microtu$ule fragments $y stimulating microtu$ule minus&end detachment from their organi0ing centers? 1ose&response studies further indicate that enhanced microtu$ule detachment from spindle poles correlate $est @ith cytoto'icity?.!/

Isolation and Synt%esis

Vin$lastine may $e isolated from the 8adagascar 4eri@inkle (Catharanthus roseus%, along @ith several of its precursors& catharanthine and vindoline? >'traction is costly and yields of vin$lastine and its precursors are lo@? >nantioselective synthesis has $een of considera$le interest in recent years, as the natural mi'ture of isomers is not an economical source for the reNuired :1+O", :1 OR stereochemistry of $iologically active vin$lastine? ;nitially, the approach depends upon an enantioselective "harpless epo'idation, @hich sets the stereochemistry at :*#? Che desired configuration around :1+ and :1 can then $e fi'ed during the ensuing steps? ;n this path@ay, vin$lastine is constructed $y a series of cycli0ation and coupling reactions @hich create the reNuired stereochemistry? Che overall yield may $e as great as **7, @hich makes this synthetic approach more attractive than e'traction from natural sources, @hose overall yield is a$out 1#7?.+/ "tereochemistry is controlled through a mi'ture of chiral agents ("harpless catalysts%, and reaction conditions (temperature, and selected enantiopure starting materials%?.)/

Indications
Vin$lastine is a component of a num$er of chemotherapy regimens, including 2<V1 for -odgkin lymphoma? ;t is also used to treat histiocytosis according to the esta$lished protocols of the -istiocytosis 2ssociation of 2merica?

As,irin

-ama sistematis (IUPAC)

asam *&asetil$en0oat

Data &linis .at. &e%amilan :(23% 1(3"% Status %u&um !ute 3nscheduled (23% G"9 (3J% AC: (3"% 8ost commonly oral, also rectal? 9ysine acetylsalicylate may $e given ;V or ;8 P%armaco&inetic data 'ioa$aila(ilitas Rapidly and completely a$sor$ed I&atan ,rotein ((?+7 Meta(olisme 3a&tu ,aru% "&s&resi -epatic 3##P+!# mg dose: 3?1P3?* h 1 g dose: ! h * g dose: ( h Renal Pengenal -omor CAS .ode A+C Pu(C%em Drug'an& C%emS,ider !#&),&* 2#121#! <#12:#+, M#*<2#1 :;1 ** 24R1##*+ *1!) *&acetylo'y$en0oic acid Sinonim acetylsalicylate acetylsalicylic acid A&acetylsalicylic acid Data &imia Formula Massa mol. C(H,0 1,#?1!) g5mol

SMI "S

e8olecules Q 4u$:hem Data )isi&

.e,adatan +iti& le(ur +iti& didi% .elarutan dalam air

1? # g5cmR 13! S: (*)! SF% 1 # S: (*, SF% (decomposes% 3 mg5m9 (*# S:%

As,irin atau asam asetilsalisilat (asetosal% adalah seEenis o$at turunan dari salisilat yang sering digunakan se$agai senya@a analgesik (penahan rasa sakit atau nyeri minor%, antipiretik (terhadap demam%, dan anti&inflamasi (peradangan%? 2spirin Euga memiliki efek antikoagulan dan dapat digunakan dalam dosis rendah dalam tempo lama untuk mencegah serangan Eantung? Jepopuleran penggunaan aspirin se$agai o$at dimulai pada tahun 1(1, ketika terEadi pandemik flu di $er$agai @ilayah dunia?.1/ 2@al mula penggunaan aspirin se$agai o$at diprakarsai oleh -ippocrates yang menggunakan ekstrak tum$uhan @illo@ untuk menyem$uhkan $er$agai penyakit? Jemudian senya@a ini dikem$angkan oleh perusahaan <ayer menEadi senya@a asam asetilsalisilat yang dikenal saat ini? 2spirin adalah o$at pertama yang dipasarkan dalam $entuk ta$let? "e$elumnya, o$at diperdagangkan dalam $entuk $u$uk (puyer%? 1alam menyam$ut 4iala 1unia F;F2 *##+ di Jerman, replika ta$let aspirin raksasa dipaEang di <erlin se$agai $agian dari pameran ter$uka 1eutschland, 9and der ;deen (BJerman, negeri $er$agai ideB%?

Da)tar isi

1 2@al mula o 1?1 "eEarah penemuan o 1?* Laman modern * <ayer 3 JerEa 2spirin 9ihat pula ! 4ranala luar + Referensi

A1al mula

Sejarah penemuan
"enya@a alami dari tum$uhan yang digunakan se$agai o$at ini telah ada seEak a@al mula perada$an manusia? 1i mulai pada perada$an 8esir kuno, $angsa terse$ut telah menggunakan suatu senya@a yang $erasal dari daun @illo@ untuk menekan rasa sakit? 4ada era yang sama, $angsa "umeria Euga telah menggunakan senya@a yang serupa untuk mengatasi $er$agai Eenis penyakit? -al ini tercatat dalam ukiran&ukiran pada $e$atuan di daerah terse$ut? <arulah pada tahun ## "8, filsafat -ippocrates menggunakannya se$agai tanaman o$at yang kemudian segera terse$ar luas?.*/

Zaman modern
Reverend >d@ard "tone dari :hipping Morton, ;nggris, merupakan orang pertama yang mempu$likasikan penggunaan medis dari aspirin? 4ada tahun 1)+3, ia telah $erhasil melakukan pengo$atan terhadap $er$agai Eenis penyakit dengan menggunakan senya@a terse$ut?.3/ 4ada tahun 1,*+, peneliti $erke$angsaan ;talia, <rugnatelli dan Fontana, melakukan uEi co$a terhadap penggunaan suatu senya@a dari daun @illo@ se$agai agen medis?. / 1ua tahun $erselang, pada tahun 1,*,, seorang ahli farmasi Jerman, <uchner, $erhasil mengisolasi senya@a terse$ut dan di$eri nama salicin yang $erasal dari $ahasa latin @illo@, yaitu salix? "enya@a ini memiliki aktivitas antipiretik yang mampu menyem$uhkan demam? 4enelitian mengenai senya@a ini $erlanEut hingga pada tahun 1,3# ketika seorang ilmu@an 4erancis $ernama 9erou' $erhasil mengkristalkan salicin? 4enelitian ini kemudian dilanEutkan oleh ahli farmasi Jerman $ernama 8erck pada tahun 1,33? "e$agai hasil penelitiannya, ia $erhasil mendapatkan kristal senya@a salicin dalam kondisi yang sangat murni?.!/ "enya@a asam salisilat sendiri $aru ditemukan pada tahun 1,3( oleh Raffaele 4iria dengan rumus empiris :)-+A3?

'ayer
<ayer meupakan perusahaan pertama yang $erhasil menciptakan senya@a aspirin (asam asetilsalisilat%? ;de untuk memodifikasi senya@a asam salisilat dilatar$elakangi oleh $anyaknya efek negatif dari senya@a ini? 4ada tahun 1( !, 2rthur >ichengrun dari perusahaan <ayer mengemukakan idenya untuk menam$ahkan gugus asetil dari senya@a asam salisilat untuk mengurangi efek negatif sekaligus meningkatkan efisiensi dan toleransinya?.+/ 4ada tahun 1,(), Feli' -offmann $erhasil melanEutkan gagasan terse$ut dan menciptakan senya@a asam asetilsalisilat yang kemudian umum dikenal dengan istilah aspirin? 2spirin merupakan akronim dari: A s,ir s,iraea in : Gugus asetil : nama $unga terse$ut dalam $ahasa 9atin : suku kata tam$ahan yang sering kali digunakan : untuk 0at pada masa terse$ut?

2spirin adalah 0at sintetik pertama di dunia dan penye$a$ utama perkem$angan industri farmateutikal? <ayer mendaftarkan aspirin se$agai merek dagang pada + 8aret 1,((?

Feli' -offmann $ukanlah orang pertama yang $erusaha untuk menciptakan senya@a aspirin ini? "e$elumnya pada tahun 1,!3, seorang ilmu@an 4erancis $ernama Frederick Gerhardt telah menco$a untuk menciptakan suatu senya@a $aru dari ga$ungan asetil klorida dan sodium salisilat?.)/ 2spirin diEual se$agai o$at pada tahun 1,(( setelah Feli' -offmann $erhasil memodifikasi asam salisilat, senya@a yang ditemukan dalam kulit kayu dedalu? <ayer kehilangan hak merek dagang setelah pasukan sekutu merampas dan menEual aset luar perusahaan terse$ut setelah 4erang 1unia 4ertama? 1i 2merika "erikat (2"%, hak penggunaan nama aspirin telah di$eli oleh 2" melalui "terling 1rug ;nc?, pada 1(1,? Walaupun masa patennya $elum $erakhir, <ayer tidak $erhasil menghalangi saingannya dari peniruan rumus kimia dan menggunakan nama aspirin? 2ki$atnya, "terling gagal untuk menghalangi B2spirinB dari penggunaan se$agai kata generik? 1i negara lain seperti Janada, B2spirinB masih dianggap merek dagang yang dilindungi?

.er4a As,irin

:oated 3*! mg aspirin ta$lets 8enurut kaEian John Vane, aspirin mengham$at pem$entukan hormon dalam tu$uh yang dikenal se$agai prostaglandins? "iklooksigenase, seEenis en0im yang terli$at dalam pem$entukan prostaglandins dan trom$oksan, terhenti tak $er$alik apa$ila aspirin mengasetil en0im terse$ut? Prostaglandins ialah hormon yang dihasilkan di dalam tu$uh dan mempunyai efek pel$agai di dalam tu$uh termasuk proses penghantaran rangsangan sakit ke otak dan pemodulatan termostat hipotalamus? Crom$oksan pula $ertanggungEa@a$ dalam pengagregatan platlet? "erangan Eantung dise$a$kan oleh penggumpalan darah dan rangsangan sakit menuEu ke otak? Aleh itu, pengurangan gumpalan darah dan rangsangan sakit ini dise$a$kan konsumsi aspirin pada kadar yang sedikit dianggap $aik dari segi pengo$atan? Mamun, efeknya darah lam$at mem$eku menye$a$kan pendarahan $erle$ihan $isa CerEadi? Aleh itu, mereka yang akan menEalani pem$edahan atau mempunyai masalah pendarahan tidak diper$olahkan mengonsumsi aspirin?

i%at ,ula

Jenis&Eenis o$at analgesik yang lain ialah:

4arasetamol Jodeina >sterifikasi 2spirin

2spirin ini di$uat dengan cara esterifikasi, dimana $ahan aktif dari aspirin yaitu asam salisitat direaksikan dengan asam asetat anhidrad atau dapat Euga direaksikan dengan asam asetat glacial $ila asam asetat anhidrad sulit untuk ditemukan? 2sam asetat anhidrad ini dapat digantikan dengan asam asetat glacial karena asam asetat glacial ini $ersifat murni dan tidak mengandung air selain itu asam asetat anhidrad Euga ter$uat dari dua asan asetat galsial sehingga pada pereaksian volumenya semua digandakan? 4ada proses pem$uatan reaksi esterifikasi ini di$antu oleh suatu katalis asam untuk mempercepat reaksi? Cetapi pada penam$ahan katalis ini tidak terlalu $erefek maka dilakukan lah pemanasan untuk mempercepat reaksinya? 4ada pem$uatan aspirin Euga ditam$ahkan air untuk melakukan rekristalisasi $erlangsung cepat dan akan ter$entuk endapan? >ndapan inilah yang merupakanaspirin?

5uinine
From Wikipedia, the free encyclopedia Jump to: navigation, search Mot to $e confused @ith Nuinone? =uinine

Systematic (IUPAC) name

(R%&(+&metho'yNuinolin& &yl%((1R,*", R,!"%&!&vinylNuinuclidin&*& yl%methanol

Clinical data +rade names =ualaNuin AHFS/Drugs.com monograph MedlinePlus a+,*3** Pregnancy cat. : (3"2%, 1 (2u% egal status R'&only 3"2 !outes Aral, intravenous P%armaco&inetic data 'ioa$aila(ility )+ to ,,7 Protein (inding 6)#7 -epatic (mostly :K432 and Meta(olism :K4*:1(&mediated% Hal)*li)e 61, hours "#cretion Renal (*#7% Identi)iers CAS num(er 13#&(!&# A+C code 8#(22#1 4#1<:#1 Pu(C%em :;1 ,! ( IUPHA! ligand *!1#

Drug'an& C%emS,ider U-II ."// C%"'I C%"M' Formula Mol. mass "8;9>".sho@/ ;n:h;.sho@/

1<## +, , (,( 2)V*)4-:)2 1#, +# :-><;:1!,! :->8<91)# C%emical data C*#H* -*0* 3* ? 1) g5mol

P%ysical data Melt. ,oint 1)) S: (3!1 SF% (1%at is t%is2) ($eri)y) 5uinine (3" 5k@anan5, 3J 5k@nin5 or 5k@nin5 KWIN-een% is a natural @hite crystalline alkaloid having antipyretic (fever&reducing%, antimalarial, analgesic (painkilling%, and anti&inflammatory properties and a $itter taste? ;t is a stereoisomer of Nuinidine @hich, unlike Nuinine, is an antiarrhythmic? =uinine contains t@o maEor fused& ring systems: the aromatic Nuinoline and the $icyclic Nuinuclidine? Chough it has $een synthesi0ed in the la$, Nuinine occurs naturally in the $ark of the cinchona tree? Che medicinal properties of the cinchona tree @ere originally discovered $y the =uechua, @ho are indigenous to 4eru and <oliviaF later, the Jesuits @ere the first to $ring the cinchona to >urope? =uinine @as the first effective treatment for malaria caused $y Plasmodium falciparum, appearing in therapeutics in the 1)th century? ;t remained the antimalarial drug of choice until the 1( #s, @hen other drugs replaced it that have less unpleasant side effects? "ince then, many effective antimalarials have $een introduced, although Nuinine is still used to treat the disease in certain critical circumstances, such as severe malaria, and in impoverished regions due to its lo@ cost? =uinine is availa$le @ith a prescription in the 3nited "tates and over&the&counter, in minute Nuantities, in tonic @ater? =uinine is also used to treat lupus and arthritis? =uinine @as also freNuently prescri$ed in the 3" as an Boff&la$elB treatment for nocturnal leg cramps, $ut this has since $een prohi$ited, in effect, $y an F12 statement @arning against the practice?.1/ =uinine is very sensitive to ultraviolet light (3V% and @ill fluoresce in direct sunlight, due to its highly conEugated resonance structure (see =uinoline%?

Contents

1 8echanism of action against P. falciparum * -istory o *?1 "ynthetic Nuinine

3 1osing and indication 2dverse effects o ?1 Mon&a$ortifacient o ?* 1isease interactions o ?3 -earing impairment ! Regulation $y the 3nited "tates Food and 1rug 2dministration + Monmedical uses of Nuinine o +?1 <everages o +?* "cientific o +?3 Ather ) "ee also , References ( Further reading 1# >'ternal links

Mec%anism o) action against P. falciparum

2s @ith other Nuinoline antimalarial drugs, the mechanism of action of Nuinine has not $een fully resolved? Che most @idely accepted hypothesis of its action is $ased on the @ell&studied and closely related Nuinoline drug, chloroNuine? Chis model involves the inhi$ition of hemo0oin $iocrystalli0ation, @hich facilitates the aggregation of cytoto'ic heme? Free cytoto'ic heme accumulates in the parasites, causing their deaths?

History
=uinine.*/ is an effective muscle rela'ant, long used $y the =uechua, @ho are indigenous to 4eru, to halt shivering due to lo@ temperatures? Che 4eruvians @ould mi' the ground $ark of cinchona trees @ith s@eetened @ater to offset the $arkDs $itter taste, thus producing tonic @ater?

1(th&century illustration of Cinchona calisaya =uinine has $een used in une'tracted form $y >uropeans since at least the early 1)th century? ;t @as first used to treat malaria in Rome in 1+31?.3/ 1uring the 1)th century, malaria @as endemic to the s@amps and marshes surrounding the city of Rome? 8alaria @as responsi$le for the deaths of several popes, many cardinals and countless common Roman citi0ens? 8ost of the priests trained in Rome had seen malaria victims and @ere familiar @ith the shivering $rought on $y the fe$rile phase of the disease? Che Jesuit $rother 2gostino "alum$rino (1!+1P1+ *%, an apothecary $y training @ho lived in 9ima, o$served the =uechua using the $ark of the cinchona tree for that purpose? While its

effect in treating malaria (and hence malaria&induced shivering% @as unrelated to its effect in controlling shivering from rigors, it @as still a successful medicine for malaria? 2t the first opportunity, "alum$rino sent a small Nuantity to Rome to test as a malaria treatment? ;n the years that follo@ed, cinchona $ark, kno@n as JesuitDs $ark or 4eruvian $ark, $ecame one of the most valua$le commodities shipped from 4eru to >urope? Che form of Nuinine most effective in treating malaria @as found $y :harles 8arie de 9a :ondamine in 1)3)?. /.!/ =uinine @as isolated and named in 1,*# $y French researchers 4ierre Joseph 4elletier and Joseph <ienaimT :aventou?.+/ Che name @as derived from the original =uechua (;nca% @ord for the cinchona tree $ark, quina or quina-quina, @hich means B$ark of $arkB or Bholy $arkB? 4rior to 1,*#, the $ark @as first dried, ground to a fine po@der, and then mi'ed into a liNuid (commonly @ine% @hich @as then drunk? 9arge&scale use of Nuinine as a prophyla'is started around 1,!#? =uinine also played a significant role in the coloni0ation of 2frica $y >uropeans? =uinine had $een said to $e the prime reason 2frica ceased to $e kno@n as the B@hite manDs graveB? 2n historian has stated, Bit @as NuinineDs efficacy that gave colonists fresh opportunities to s@arm into the Gold :oast, Migeria and other parts of @est 2fricaB?.)/ Co maintain their monopoly on cinchona $ark, 4eru and surrounding countries $egan outla@ing the e'port of cinchona seeds and saplings $eginning in the early 1(th century? Che 1utch government persisted in its attempt to smuggle the seeds, and $y the 1(3#s 1utch plantations in Java @ere producing ** million pounds of cinchona $ark, or ()7 of the @orldDs Nuinine production?.)/ 1uring World War ;;, 2llied po@ers @ere cut off from their supply of Nuinine @hen the Germans conNuered the Metherlands and the Japanese controlled the 4hilippines and ;ndonesia? Che 3nited "tates had managed to o$tain four million cinchona seeds from the 4hilippines and $egan operation of cinchona plantations in :osta Rica? Monetheless, such supplies came too lateF tens of thousands of 3" troops in 2frica and the "outh 4acific died due to the lack of Nuinine?.)/ 1espite controlling the supply, the Japanese did not make effective use of Nuinine, and thousands of Japanese troops in the south@est 4acific died as a result?.,/

Synt%etic 6uinine
8ain article: Nuinine total synthesis

Ro$ert <? Wood@ard

:inchona trees remain the only economically practical source of Nuinine? -o@ever, under @artime pressure, research to@ards its synthetic production @as undertaken? 2 formal chemical synthesis @as accomplished in 1( $y 2merican chemists R?<? Wood@ard and W?>? 1oering?.(/ "ince then, several more efficient Nuinine total syntheses have $een achieved,.1#/ $ut none of them can compete in economic terms @ith isolation of the alkaloid from natural sources? Che first synthetic organic dye, mauveine, @as discovered $y William -enry 4erkin in 1,!+ @hile he @as attempting to synthesi0e Nuinine?

Dosing and indication

2s of *##+, Nuinine is no longer recommended $y the W-A as first&line treatment for malaria, and should $e used only @hen artemisinins are not availa$le?.11/.1*/.13/.1 / =uinine is a $asic amine and is al@ays presented as a salt? Various e'isting preparations include the hydrochloride, dihydrochloride, sulfate, $isulfate and gluconate? Chis makes Nuinine dosing complicated, since each of the salts has a different @eight? Che follo@ing amounts of each salt form contain eNual amounts of Nuinine:

Nuinine $ase 1## mg Nuinine $isulfate 1+( mg Nuinine dihydrochloride 1** mg Nuinine hydrochloride 111 mg Nuinine sulfate (actually (Nuinine%*-*"A U*-*A% 1*1 mg Nuinine gluconate 1+# mg

2ll Nuinine salts may $e given orally or intravenously (;V%F Nuinine gluconate may also $e given intramuscularly (;8% or rectally (4R%?.1!/.1+/ Che main pro$lem @ith the rectal route is the dose can $e e'pelled $efore it is completely a$sor$edF in practice, this is corrected $y giving a half dose again? Che ;V dose of Nuinine is , mg5kg of Nuinine $ase every eight hoursF the ;8 dose is 1*?, mg5kg of Nuinine $ase t@ice dailyF the 4R dose is *# mg5kg of Nuinine $ase t@ice daily? Creatment should $e given for seven days? For at least the ;V formulation, a loading dose of *# mg5kg is reNuired? Che preparations availa$le in the 3J are Nuinine sulfate (*##&mg or 3##&mg ta$lets% and Nuinine hydrochloride (3## mg5ml for inEection%? =uinine is not licensed for ;8 or 4R use in the 3nited Jingdom? Che adult dose in the 3J is +## mg Nuinine dihydrochloride ;V or +## mg Nuinine sulfate orally every eight hours? For nocturnal leg cramps, the dosage is *##P3## mg at night?.1)/ ;n the 3nited "tates, Nuinine sulfate is commercially availa$le in 3* &mg ta$lets under the $rand name =ualaNuinF the adult dose is t@o ta$lets every eight hours? Mo inEecta$le preparation of Nuinine is licensed in the 3"F Nuinidine is used instead?.1,/.1(/

Ad$erse e))ects
8ain article: :inchonism =uinine can, in therapeutic doses, cause cinchonismF in rare cases, it may even cause death (usually $y pulmonary edema%? Che development of mild cinchonism is not a reason for stopping or interrupting Nuinine therapy, and the patient should $e reassured? <lood glucose levels and electrolyte concentrations must $e monitored @hen Nuinine is given $y inEection? Che patient should ideally $e in cardiac monitoring @hen the first Nuinine inEection is given (these precautions are often unavaila$le in developing countries @here malaria is endemic%? :inchonism is much less common @hen Nuinine is given $y mouth, $ut oral Nuinine is not @ell tolerated (Nuinine is e'ceedingly $itter and many patients @ill vomit after ingesting Nuinine ta$lets%: Ather drugs such as Fansidar (sulfado'ine @ith pyrimethamine% or 8alarone (proguanil @ith atovaNuone% are often used @hen oral therapy is reNuired? =uinine ethyl car$onate is tasteless and odourless,.*#/ $ut is availa$le commercially only in Japan? <lood glucose, electrolyte and cardiac monitoring are not necessary @hen Nuinine is given $y mouth? =uinine can cause paralysis if accidentally inEected into a nerve? ;t is e'tremely to'ic in overdose, and the advice of a poisons specialist should $e sought immediately? =uinine in some cases can lead to constipation,.*1/ erectile dysfunction, or diarrhea? The New or! Times "aga#ine descri$ed a case, presenting @ith fever, hypotension, and $lood a$normalities mimicking septic shock?.**/

-on*a(orti)acient
1espite popular $elief, Nuinine is not an effective a$ortifacient (a su$stance that may induce a$ortion% (in the 3", Nuinine is listed as pregnancy category 1 .*3/%? 4regnant @omen @ho take to'ic doses of Nuinine @ill suffer from renal failure $efore e'periencing any kind of Nuinine&induced a$ortion?.* / ;ndeed, Nuinine is the only drug recommended $y the W-A as first&line treatment for uncomplicated malaria in pregnancy?.*!/

Disease interactions
=uinine can cause hemolysis in G+41 deficiency (an inherited deficiency%, $ut this risk is small and the physician should not hesitate to use Nuinine in patients @ith G+41 deficiency @hen there is no alternative? =uinine can also cause drug&induced immune throm$ocytopenic purpura? "ymptoms can $e severe enough to reNuire hospitali0ation and platelet transfusion, @ith several cases resulting in death?.*+/ =uinine can cause a$normal heart rhythms and should $e avoided if possi$le in patients @ith atrial fi$rillation, conduction defects or heart $lock?

Hearing im,airment
"ome studies have related the use of Nuinine and hearing impairment, particularly high& freNuency loss, $ut it has not $een conclusively esta$lished @hether such impairment is temporary or permanent?.*)/

!egulation (y t%e United States Food and Drug Administration

From 1(+( to 1((*, the 3" Food and 1rug 2dministration (F12% received 1!) reports of health pro$lems related to Nuinine use, including *3 @hich had resulted in death?.*,/ ;n 1(( , the F12 $anned the use of over&the&counter Nuinine as a treatment for nocturnal leg cramps? 4fi0er 4harmaceuticals had $een selling the $rand name 9egatrin for this purpose? 1octors may still prescri$e Nuinine, $ut the F12 has ordered firms to stop marketing unapproved drug products containing Nuinine? Che F12 is also cautioning consumers a$out off&la$el use of Nuinine to treat leg cramps? =uinine is approved for treatment of malaria, $ut is also commonly prescri$ed to treat leg cramps and similar conditions? <ecause malaria is life&threatening, the risks associated @ith Nuinine use are considered accepta$le @hen used to treat that affliction?.*(/ Chough 9egatrin @as $anned $y the F12 for the treatment of leg cramps, drug manufacturer 3R9 8utual has $randed a Nuinine&containing drug named =ualaNuin? ;t is marketed as a treatment for malaria and is sold in the 3nited "tates only $y prescription? ;n *## , the :1: reported only 1,3 ) confirmed cases of malaria in the 3nited "tates?.3#/

-onmedical uses o) 6uinine

Conic @ater, in normal light and B$lack lightB? ;n some areas, nonmedical use of Nuinine is regulated? For e'ample, in the 3nited "tates and Germany, Nuinine is limited to $et@een ,3 and ,! parts per million?.31/

'e$erages
=uinine is a flavour component of tonic @ater and $itter lemon? An the soda gun $ehind most $ars, tonic @ater is designated $y the letter B=B representing Nuinine? 2ccording to tradition, the $itter taste of antimalarial Nuinine tonic led <ritish colonials in ;ndia to mi' it @ith gin, thus creating the gin and tonic cocktail, @hich is still popular today in many parts of the @orld, especially the 3J, 3nited "tates, :anada, 2ustralia, and Me@ Lealand? ;n France, Nuinine is an ingredient of an ap$ritif kno@n as quinquina or B:ap :orseB? ;n ;taly, the traditional flavoured @ine <arolo :hinato is infused @ith Nuinine and local her$s and is served as a digestif? ;n :anada and ;taly, Nuinine is an ingredient in the car$onated chinotto $everages <rio and "an 4ellegrino chinotto? ;n "cotland, the company 2?G? <arr uses Nuinine as an ingredient in the car$onated and caffeinated $everage <arrDs ;rn&<ru? ;n the 3nited Jingdom, 2ustralia, Me@ Lealand, "outh 2frica and >gypt, Nuinine is an ingredient in "ch@eppes and other ;ndian tonic @aters? ;n 3ruguay and 2rgentina, Nuinine is an ingredient of a 4epsico ;nc? tonic @ater named 4aso de los Coros? ;n "outh 2frica, Nuinine is an ingredient of a :lifton ;nstant 1rink named :hikree produced $y Ciger Food <rands? ;n 1enmark, it is used as an ingredient in the car$onated sports drink Fa'e Jondi made $y Royal 3ni$re@?

Scienti)ic
<ecause of its relatively constant and @ell&kno@n fluorescence Nuantum yield, Nuinine is used in photochemistry as a common fluorescence standard? Che 3V a$sorption peaks around 3!#nm (in 3V2%? Fluorescent emission peaks at around !#nm (looking $right $lue5cyan%?.3*/ =uinine (and Nuinidine% are used as the chiral moiety for the ligands used in "harpless asymmetric dihydro'ylation? Che $ark of %emi&ia contains #?!P*7 of Nuinine? Che $ark is cheaper than $ark of Cinchona, and as it has an intense taste, it is used for making tonic @ater?.33/

0t%er
=uinine is sometimes used as a cutting agent in street drugs such as cocaine and heroin?
.3 /

=uinine is used as a treatment for Cryptocaryon irritans (commonly referred to as @hite spot, crypto or marine ich% infection of marine aNuarium fish?.3!/

Digo#in
From Wikipedia, the free encyclopedia Jump to: navigation, search Mot to $e confused @ith 1io'in? 1igo'in

Systematic (IUPAC) name

&.(3S,!%,,%,(S,1#S,1*%,13S,1 S%&3&.(*S, S,!%,+%%&!&.(*S, S,!%,+%%&!&.(*S, S,!%,+%%& ,!& dihydro'y&+&methyl&o'an&*&yl/o'y& &hydro'y&+&methyl&o'an&*&yl/o'y& &hydro'y&+&methyl&o'an& *&yl/o'y&1*,1 &dihydro'y&1#,13&dimethyl&1,*,3, ,!,+,),,,(,11,1*,1!,1+,1)& tetradecahydrocyclopenta.a/phenanthren&1)&yl/&!'&furan&*&one

Clinical data +rade names 9ano'in AHFS/Drugs.com monograph MedlinePlus a+,*3#1 Pregnancy cat. 2 (2u%, : (3?"?% " (2u%, 4A8 (3J%, &only (3?"?% egal status !outes Aral, ;ntravenous P%armaco&inetic data 'ioa$aila(ility +# to ,#7 (Aral% Protein (inding *!7 Meta(olism -epatic (1+7% 3+ to , hours Hal)*li)e "#cretion
(patients @ith normal renal function%

3?! to ! days
(patients @ith impaired renal function%

Renal Identi)iers CAS num(er *#,3#&)!&! A+C code :#122#! Pu(C%em :;1 *)* 3,! Drug'an& 1<##3(# C%emS,ider *##+!3* U-II )3J 1, C!( ."// 1##*(, C%"'I :-><;: !!1 C%"M' :->8<91)!1 C%emical data Formula C 1H+ 01 Mol. mass ),#?(3, g5mol "8;9>".sho@/ ;n:h;.sho@/ P%ysical data Melt. ,oint * (?3 S: ( ,1 SF% Solu(ility in 1ater #?#+ , mg5m9 (*# S:% (1%at is t%is2) ($eri)y) Digo#in ;MM (5ddksn5.1/% is a purified cardiac glycoside e'tracted from the fo'glove plant, (igitalis lanata..*/ ;ts corresponding aglycone is digo'igenin, and its acetyl derivative is acetyldigo'in? 1igo'in is @idely used in the treatment of various heart

conditions, namely atrial fi$rillation, atrial flutter and sometimes heart failure that cannot $e controlled $y other medication? 1igo'in preparations are commonly marketed under the trade names 9ano'in, 1igitek, and 9ano'icaps? ;t is also availa$le as a #?#! mg5ml oral solution and #?*! mg5ml or #?! mg5ml inEecta$le solution? ;t is marketed $y Gla'o"mithJline and many other pharmaceutic manufacturers?

Contents

1 8edical use * 4harmacokinetic properties 3 2dverse effects 2ctions ! 8echanism of action + "ociety and culture ) References , Further reading ( >'ternal links

Medical use
Coday, the most common indications for digo'in are atrial fi$rillation and atrial flutter @ith rapid ventricular response? <eta $lockers and5or calcium channel $lockers should $e the first choice?.3/. / -igh ventricular rate leads to insufficient diastolic filling time? <y slo@ing do@n the conduction in the 2V node and increasing its refractory period, digo'in can reduce the ventricular rate? Che arrhythmia itself is not affected, $ut the pumping function of the heart improves o@ing to improved filling? Che use of digo'in in heart pro$lems during sinus rhythm @as once standard, $ut is no@ controversial? ;n theory, the increased force of contraction should lead to improved pumping function of the heart, $ut its effect on prognosis is disputa$le, and other effective treatments are no@ availa$le? 1igo'in is no longer the first choice for congestive heart failure, $ut can still $e useful in patients @ho remain symptomatic despite proper diuretic and 2:> inhi$itor treatment? 1igitalis5digo'in has recently fallen out of favor $ecause it did not demonstrate a mortality $enefit in patients @ith congestive heart failureF ho@ever, it did demonstrate a reduction in hospitali0ations for this condition?.!/ <ecause other therapies have sho@n a mortality $enefit in congestive heart failure, ma'imi0ing other therapies (e?g?, $eta $lockers% first is recommended $efore using digo'in?

P%armaco&inetic ,ro,erties

1igo'in is usually given $y mouth, $ut can also $e given $y ;V inEection in urgent situations (the ;V inEection should $e slo@, and heart rhythm should $e monitored%? While ;V therapy may $e $etter tolerated (less nausea%, digo'in has a very long distri$ution half&life into the cardiac tissue, @hich @ill delay its onset of action $y a num$er of hours? Che half&life is a$out 3+ hours, digo'in is given once daily, usually in 1*!&Vg or *!#&Vg doses? ;n patients @ith decreased kidney function, the half&life is considera$ly longer, calling for a reduction in dose or a s@itch to a different glycoside, such as digito'in (not availa$le in the 3nited "tates%, @hich has a much longer elimination half&life of around seven days, $ut is mainly eliminated from the $ody via the liver, and thus not affected $y changes in kidney function? >ffective plasma levels vary depending on the medical indication? For congestive heart failure, levels $et@een #?! and 1?# ng5ml are recommended?.+/ Chis recommendation is $ased on post hoc analysis of prospective trials, suggesting higher levels may $e associated @ith increased mortality rates? For heart rate control (atrial fi$rillation%, plasma levels are less defined and are generally titrated to a goal heart rate? Cypically, digo'in levels are considered therapeutic for heart rate control $et@een 1?# and *?# ng5ml? ;n suspected to'icity or ineffectiveness, digo'in levels should $e monitored? 4lasma potassium levels also need to $e closely controlled (see side effects $elo@%? =uinidine, verapamil, and amiodarone increases plasma levels of digo'in ($y displacing tissue $inding sites and depressing renal digo'in clearance%, so plasma digo'in must $e monitored carefully? Researchers at Kale 3niversity looked at data from an earlier study to see if digo'in affected men and @omen differently? Chat study determined digo'in, @hich has $een used for centuries and makes the heart contract more forcefully, did not reduce deaths overall, $ut did result in less hospitali0ation? Researcher 1r? -arlan Jrumhol0 said they @ere surprised to find @omen in the study @ho took digo'in died Bmore freNuentlyB (337% than @omen @ho took a place$o pill (*(7%? Chey calculated digo'in increased the risk of death in @omen $y *37? Chere @as no difference in the death rate for men in the study? 1igo'in is also used as a standard control su$stance to test for p&glycoprotein inhi$ition?

Ad$erse e))ects
8ain article: 1igo'in to'icity Che occurrence of adverse drug reactions is common, o@ing to its narro@ therapeutic inde' (the margin $et@een effectiveness and to'icity%? 2dverse effects are concentration& dependent, and are rare @hen plasma digo'in concentration is W#?, Vg5l?.)/ Chey are also more common in patients @ith lo@ potassium levels (hypokalemia%, since digo'in normally competes @ith JX ions for the same $inding site on the MaX5JX 2C4ase pump?

:ommon adverse effects (Y17 of patients% include: loss of appetite, nausea, vomiting and diarrhea as gastrointestinal motility increases? Ather common effects are $lurred vision, visual distur$ances (yello@&green halos and pro$lems @ith color perception%, confusion, dro@siness, di00iness, insomnia, nightmares, agitation, and depression, as @ell as a higher acute sense of sensual activities?.,/ 9ess freNuent adverse effects (#?17P17% include: acute psychosis, delirium, amnesia, convulsions, shortened =R" comple', atrial or ventricular e'trasystoles, paro'ysmal atrial tachycardia @ith 2V $lock, ventricular tachycardia or fi$rillation, and heart $lock?.)/ Rarely, digo'in has $een sho@n to cause throm$ocytopenia? Gynaecomastia (enlargement of $reast tissue% is mentioned in many te't$ooks as a side effect, thought to $e due to the estrogen&like steroid moiety of the digo'in molecule,.(/ $ut @hen systematically sought, the evidence for this is eNuivocal?.1#/ Che pharmacological actions of digo'in usually result in electrocardiogram changes, including "C depression or C @ave inversion, @hich do not indicate to'icity? 4R interval prolongation, ho@ever, may $e a sign of digo'in to'icity? 2dditionally, increased intracellular :a*X may cause a type of arrhythmia called $igeminy (coupled $eats%, eventually ventricular tachycardia or fi$rillation? Che com$ination of increased (atrial% arrhythmogenesis and inhi$ited atrioventricular conduction (for e'ample paro'ysmal atrial tachycardia @ith 2&V $lock & so&called B42C @ith $lockB% is said to $e pathognomonic (i?e? diagnostic% of digo'in to'icity?.11/ 2n often descri$ed, $ut rarely seen, adverse effect of digo'in is a distur$ance of color vision (mostly yello@ and green% called 'anthopsia? Vincent van GoghDs BKello@ 4eriodB may have someho@ $een influenced $y concurrent digitalis therapy? Ather oculoto'ic effects of digo'in include generali0ed $lurry vision, as @ell as seeing a BhaloB around each point of light?.1*/ Che latter effect can also $e seen in van GoghDs "tarry Might? >vidence of van GoghDs digo'in use is supported $y multiple self portraits that include the fo'glove plant, from @hich digo'in is o$tained? (e?g? 4ortrait of 1r? Gachet% 1igo'in plasma concentrations may increase @hile on antimalarial medication hydro'ychloroNuine ($ased on t@o case reports from 1(,*%?.13/ ;n overdose, the usual supportive measures are needed? ;f arrhythmias prove trou$lesome, or malignant hyperkalaemia occurs (ine'ora$ly rising potassium level due to paralysis of the cell mem$rane&$ound, 2C4ase&dependent Ma5J pumps%, the specific antidote is antidigo'in (anti$ody fragments against digo'in, trade names 1igi$ind and 1igifa$%?.1 / Co'icity can also $e treated @ith higher than normal doses of potassium? 1igo'in is not removed $y hemodialysis or peritoneal dialysis @ith enough effectiveness to treat to'icity? 1igo'in has potentially dangerous interactions @ith verapamil,.1!/ amiodarone, erythromycin, and epinephrine (as @ould $e inEected @ith a local anesthetic%?

Actions
Chis section does not cite any re)erences or sources? )*pril +,-+.

Che main pharmacological effects of digo'in are on the heart? >'tracardiac effects are responsi$le for some of the therapeutic and many of the adverse effects (see $elo@%? ;t has mechanical effects as it increases myocardial contractilityF ho@ever, the duration of the contractile response is Eust slightly increased? Averall, the heart rate is decreased, @hile $lood pressure increases as the stroke volume is increased, leading to increased tissue perfusion? 8yocardial efficiency is due to improved hemodynamics, and the ventricular function curve is improved? Ather, electrical effects are an initial $rief increase in action potential, follo@ed $y a decrease as the JX conductance increases due to an increased intracellular amounts of :a*X ions? Che refractory period of the atria and ventricles is decreased, @hile it increases in the sinoatrial and 2V nodes? 2 less negative resting mem$rane potential is made, leading to increased e'cita$ility? Ather, more indirect effects are cholinomimetic $ecause of vagal stimulation, giving rise to 2V nodal delay? Che conduction velocity increases in the atria, $ut decreases in the 2V node? Che effect upon 4urkinEe fi$ers and ventricles is negligi$le? 2utomaticity is also increased, in the atria, 2V node, 4urkinEe fi$ers and ventricles? >:G changes are increased 4R interval, due to decreased 2V conduction, and a decreased =C interval $ecause of the altered duration of decreased action potential? 2lso, the C @ave is inverted, accompanied $y "C depression? ;t may cause 2V Eunctional rhythm and ectopic $eats ($igeminy% resulting in ventricular tachycardia and fi$rillation? "light vasodilation is seen in heart failure? Chis effect is contrary to effects that should $e seen as a result of increased intracellular calcium levels, $ut this occurs since digo'in improves hemodynamics, @hich leads to restored angiotensin levels and decreased sympathetic discharge, causing indirect vasodilation? 1igo'in also affects the kidney $y increased renal $lood flo@ and increased glomerular filtration rate? 2 mild diuretic effect is seen only in heart failure?

Mec%anism o) action
Che mechanism of action is not completely understoodF ho@ever, the current hypothesis is outlined $elo@? 1igo'in $inds to a site on the e'tracellular aspect of the I&su$unit of the MaX5JX 2C4ase pump in the mem$ranes of heart cells (myocytes% and decreases its function? Chis causes an increase in the level of sodium ions in the myocytes, @hich leads to a rise in the level of intracellular calcium ions? Chis occurs $ecause the sodium5calcium e'changer on the plasma mem$rane depends on a constant in@ard sodium gradient to pump out calcium? 1igo'in decreases the sodium concentration gradient and the su$seNuent calcium outflo@, thus raising the calcium concentration in myocardiocytes and pacemaker cells?

;ncreased intracellular calcium lengthens phase and phase # of the cardiac action potential, @hich leads to a decrease in heart rate?.1+/ ;ncreased amounts of :a*X also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential? Chis leads to increased contractility (the force of contraction% of the heart @ithout increasing heart energy e'penditure? Chere is also evidence that digo'in increases vagal activity, there$y decreasing heart rate $y slo@ing depolari0ation of pacemaker cells in the 2V node?.1)/ Chis negative chronotropic effect @ould therefore $e synergistic @ith the direct effect on cardiac pacemaker cells? 1igo'in is used @idely in the treatment of various arrhythmias?

Society and culture

:harles :ullen admitted in *##3 to killing as many as # hospital patients @ith overdoses of heart medicationZusually digo'inZat hospitals in Me@ Jersey and 4ennsylvania over his 1+&year career as a nurse? An 8arch 1#, *##+, he @as sentenced to 1, consecutive life sentences and is not eligi$le for parole?.1,/ An 2pril *!, *##,, the F12 issued a press release.1(/ alerting the pu$lic to a :lass ; recall of 1igitek, a $rand of digo'in produced $y 8ylan?.*#/ "ome ta$lets had $een released at dou$le thickness and therefore dou$le strength, causing some patients to e'perience digo'in to'icity? 2 class&action la@suit against the ;celandic generic drug maker 2ctavis @as announced t@o @eeks later?.*1/ An 8arch 31, *##(, the F12 announced another generic digo'in pill recall $y posting this company press release on the agencyDs @e$ site: B:araco 4harmaceutical 9a$oratories, 9td? 2nnounces a Mation@ide Voluntary Recall of 2ll 9ots of 1igo'in Ca$lets 1ue to "i0e Varia$ilityB? Chis 8arch 31 press release from :araco, a generic pharmaceutical company, states: .2ll/ ta$lets of :araco $rand 1igo'in, 3"4, #?1*! mg, and 1igo'in, 3"4, #?*! mg, distri$uted prior to 8arch 31, *##(, @hich are not e'pired and are @ithin the e'piration date of "eptem$er, *#11, are $eing voluntarily recalled to the consumer level? Che ta$lets are $eing recalled $ecause they may differ in si0e and therefore could have more or less of the active ingredient, digo'in? 2 *##, study suggested digo'in has $eneficial effects not only for the heart, $ut also in reducing the risk of certain kinds of cancer?.**/ -o@ever, comments on this study suggested that digo'in is not effective at reducing cancer risk at therapeutic concentrations of the drug,.*3/ so the results need further investigation?.* /

Cam,tot%ecin
From Wikipedia, the free encyclopedia Jump to: navigation, search :amptothecin

Systematic (IUPAC) name

(S%& &ethyl& &hydro'y&1'&pyrano.3D, D:+,)/indoli0ino.1,*&$/ Nuinoline&3,1 &( ',1*'%&dione

Clinical data Pregnancy cat. [ egal status [ Identi)iers

CAS num(er )+,(&#3& A+C code Mone Pu(C%em :;1 *!3, Drug'an& 1<# +(# C%emS,ider **))! U-II \C3L! L*,2 ."// :#1,() C%"'I :-><;:*)+!+ C%"M' :->8<9+! C%emical data Formula C*#H1+-*0 Mol. mass 3 ,?3!* g5mol "8;9>".sho@/ ;n:h;.sho@/ (1%at is t%is2) ($eri)y) Cam,tot%ecin (CP+) is a cytoto'ic Nuinoline alkaloid @hich inhi$its the 1M2 en0yme topoisomerase ; (topo ;%? ;t @as discovered in 1(++ $y 8? >? Wall and 8? :? Wani in systematic screening of natural products for anticancer drugs? ;t @as isolated from the $ark and stem of Camptotheca acuminata (:amptotheca, -appy tree%, a tree native to :hina used as a cancer treatment in Craditional :hinese 8edicine?.1/ :4C sho@ed remarka$le anticancer activity in preliminary clinical trials $ut also lo@ solu$ility and (high% adverse drug reaction? <ecause of these disadvantages synthetic and medicinal chemists have developed numerous syntheses of :amptothecin.*/.3/. / and various derivatives to increase the $enefits of the chemical, @ith good results? C@o :4C analogues have $een approved and are used in cancer chemotherapy.!/ today, topotecan and irinotecan?.+/.)/

Contents

1 "tructures * <inding 3 4hysical and chemical properties "2R P "tructure&activity relationship o ?1 2& and <&ring modification ?1?1 2lkyl su$stitution ?1?* -e'acyclic :4C analogues o ?* :& and 1&ring modification o ?3 >&ring modifications ! :4C analogues + References

Structures
:4C has a planar pentacyclic ring structure, that includes a pyrrolo.3, &H/&Nuinoline moiety (rings 2, < and :%, conEugated pyridone moiety (ring 1% and one chiral center at position *# @ithin the alpha&hydro'y lactone ring @ith ("% configuration (the >&ring%? ;ts planar structure is thought to $e one of the most important factors in topoisomerase inhi$ition?.,/.(/

<inding of :4C to topo ; and 1M2

'inding
:4C $inds to the topo ; and 1M2 comple' (the covalent comple'% resulting in a ternary comple', and there$y sta$ili0ing it? Chis prevents 1M2 re&ligation and therefore causes 1M2 damage @hich results in apoptosis? :4C $inds $oth to the en0yme and 1M2 @ith hydrogen $onds? Che most important part of the structure is the >&ring @hich interacts from three different positions @ith the en0yme? Che hydro'yl group in position *# forms hydrogen $ond to the side chain on aspartic acid num$er !33 (2sp!33% in the en0yme? ;tOs critical that the configuration of the chiral car$on is ("% $ecause (R% is inactive? Che lactone is $onded @ith t@o hydrogen $onds to the amino groups on arginine 3+ (2rg3+ %? Che 1&ring interacts @ith the X1 cytosine on non&cleaved strand and sta$ili0es the topo ;&1M2 covalent comple' $y forming hydrogen $ond? Chis hydrogen $ond is $et@een car$onyl group in position 1) on the 1&ring and amino group on the pyrimidine ring of X1 cytosine?.1#/.11/ Co'icity of :4C is primarily a result of conversion of single& strand $reaks into dou$le&strand $reaks during the "&phase @hen the replication fork collides @ith the cleavage comple'es formed $y 1M2 and :4C?.1*/

P%ysical and c%emical ,ro,erties

Che lactone ring in :4C is highly suscepti$le to hydrolysis? Che open ring form is inactive and it must therefore $e closed to inhi$it topo ;? Che closed form is favored in acidic condition, as it is in many cancer cells microenvironment? :4C is transported in to the cell $y passive diffusion? :ellular uptake is favored $y lipophilicity, @hich enhances intracellular accumulation? 9ipophilicity makes compounds more sta$le $ecause of improved lactone partitioning into red $lood cells and conseNuently less hydrolysis of the lactone? :4C has affinity for human serum al$umin (-"2%, especially the car$o'ylate form of :4C? <ecause of that, the eNuili$rium $et@een the lactone ring and the car$o'ylate form is driven to@ard the car$o'ylate? Reduced drug&-"2 interactions could result in improved activity?.1#/.13/

SA! 7 Structure*acti$ity relations%i,

:amptothecin "tudies have sho@n that su$stitution at position ), (, 1# and 11 can have positive effect on :4C activity and physical properties, e?g? potency and meta$olic sta$ility? >nlargement of the lactone ring $y one methylene unit also enhances its a$ilities, as in homocamptothecin? "u$stitution at position 1* and 1 leads to inactive derivative?.13/

A- and B-ring modification

Al&yl su(stitution
2lkyl su$stitution at position ) has sho@n increased cytoto'icity, such as ethyl (:*-!% or chloromethyl (:-*:l%? Chese groups are a$le to react @ith the 1M2 in the presence of topo ; @hich leads to more tumor activity? ;t has also $een sho@n that increasing the length of the car$on chain (in position )% leads to increased lipophilicity and conseNuently greater potency and sta$ility in human plasma?.1#/.13/ Ather )&modified :4C analogues are silatecans and karenitecins? Chey are potent inihi$itors on topo ; and $oth have alkylsilyl groups in position ) @hich make them lipophilic and more sta$le? "ilatecans or )&silylcampthothecins have sho@n reduced drug&-"2 interactions @hich contri$utes to its $lood sta$ility and they can also cross the $lood $rain $arrier? 1<&+) is a 1#&hydro'y derivative and is among the most active silatecans? <M413!# @hich $elongs to the series of karenitecins e'hi$its cytoto'ic activity and a$ility to overcome drug resistance? "till another route to make :4COs lipophilic is to introduce lipophilic su$stituents, such as iminomethyl or o'yiminomethyl moieties? Ane of the most potent

compounds is the o'yiminomethyl derivative "C1 ,1 that has the advantage to overcome drug resistance caused $y transport systems?.13/ <asic nitrogen in a car$on chain at position ) makes the compound more hydrophilic and hence more @ater&solu$le? For e'ample is a derivate called :J1&+#*, @hich is a potent topo ; inhi$itor and successfully overcomes the poor @ater solu$ility and to'icity seen @ith :4C?.13/.1 / :onsidera$ly greater activity can $e achieved $y putting electron&@ithdra@ing groups like amino, nitro, $romo or chloro at position ( and 1# and hydro'yl group at position 1# or 11? <ut these compounds are relatively insolu$le in aNueous solutions, @hich causes difficulty in administrations? 8etho'y group at $oth position 1# and 11 simultaneously leads to inactivity?.,/.13/

He#acyclic CP+ analogues

-e'acyclic :4C analogues have sho@n great potency? For e'ample methylenedio'y or ethylenedio'y group connected $et@een 1# and 11 form a ! or + mem$ered ring @hich leads to more @ater&solu$le derivates and increased potency? Researches have sho@n that ethylenedio'y analogues are less potent than methylenedio'y? Che reason is the unfavora$le steric interactions of ethylenedio'y analogues @ith the en0yme?.,/.13/ 2dding amino or chloro group at (th position or chloromethyl group at )th position to these 1#, 11&methylenedio'y or ethylenedio'y analogues results in compounds @ith even greater cytoto'icity $ut @eaker solu$ility in @ater? Co yield 1#, 11&methylenedio'y or ethylenedio'y analogues @ith good @ater solu$ility a good @ay is to introduce a @ater solu$ilising su$stituent at position )? 9urtotecan meets those reNuirementsF itOs a 1#, 11& ethylenedio'y analogue @ith a &methylpipera0ino&methylene at position ) and has sho@n a great potency in clinical researches?.,/ 2 ring can also $e formed $et@een position ) and (, like position 1# and 11? Chat gives ne@ opportunities to make @ater&solu$le derivatives .!/? Chese he'acyclic :4C $ecome more active @hen electron&@ithdra@ing groups are put in position 11 and methyl or amino groups at 1#? >'atecan is an e'ample of he'acyclic :4C that has a + mem$ered ring over position ) and (, and is 1#&methyl, 11&fluoro su$stituted . /? ;t is @ater&solu$le and more potent than topotecan?.,/.13/.1!/

C- and D-ring modification

Che 1& and :&rings have an essential role in the antitumor activity? Replacement in any position results in much less potent compound than parent compound in other cytoto'icity assay?.,/

-omocamptothecin

E-ring modifications
Che >&ring doesnOt allo@ many structural changes @ithout losing :4C activity? Ane possi$le replacement is changing the hydro'yl group to :l, F or <r $ecause their polari0a$ility is sufficient to sta$ili0e the en0yme&comple'?.13/ 2nother possi$le modification is to insert a methylene $et@een hydro'yl and lactone on the >&ring yielding a seven mem$ered H&hydro'ylactone group, so&called homocamptothecin (h:4C%? Che h:4COs hydro'yl has less inductive effect on the car$o'yl group @hich makes the lactone very reactive? Chis enhances the interaction of the free hydro'yl group optimally @ith topo ; and the covalent comple' that forms in its presence are more sta$le? Che >&ring of h:4C opens more slo@ly and the opening is irreversi$le? h:4Cs e'hi$it enhanced human plasma sta$ility $ecause of decreased protein $inding and more affinity for red $lood cells than :4C?.,/.13/

CP+ analogues
"ince the discovery of :4C many analogues have $een synthesi0ed? <elo@ is a schematic vie@ of the :4C analogues that have $een mentioned in the te't a$ove?

Analogue

!8

!9

!:

!;

Copotecan (-ycamtin%

&-

:-*M(:-3%*

&A-

;rinotecan (:4C&11, :amptosar%

:-*:-3

1< +) (2R+)%

A-

<M4 13!# >'atecan

:-*:-*"i(:-3%3

:-3

9urtotecan "C 1 ,1 :J1 +#* :-]MA:(:-3%3 :-*:-*M-:-(:-3%*

:4C is linked to a cyclode'trin&$ased polymer to form the investigational anti&cancer drug :R9\1#1?.1+/

Morphine, C17H19NO3, is the most abundant of opium s !" a#$a#oids, a%%ountin& for 9 to 1"' of opium(e)tra%t b* mass+ Named after the ,oman &od of dreams, Morpheus, -ho a#so be%ame the &od of s#umber, the dru& morphine, appropriate#* enou&h, numbs pain, a#ters mood and indu%es s#eep+ .ess popu#ar and #ess mentioned effe%ts in%#ude nausea, /omitin& and de%reased &astrointestina# moti#it*+ 01t s a &reat %onstipator, and in 2uerin s paintin&, 1sis is perhaps brin&in& Morpheus a #a)ati/e+3 Morphine and its re#ated s*ntheti% deri/ati/es, $no-n as opioids, are so far unbeatab#e at du##in& %hroni% or so(%a##ed 4s#o-5 pain, but unfortunate#* the* are a## ph*si%a##* addi%ti/e+ 6urin& the 7meri%an Ci/i# 8ar, "99 999 so#diers be%ame addi%ted to morphine+:oth morphine and its h*drated form, C17H19NO3.H!O, are sparin&#* so#ub#e in -ater+ 1n fi/e #itres of -ater, on#* one &ram of the h*drate -i## disso#/e+ ;or this reason, pharma%euti%a# %ompanies produ%e su#phate and h*dro%h#oride sa#ts of the dru&, both of -hi%h are o/er 399 times more -ater(so#ub#e than its parent mo#e%u#e+ 8hereas the pH of a saturated morphine h*drate so#ution is <+=, the sa#ts are a%idi%+ >in%e the* deri/e from a stron& a%id but -ea$ base, the* are both at about pH ? =@ %onseAuent#*,in maufa%turin& sta&e,the morphine sa#ts are mi)ed -ith sma## amounts of NaOH to ma$e them suitab#e for inBe%tion+

Mor,%ine<s C%emistry
Che three dimensiona# stru%ture of morphine is fas%inatin&+ 1t %onsists of fi/e rin&s, three of -hi%h are appro)imate#* in the same p#ane+ Che other t-o rin&s, in%#udin& the nitro&en one, are ea%h at ri&ht an&#es to the other trio+

Opioid ana#&esi%s, in%#udin& morphine, %odeine, #e/orphano#, heroin and stru%tura##* #ess simi#ar dru&s su%h as meperidine a## ha/e an aromati% rin& and a Auaternar* %arbon atom #in$ed to a tertiar* amine &roup b* t-o other %arbon atoms+ Chis is $no-n as the morphine ru#e, but it shou#d be pointed out that a## of the opioids be#oa#so ha/e a meth*# &roup atta%hed to a nitro&en atom+ >ubstitute morphine s meth*# &roup -ith a propen*# &roup, and *ou %reate na#orphine, an anta&onist -hi%h %ounters morphine s effe%ts+ >imi#ar#*, h*dromorphone, a $etone /ersion of morphine fi/e times more po-erfu# than its parent mo#e%u#e be%omes the anta&onist h*dromorphone b* the same substitution of a CH 3 -ith a CH!CH?CH! &roup+ More &enera##*, morphine s (phen*#eth*#amine unit 0essentia##* -hat 1 Bust des%ribed minus the Auaternar* %arbon atom3 is a#so found at the tai#(end of en$epha#in mo#e%u#es+ Dn$epha#ins are sma##er /ersions of endorphins, -hi%h are produ%ed natura##* in the brain, pituitar* and other tissues, -here the* a%t /er* mu%h #i$e opium s mo#e%u#es+

Agonists and Antagonists

Agonists

"orphine/s Cousins

Antagonists

P%ysiology
Morphine a%ts on a spe%ifi% re%eptor of ner/e %e##s+ More spe%ifi%a##* man* su%h re%eptors are found in the spina# %ord s substantia gelatinosa, a re&ion -here pain si&na#s are first pro%essed+ Che ar%hite%ture of the morphine re%eptor is -hat di%tates the morphine ru#e+ Chere is a f#at part that binds to the aromati% rin&, a %a/it* that attra%ts the t-o %arbon atoms and an anioni% site that a%%ommodates the tertiar* nitro&en atom+ 8hen morphine or another a&onist binds to the re%eptor, the %e## membrane s affinit* for sodium ion %han&es+ Chis e/entua##* redu%es the re#ease of neurotransmitters from the affe%ted neurons+ 1n/esti&ators #earned about morphine s mode of a%tion b* app#*in& it and other opiates 0in%#udin& en$epha#in3 to &uinea(pi& intestines+ 08hat e#se -as &on& to ser/e as the &uinea pi& for their e)perimentsE3 1n the presen%e of anta&onists, NaF affinit* -as restored and intestina# %ontra%tions -hi%h had dropped pre%ipitous#* shot up a&ain+ Not a## opiates are %reated eAua##*+ Codeine is on#* 9+1 ' as potent as morphine in bindin& to re%eptors+ :ut be%ause %odeine is %on/erted to morphine b* the #i/er 0a## that has to happen is that the OCH3 &roup &ets rep#a%ed b* OH3 it be%omes !9' as stron& as the #atter o/era##+ 1n the #ate 1<99 s, the :a*er %ompan*, in hopin& to %ome up -ith a non(addi%ti/e pain $i##er, tried to a%et*#ate both of morphine s h*dro)*# &roups+ 7fter a##, this -as in a -a* simi#ar to ho- the* had %on/erted sa#i%*#i% a%id into aspirin+ :ut embarassin&#*, :a*er in/ented heroin in the pro%ess+

Analysis
Che 191" Harrison Nar%oti%s Ca) 7%t in the Gnited >tates made possession of morphine a %rimina# a%t+ ;orensi% s%ientists e)p#oit a &roup %hara%teristi% propert* of morphine and its re#ated %ompoundsH a pe%u#iar rea%tion -ith Me%$eIs 0or .afonIs3 rea&ent+ Che rea&ent %onsists of se#enious a%id 0H!>eO33in %on%entrated su#furi% a%id 0H!>O"3+ 1f morphine and the rea&ent rea%t, the fo##o-in& %o#ours appearH &reen, then Aui%$#* a &reenish b#ue, %han&in& to b#ue, ne)t s#o-#* to b#uish &reen -ith a *e##o-(bro-n ed&e, then fina##* o#i/a%eous &reen+ Chis is one of a /ariet* of %o#or tests that are used+ Most, ho-e/er, are presumpti/e tests, meanin& that the* su&&est the presen%e of opiates but donIt abso#ute#* pro/e it+ ;ina# %onfirmation is obtained throu&h instrumentation, either &as %hromato&raph*(mass(spe%trometr* or b* ;ourier Cransform 1nfrared >pe%tros%op*+ M8R has also $een used to identify heroin?

Mor)ina
1ari Wikipedia $ahasa ;ndonesia, ensiklopedia $e$as 'elum Di,eri&sa 9angsung ke: navigasi, cari

"truktur kimia 8orfina Mor)ina adalah alkaloid analgesik yang sangat kuat dan merupakan agen aktif utama yang ditemukan pada opium? 8orfina $ekerEa langsung pada sistem saraf pusat untuk menghilangkan rasa sakit? >fek samping morfina antara lain adalah penurunan kesadaran, euforia, rasa kantuk, lesu, dan penglihatan ka$ur? 8orfina Euga mengurangi rasa lapar, merangsang $atuk, dan meye$a$kan konstipasi? 8orfina menim$ulkan ketergantungan tinggi di$andingkan 0at&0at lainnya? 4asien ketergantungan morfina Euga dilaporkan menderita insomnia dan mimpi $uruk? Jata BmorfinaB $erasal dari 8orfeus, de@a mimpi dalam mitologi Kunani? 8orfin (;MM% (diucapkan 5 n mJrfi 5 % ( 8" CDrusk , 8";R , 2vin0a , Jadian , Aramorph , Ro'anol , Japanol % adalah potensial candu analgesik o$at dan dianggap se$agai prototipikal opioid ? -al ini ditemukan pada 1,# oleh Friedrich "ert^rner , pertama didistri$usikan oleh Friedrich "ert^rner pada tahun 1,1), dan komersial pertama diEual oleh 8erck pada tahun 1,*), yang pada @aktu itu se$uah toko kimia kecil? ;tu le$ih $anyak digunakan setelah penemuan Earum suntik pada tahun 1,!)? ;ni mengam$il nama dari Cuhan Kunani mimpi 8orpheus ( Kunani : _`abcId %? 8orfin adalah paling $anyak mengandung alkaloid yang ditemukan di opium , getah kering (lateks% yang $erasal dari hasil getah irisan $iEi mentah opium, atau dinamakan, poppy, 4apaver somniferum ? 8orfin adalah pemurnian pertama dari sum$er tanaman dan merupakan salah satu dari sedikitnya mengandung !# macam alkaloid dari $e$erapa Eenis dalam opium, 4oppy "tra@ Jonsentrat , dan turunan opium lainnya? 8orfin umumnya , sampai 1) persen dari $erat kering opium, @alaupun khusus di$esarkan kultivar mencapai *+ persen atau menghasilkan morfin sedikit sekali, di $a@ah 1 persen, mungkin turun menEadi #,# persen? Varietas yang terakhir, termasuk D4r0emkoD dan Morman DkultivarD dari opium poppy, digunakan untuk menghasilkan dua

alkaloid lain, te$ain dan oripavine , yang digunakan dalam pem$uatan&sintetik dan semi sintetik opioid seperti o'ycodone dan etorphine dan $e$erapa Eenis o$at? ( 4? $racteatum % tidak mengandung morfin atau kodein, atau lainnya narkotika fenantrena tipe, alkaloid? "pesies ini le$ih merupakan sum$er te$ain ? CerEadinya morfin di lain papaverales dan 4apaveraceae , serta pada $e$erapa Eenis hop dan mur$ei pohon $elum dikonfirmasi? 8orfin diproduksi paling dominan di a@al siklus hidup tanaman? 8ele@ati titik optimum untuk ekstraksi, $er$agai proses di pa$rik memproduksi kodein , te$ain , dan dalam $e$erapa kasus Eumlah dia$aikan hidromorfon , dihydromorphine , dihydrocodeine , tetrahydrothe$aine, dan 'ana' (senya@a ini agak disintesis dari te$ain dan oripavine%? Cu$uh manusia memproduksi endorphines , yang neuropeptida , dengan efek yang sama? 1alam pengo$atan klinis, morfin dianggap se$agai standar emas, atau patokan, dari analgesik digunakan untuk meringankan penderitaan $erat atau sakit dan penderitaan ? "eperti opioid lain, misalnya oksikodon (A'y:ontin, 4ercocet, 4ercodan%, hidromorfon (1ilaudid, 4alladone%, dan diacetylmorphine ( heroin %, morfin langsung mempengaruhi pada sistem saraf pusat (""4% untuk meringankan rasa sakit ? 8orfin memiliki potensi tinggi untuk kecanduan , toleransi dan psikologis ketergantungan $erkem$ang dengan cepat, meskipun Fisiologis ketergantungan mungkin mem$utuhkan $e$erapa $ulan untuk $erkem$ang?

Atro,ine
From Wikipedia, the free encyclopedia Jump to: navigation, search 2tropine

Systematic (IUPAC) name

(%S%&(,&methyl&,&a0a$icyclo.3?*?1/oct&3&yl% 3&hydro'y&*&phenylpropanoate

Clinical data +rade names 2tropen AHFS/Drugs.com monograph MedlinePlus a+,* ,) Pregnancy cat. : (3"% egal status 4rescription only !outes Aral, ;V, ;8, rectal P%armaco&inetic data 'ioa$aila(ility *!7 !#7 hydrolysed to tropine and Meta(olism tropic acid Hal)*li)e * hours "#cretion !#7 e'creted unchanged in urine Identi)iers CAS num(er !1&!!&, A+C code 2#3<2#1 "#1F2#1 Pu(C%em :;1 1) 1) IUPHA! ligand 3*# Drug'an& 1<##!)* C%emS,ider 1#1( 1#! U-II ):#+()1R(; ."// 1##113

C%"'I C%"M' Formula Mol. mass "8;9>".sho@/ ;n:h;.sho@/

:-><;:1++, :->8<91(! C%emical data C1)H*3-03 *,(?3+(

(1%at is t%is2) ($eri)y) Atro,ine is a naturally occurring tropane alkaloid e'tracted from deadly nightshade (*tropa 0elladonna%, Jimson @eed ((atura stramonium%, mandrake ("andragora officinarum% and other plants of the family "olanaceae? ;t is a secondary meta$olite of these plants and serves as a drug @ith a @ide variety of effects? ;t is a competitive antagonist for the muscarinic acetylcholine receptor types 81, 8*, 83, 8 and 8!?.1/ ;t is classified as an anticholinergic drug (parasympatholytic%? Che species name B$elladonnaB (B$eautiful @omanB in ;talian% comes from the original use of deadly nightshade as a @ay of dilating @omenDs pupils to make them $eautiful? <oth atropine and the genus name for deadly nightshade derive from 2tropos, one of the three Fates @ho, according to Greek mythology, chose ho@ a person @as to die? 2tropine is a core medicine in the World -ealth Argani0ationDs B>ssential 1rugs 9istB, @hich is a list of minimum medical needs for a $asic health care system?.*/

Contents

1 4hysiological effects and uses o 1?1 Aphthalmic use o 1?* Resuscitation o 1?3 "ecretions and $ronchoconstriction o 1? Creatment for organophosphate poisoning o 1?! Aptical penalisation o 1?+ "ide&effects and overdose * :hemistry and pharmacology 3 -istory Matural sources ! "ynthesis + <iosynthesis ) "ee also , References ( >'ternal links

P%ysiological e))ects and uses

Working as a nonselective muscarinic acetylcholinergic antagonist, atropine increases firing of the sinoatrial node ("2% and conduction through the atrioventricular node (2V% of the heart, opposes the actions of the vagus nerve, $locks acetylcholine receptor sites, and decreases $ronchial secretions? ;n general, atropine lo@ers the parasympathetic activity of all muscles and glands regulated $y the parasympathetic nervous system? Chis occurs $ecause atropine is a competitive antagonist of the muscarinic acetylcholine receptors (acetylcholine $eing the main neurotransmitter used $y the parasympathetic nervous system%? Cherefore, it may cause s@allo@ing difficulties and reduced secretions?

Ophthalmic use
Copical atropine is used as a cycloplegic, to temporarily paraly0e the accommodation refle', and as a mydriatic, to dilate the pupils? 2tropine degrades slo@ly, typically @earing off in ) to 1 days, so it is generally used as a therapeutic mydriatic, @hereas tropicamide (a shorter&acting cholinergic antagonist% or phenylephrine (an I&adrenergic agonist% is preferred as an aid to ophthalmic e'amination? 2tropine induces mydriasis $y $locking contraction of the circular pupillary sphincter muscle, @hich is normally stimulated $y acetylcholine release, there$y allo@ing the radial pupillary dilator muscle to contract and dilate the pupil? 2tropine induces cycloplegia $y paraly0ing the ciliary muscles, @hose action inhi$its accommodation to allo@ accurate refraction in children, helps to relieve pain associated @ith iridocyclitis, and treats ciliary $lock (malignant% glaucoma? 2tropine is contraindicated in patients pre&disposed to narro@ angle glaucoma? 2tropine can $e given to patients @ho have direct glo$e trauma?

Resuscitation
;nEections of atropine are used in the treatment of $radycardia (an e'tremely lo@ heart rate%? 2tropine $locks the action of the vagus nerve, a part of the parasympathetic system of the heart @hose main action is to decrease heart rate? Cherefore, its primary function in this circumstance is to increase the heart rate? 2tropine @as previously included in international resuscitation guidelines for use in cardiac arrest associated @ith asystole and 4>2, $ut @as removed from these guidelines in *#1# due to a lack of evidence?.3/ For symptomatic $radycardia, the usual dosage is #?! to 1 mg ;V push, may repeat every 3 to ! minutes up to a total dose of 3 mg (ma'imum #?# mg5kg%?. / 2tropine is also useful in treating second&degree heart $lock 8o$it0 Cype 1 (Wencke$ach $lock%, and also third&degree heart $lock @ith a high 4urkinEe or 2V&nodal escape rhythm? ;t is usually not effective in second&degree heart $lock 8o$it0 type *, and in third&degree heart $lock @ith a lo@ 4urkinEe or ventricular escape rhythm? 2tropine is contraindicated in ischemia&induced conduction $lock, $ecause the drug increases o'ygen demand of the 2V nodal tissue, there$y aggravating ischemia and the resulting heart $lock?

Ane of the main actions of the parasympathetic nervous system is to stimulate the 8* muscarinic receptor in the heart, $ut atropine inhi$its this action?

Secretions and bronchoconstriction

2tropineDs actions on the parasympathetic nervous system inhi$it salivary and mucus glands? Che drug may also inhi$it s@eating via the sympathetic nervous system? Chis can $e useful in treating hyperhidrosis, and can prevent the death rattle of dying patients? >ven though atropine has not $een officially indicated for either of these purposes $y the F12, it has $een used $y physicians for these purposes?.!/

Treatment for organophosphate poisoning

2tropine is not an actual antidote for organophosphate poisoning? -o@ever, $y $locking the action of acetylcholine at muscarinic receptors, atropine also serves as a treatment for poisoning $y organophosphate insecticides and nerve gases, such as ta$un (G2%, sarin (G<%, soman (G1% and V\? Croops @ho are likely to $e attacked @ith chemical @eapons often carry autoinEectors @ith atropine and o$ido'ime, @hich can $e Nuickly inEected into the thigh? 2tropine is often used in conEunction @ith pralido'ime chloride? 2tropine is given as a treatment for "931G> (salivation, lacrimation, urination, diaphoresis, gastrointestinal motility, emesis% symptoms caused $y organophosphate poisoning? 2nother mnemonic is 138<<>9"", @hich stands for diarrhea, urination, miosis, $radycardia, $ronchoconstriction, e'citation (as of muscle in the form of fasciculations and :M"%, lacrimation, salivation, and s@eating (only sympathetic innervation using 8usc receptors%? "ome of the nerve agents attack and destroy acetylcholinesterase $y phosphorylation, so the action of acetylcholine $ecomes prolonged, pralido'ime (*&428% is the cure for organophosphate poisoning $ecause it can cleave this phosphorylation? 2tropine can $e used to reduce the effect of the poisoning $y $locking muscarinic acetylcholine receptors, @hich @ould other@ise $e overstimulated $y e'cessive acetylcholine accumulation?

Optical penalisation
;n refractive and accommodative am$lyopia, @hen occlusion is not appropriate sometimes atropine is given to induce $lur in the good eye?.+/

Side-effects and o erdose

2dverse reactions to atropine include ventricular fi$rillation, supraventricular or ventricular tachycardia, di00iness, nausea, $lurred vision, loss of $alance, dilated pupils, photopho$ia, dry mouth and potentially e'treme confusion, dissociative hallucinations and e'citation especially amongst the elderly? Chese latter effects are $ecause atropine is a$le to cross the $loodP$rain $arrier? <ecause of the hallucinogenic properties, some have used the drug recreationally, though this is potentially dangerous and often unpleasant?

;n overdoses, atropine is poisonous? 2tropine is sometimes added to potentially addictive drugs, particularly anti&diarrhea opioid drugs such as dipheno'ylate or difeno'in, @herein the secretion&reducing effects of the atropine can also aid the anti&diarrhea effects? 2lthough atropine treats $radycardia (slo@ heart rate% in emergency settings, it can cause parado'ical heart rate slo@ing @hen given at very lo@ doses, presuma$ly as a result of central action in the :M"?.)/ 2tropine is incapacitating at doses of 1# to *# mg per person? ;ts 91!# is estimated to $e !3 mg per person (per oral% @ith a pro$it slope of 1?,?.,/ Che antidote to atropine is physostigmine or pilocarpine? 2 common mnemonic used to descri$e the physiologic manifestations of atropine overdose is: Bhot as a hare, $lind as a $at, dry as a $one, red as a $eet, and mad as a hatterB?.(/ Chese associations reflect the specific changes of @arm, dry skin from decreased s@eating, $lurry vision, decreased s@eating5lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type and !? Chis set of symptoms is kno@n as anticholinergic to'idrome, and may also $e caused $y other drugs @ith anticholinergic effects, such as scopolamine, diphenhydramine, phenothia0ine antipsychotics and $en0tropine?.1#/

C%emistry and ,%armacology

2tropine is a racemic mi'ture of d&hyoscyamine and l&hyoscyamine, @ith most of its physiological effects due to l&hyoscyamine? ;ts pharmacological effects are due to $inding to muscarinic acetylcholine receptors? ;t is an antimuscarinic agent? "ignificant levels are achieved in the :M" @ithin 3# minutes to 1 hour and disappears rapidly from the $lood @ith a half&life of * hours? 2$out +#7 is e'creted unchanged in the urine, most of the rest appears in urine as hydrolysis and conEugation products? >ffects on the iris and ciliary muscle may persist for longer than )* hours? Che most common atropine compound used in medicine is atropine sulfate (monohydrate% (:1)-*3MA3%*U-*"A U-*A, the full chemical name is 1I -, !I -&Cropan&3& I ol (e%&tropate(ester%, sulfate monohydrate? Che vagus (parasympathetic% nerves that innervate the heart release acetylcholine (2:h% as their primary neurotransmitter? 2:h $inds to muscarinic receptors (8*% that are found principally on cells comprising the sinoatrial ("2% and atrioventricular (2V% nodes? 8uscarinic receptors are coupled to the Gi&proteinF therefore, vagal activation decreases c284? Gi&protein activation also leads to the activation of J2:h channels that increase potassium efflu' and hyperpolari0es the cells? ;ncreases in vagal activity to the "2 node decreases the firing rate of the pacemaker cells $y decreasing the slope of the pacemaker potential (phase of the action potential%F this decreases heart rate (negative chronotropy%? Che change in phase slope results from alterations in potassium and calcium currents, as @ell as the slo@&in@ard sodium current

that is thought to $e responsi$le for the pacemaker current (;f%? <y hyperpolari0ing the cells, vagal activation increases the cellDs threshold for firing, @hich contri$utes to the reduction the firing rate? "imilar electrophysiological effects also occur at the 2V nodeF ho@ever, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the 2V node (negative dromotropy%? ;n the resting state, there is a large degree of vagal tone on the heart, @hich is responsi$le for lo@ resting heart rates? Chere is also some vagal innervation of the atrial muscle, and to a much lesser e'tent, the ventricular muscle? Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy% and even smaller decreases in ventricular contractility? 8uscarinic receptor antagonists $ind to muscarinic receptors there$y preventing 2:h from $inding to and activating the receptor? <y $locking the actions of 2:h, muscarinic receptor antagonists very effectively $lock the effects of vagal nerve activity on the heart? <y doing so, they increase heart rate and conduction velocity?

History
"andragora (mandrake% @as descri$ed $y Cheophrastus in the fourth century <?:? for treatment of @ounds, gout, and sleeplessness, and as a love potion? <y the first century 2?1? 1ioscorides recogni0ed @ine of mandrake as an anaesthetic for treatment of pain or sleeplessness, to $e given prior to surgery or cautery?.(/ Che use of "olanaceae containing tropane alkaloids for anesthesia, often in com$ination @ith opium, persisted throughout the Roman and ;slamic >mpires and continued in >urope until superseded $y the use of ether, chloroform, and other modern anesthetics? 2tropine e'tracts from the >gyptian hen$ane @ere used $y :leopatra in the last century <?:? to dilate her pupils, in the hope that she @ould appear more alluring? ;n the Renaissance, @omen used the Euice of the $erries of *tropa 0elladonna to enlarge the pupils of their eyes, for cosmetic reasons? Chis practice resumed $riefly in the late nineteenth& and early t@entieth&century in 4aris? Che mydriatic effects of atropine @ere studied among others $y the German chemist Friedlie$ Ferdinand Runge (1)(!P1,+)%? ;n 1,31, the German pharmacist -einrich F? G? 8ein (1)((&1,+ %.11/ succeeded in preparing atropine in pure crystalline form?.1*/ Che su$stance @as first synthesi0ed $y German chemist Richard Willstftter in 1(#1?.13/

-atural sources
2tropine is found in many mem$ers of the "olanaceae family? Che most commonly& found sources are *tropa 0elladonna, (atura inoxia, (. metel, and (. stramonium? Ather sources include mem$ers of the 1rugmansia and 'yoscyamus genera? Che Nicotiana genus (including the to$acco plant, N. ta0acum% is also found in the "olanaceae family, $ut these plants do not contain atropine or other tropane alkaloids?

Synt%esis
2tropine can $e synthesi0ed $y the reaction of tropine @ith tropic acid in the presence of hydrochloric acid?

'iosynt%esis

<iosynthesis of atropine starting from 9&4henylalanine Che $iosynthesis of atropine starting from 9&4henylalanine first undergoes a transamination forming phenylpyruvic acid @hich is then reduced to phenyl&lactic acid?.1 / :oen0yme 2 then couples phenyl&lactic acid @ith tropine forming littorine, @hich then undergoes a radical rearrangement initiated @ith a 4 !# en0yme forming hyoscyamine aldehyde?.1 / 2 dehydrogenase then reduces the aldehyde to a primary alcohol making (&%& hyoscamine, @hich upon racemi0ation forms atropine?.1 /