Download - Clase de Blocante de Canale de Calciu
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8/19/2019 Clase de Blocante de Canale de Calciu
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CLASE DE BLOCANTE DE CANALE DE CALCIU
Blocantele canalelor de Calciu=grup heterogen de compusi clasifcati dupastructura chimica in
!"dialchilamine #$erapamil%
&"'en(otia(epine #diltia(em%
)"dihidropiridine# ni*edipina + amlodipina + *elodipina + nimodipina%
,"di*enilpipera(ine #-unari(ina%
!"Dialchilamine# $erapamil%
Dialchilaminele=grup de compusi chimici organici+ deri$ati din amoniac#N.)% +
prin inlocuirea a & din cei ) atomi de .idrogen cu radicali alchil #/% 0#=amine
secundare ali*atice%
1ormula generala
2UBC.E3
4erapamil
Sinonime #Denumire moleculara %
=Ipo$eratril=Dilacoran=Isoptin=Calan
1ormula moleculara C&5.)6N&O,
Denumire IU2AC 2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-
ylpentanenitrile
&7#)+,7dimetro8i*enil%79:&7#)+,7dimeto8i*enil%etil7metilamino;7&7propanil7pentanitril
!& g?mol
2roprietati e8perimentale
7punct de fer'ere &,)7&, o C la !">> E7>& mm .g
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7punct de topire @&9oC
7solu'ilitate in apa ,",5 mg?l
7pa 6"&
7*armacologie
7 4erapamil='locant de canale de calciu + de tip L + ce are si e*ect
antiaritmic"Stereoi(omerul de8trogir este mai efcient in reducerea tensiunii
arteriale comparati$ cu cel le$ogir"Cu toate acestea + stereoi(omerul le$ogir a
do$edit o potenta de &> de ori mai mare decat a celui de8trogir pentru
prelungirea inter$alului 2/ in tratamentul artimiilor"
7$erapamilul inhi'a in-u8ul transmem'ranar al ionilor de Ca e8tracelular in celule
miocardice si musculare netede $asculare + determinand dilatarea principalelor
artere coronare si sistemici + precum si scaderea contractilitatii miocardului
7inhi'a pompa 27glicoproteinei+ care este suprasolicitata in ca(ul unor tumori
re(istente la tratament + crescand ast*el efcacitatea agentilor antineopla(ici"
7a'sor'tie >
7eliminare 75> su' *orma de meta'oliti in urina ! ?mai mult su' *orma de
meta'oliti in *ecale #in 9 (ile %
7)7, nemeta'oli(at + in urina
7timp de inumatatire &"675", ore
7mecanism de actiune 7inhi'a canalele $olta dependente de Calciu
7e*ectul pe canalele de Calciu de tip L din inima
scaderea inotropiei si cronotropiei cardiace =Fscad *rec$enta cardiaca si
tensiunea arteriala
7to8icitate LD9>=6 mg? Gg #i"$" Hsoareci%
7legare de proteine >
7utili(at su' *orma de CLO/.ID/AT DE 4E/A2A3IL
Clorhidrat de 4erapamil
7*ormula moleculara C&5.)ClN&O,
7greutate moleculara ,!">&9 g?mol
7su'stanta cristalina
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7punct de topire !)!7!))o C
7solu'ilitate in apa 6) mg?ml
&"BENOTIAE2INE #DILTIAE3%
7Ben(otia(epine=clasa de su'stante heterociclite deri$ata din tia(epine+ cecontine un inel 'en(enic"
7Tia(epine=compusi o'tinuti prin su'stitutia unui car'on din tiepina cu un atom
de N0 in *unctie de locatia N+ se pot o'tine !+) Htia(epina sau !+,7tia(epina "
7Tiepina=compus heterociclic nesaturat + cu atomi de C si un atom de S
Tiepina
!+)7Tia(epina
!+,7Tia(epina
Ben(otia(epina
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Diltia(em=compus 'en(otia(epinic cu rol de 'locant de canale de Ca
1ormula moleculara C&&.&N&O,S
Denumire IU2AC :#&S+)S%797:&7#dimethJlamino%ethJl;7&7#,7metho8JphenJl%7,7o8o7
&+)7dihJdro7!+97'en(othia(epin7)7Jl; acetate
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7meta'oli(are intensa la primul pasa hepatic +prin de(acetilare
7timp de inumatatire )75 ore
7elimimare 9 prin 'ila )9 prin urina #@9 se elimina prin urina +
nemeta'oli(at %
7mecanism de actiune inter*erK cu in-u8ul intracelular lent #depolari(area% de
la ni$elul esuturilor e8cita'ile+ Mmpiedicand reali(area legKturii dintre e8citaie i
contracie Mn di*erite esuturi miocardice+ *KrK a modifca potenialul de
aciune=Frela8area musculaturii netede coronariene i dilatarea arterelor
coronare mici i mari la concentraii ale medicamentului cu e*ect inotrop negati$
mic sau a'sent+ ceea ce duce la creterea -u8ului coronarian+ cu scKderea in
*unctie de do(K a tensiunii arteriale sistemice i a re(istenei $asculare
peri*erice"
)"DI.ID/O2I/IDINE # NI1EDI2INA + A3LODI2INA+ 1ELODI2INA + NI3ODI2INA %
DI.ID/O2I/IDINA# !+, Hdihidropiridina%= compus chimic *ormat din dintr7un ciclu
nesaturat ce contine 9 atomi de C si un atom de N"
3ecanism de actiune
7dihidropiridinele acionea(K Mn cadrul mecanismului de contracie muscularK
dupK ce su'stanta este acti$ata de un potenial de aciune+ $a su*eri o
schim'are con*ormationala+producandu7se *enomenul de cuplare
mecanicK"Acesta $a pro$oca o schim'are con*ormationala intr7un alt tip de
canale din grosimea mem'ranei reticulului sarcoplasmic #canale rJanodine%+ care
produc de iePirea calciului din reticulul sarcoplasmic al f'rei musuclare +
re(ultand Mn cele din urmK contractia musculara"
7actiune in principal la ni$el $ascular
NI1EDI2INA
7*ormula moleculara C!5.!6N&O
7greutate moleculara ),")),& g?mol
7mecanism de actiune =mec de la 4erapamil
7denumire IU2AC dimethJl &+7dimethJl7,7#&7nitrophenJl%7!+,7dihJdropJridine7
)+97dicar'o8Jlate
2roprietati e8perimentale
7descriere f(ica pudra ?structura cristalina de culoare gal'ena + inodora
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7punct de topire !5&7!5, o C
7solu'ilitate # la &> o C %
7in acetona &9> g?l
7in clorura de metilen !> g?l
7in cloro*orm !,> g?l
7in acetat de etil 9> g?l
7in metanol & g?l
7in etanol !5 g?l
7insolu'ila in apa
7descompunere prin incal(ire pana la descompunere + emite $apori to8ici deo8i(i de N
1armacologie
7mecanism de actiune Ni*edipina se leaga de canale de Ca inacti$e +
sta'ili(andu7le con*ormatia "Dat find ca depolari(area durea(a mai mult in
celulele musculare netede ale arteriolelor + comparati$ cu cea din celulele
miocardine + pre(enta canalelor inacti$e este mai *rec$enta in celulele musculare
netede"2re*erinta ni*edipinei pentru su'unitatie de tip alpha7! a canalelor +ii o*era
selecti$itate arteriala suplimentara "La concentratii terapeutice + poate a$ea un
e*ect relati$ sca(ut asupra celulelor miocardice si asupra celor conducatoare "2rin
'locarea canalelor de Calciu + Ni*edipina inhi'a spasmul arterelor coronare si
dilatea(a arterele sistemice + re(ultand cresterea aportului de o8igen la ni$elul
miocardului + concomitent cu scaderea tensiunii arteriale "
Ni*edipina este un $asodilatator arterial peri*eric ce actionea(a in mod direct pe
musculatura neteda $asculara "2rin legarea ni*edipinei de canalele $olta7
dependente + posi'il controlate de receptori +e8istente in musculatura neteda
$aculara duce la o scadere a in-u8ului de Ca in aceste canale"Depo(itele de Ca
intracelular in celulele musculare $asculare sunt limitate + depin(and ast*el de
in-u8ul de Ca e8tracelular pentru a se putea reali(a contractia "/educereain-u8ului de Ca datorita Ni*edipinei duce la $asodilatatie arteriala si scade
re(istenta peri*erica $asculare + ducand la reducerea tensiunii arteriale"
Ni*edipine is a peripheral arterial $asodilator Qhich acts directlJ on $ascular
smooth muscle" The 'inding o* ni*edipine to $oltage7dependent and possi'lJ
receptor7operated channels in $ascular smooth muscle results in an inhi'ition o*
calcium in-u8 through these channels" Stores o* intracellular calcium in $ascular
smooth muscle are limited and thus dependent upon the in-u8 o* e8tracellular
calcium *or contraction to occur" The reduction in calcium in-u8 'J ni*edipine
causes arterial $asodilation and decreased peripheral $ascular resistance Qhichresults in reduced arterial 'lood pressure"
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US Natl Inst .ealth0 DailJ3ed" Current 3edication In*ormation *or ADALAT CC
#ni*edipine% ta'let+ flm coated #Rune &>>%" A$aila'le *rom+ as o* Octo'er !9+
&>> http??dailJmed"nlm"nih"go$?dailJmed?drugIn*o"c*mid=!>>6
Ni*edipina scade contractilitate musculaturii netede arteriale si in consecinta
$asoconstrictia prin inhi'area in-u8ului de ioni de Ca prin canalele de Ca de tip L"Ionii de Ca care intra in celula prin aceste canale se leaga de calmodulina
"Comple8ul Ca7calmodulina acti$ea(a lantul *oto7mio(in7Gina(ei #3LC%"3LC
acti$ata catali(ea(a *os*orilarea mio(inei + punct cheie in contractia musculara"
Amplifcarea semnalului este o'tinuta prin eli'erarea de Ca din reticulul
sarcoplasmic cu autorul receptorilor rJanodini"Inhi'area -u8ului initial de Ca
inhi'a procesele contractile ale celulelor musculare netede+ cau(and dilatarea
arterelor coronare si sistemice+ cresterea aportului de o8igen la tesutul
miocardic + scaderea re(istentei totale peri*erice +scaderea tensiunii arteriale
sistemice "
Ni*edipine decreases arterial smooth muscle contractilitJ and su'seuent
$asoconstriction 'J inhi'iting the in-u8 o* calcium ions through L7tJpe calcium
channels" Calcium ions entering the cell through these channels 'ind to
calmodulin" Calcium7'ound calmodulin then 'inds to and acti$ates mJosin light
chain Ginase #3LC%" Acti$ated 3LC catalJ(es the phosphorJlation o* the
regulatorJ light chain su'unit o* mJosin+ a GeJ step in muscle contraction" Signal
amplifcation is achie$ed 'J calcium7induced calcium release *rom the
sarcoplasmic reticulum through rJanodine receptors" Inhi'ition o* the initial in-u8o* calcium inhi'its the contractile processes o* smooth muscle cells+ causing
dilation o* the coronarJ and sJstemic arteries+ increased o8Jgen deli$erJ to the
mJocardial tissue+ decreased total peripheral resistance+ decreased sJstemic
'lood pressure"
A'sor'tie +Distri'utie si E8cretie
Apro8imati$ > din do(a administrata oral prin capsule con$entionale este rapid
a'sor'ita din tractul gastro7intestinal"Doar ,9759 din do(a administrata oral
aunge in circulatia sistemica nemeta'oli(ata + intrucat Ni*edipina este
meta'oli(ata la primul pasa prin fcat"4ar*ul concentratiei serice este de o'iceiatins la >"97& ore dupa administrarea orala "
A'sorption+ Distri'ution and E8cretion
Appro8imatelJ > o* an oral dose o* ni*edipine is rapidlJ a'sor'ed *rom the "97&
hours a*ter oral administration as con$entional capsules" 1ood appears to
decrease the rate 'ut not the e8tent o* a'sorption o* ni*edipine as con$entionalcapsules"
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=10098http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=10098
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American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
Concentratia plasmatica a ni*edipinei creste gradulat + cu o rata controlata + dupa
adminsitrarea de ta'lete cu e*ect retard si atinge platoul la apro8imati$ ore
dupa prima do(a"2entru do(ele urmatoare +concentratiile plasmatice se mentin la
acest platou + cu minime $ariatii pentru inter$alul de do(are de &, de ore "S7a
o'ser$at un indice de -uctuatie #raport $ar*?concentratie plasmatica % de , ori
mai mare la capsula de ni*edipina cu eli'erare imediata cu administrare de ) ori
pe (i comparati$ cu administrarea ni*edipinei cu eli'erare prelungita o data pe (i"
2lasma drug concentrations rise at a gradual+ controlled rate a*ter a ni*edipine
e8tended7release ta'let dose and reach a plateau at appro8imatelJ si8 hours
a*ter the frst dose" 1or su'seuent doses+ relati$elJ constant plasma
concentrations at this plateau are maintained Qith minimal -uctuations o$er the&,7hour dosing inter$al" A'out a *our7*old higher -uctuation inde8 #ratio o* peaG
to trough plasma concentration% Qas o'ser$ed Qith the con$entional immediate7
release ni*edipine capsule at t"i"d" dosing than Qith once dailJ ni*edipine
e8tended7release ta'let"
US Natl Inst .ealth0 DailJ3ed" Current 3edication In*ormation *or Ni*edipine
#ni*edipine% ta'let+ flm coated+ e8tended release #3aJ &>>%" A$aila'le *rom+ as
o* Octo'er !9+ &>> http??dailJmed"nlm"nih"go$?dailJmed?drugIn*o"c*mid=!!96
*rom .SDB
At steadJ7state the 'ioa$aila'ilitJ o* thed decreased a*terload" The $asodilatorJ
eects o* ni*edipine result in an o$erall decrease in 'lood pressure" At steadJ7
state the 'ioa$aila'ilitJ o* the ni*edipine e8tended7release ta'let is 6 relati$e
to immediate7release ni*edipine capsules" Administration o* the ni*edipine
e8tended7release ta'let in the presence o* *ood slightlJ alters the earlJ rate o*
drug a'sorption+ 'ut does not in-uence the e8tent o* drug 'ioa$aila'ilitJ"
3arGedlJ reduced >%" A$aila'le *rom+ as
o* Octo'er !9+ &>> http??dailJmed"nlm"nih"go$?dailJmed?drugIn*o"c*mid=!!96
*rom .SDB
The manu*acturer states that relati$e oral 'ioa$aila'ilitJ diers little i*
con$entional ni*edipine capsules are sQalloQed intact+ 'itten and sQalloQed+ or
'itten and held su'linguallJ" .oQe$er+ some data indicate that the rate and
e8tent o* a'sorption o* ni*edipine *olloQing su'lingual administration maJ 'e
decreased su'stantiallJ" Oral 'ioa$aila'ilitJ o* ni*edipine maJ 'e increased up totQo*old in patients Qith li$er cirrhosis"
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American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
Binding o* ni*edipine to plasma proteins is concentration dependent and ranges
*rom &76" 2rotein 'inding maJ 'e reduced in patients Qith renal or hepatic
#eg+ li$er cirrhosis% impairment"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
Ni*edipine is distri'uted into milG"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
Appro8imatelJ >76> o* an oral dose o* ni*edipine is e8creted as meta'olites in
the urine+ Qith onlJ traces #less than >"!% o* an oral dose 'eing e8creted in
urine as unchanged drug" The remainder o* a dose is e8creted in the *eces as
meta'olites+ possi'lJ $ia 'iliarJ elimination" Ni*edipine appears to 'e negligi'lJ
remo$ed 'J hemodialJsis or hemoper*usion"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
1olloQing I4 administration o* ni*edipine+ 'odJ clearance o* the drug is 9! and
),6 mL?minute in Joung adults and geriatric indi$iduals+ respecti$elJ"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
1olloQing oral administration o* Adalat CC e8tended7release ni*edipine ta'lets in
healthJ geriatric indi$iduals #older than > Jears o* age%+ the mean peaG plasma
concentrations and a$erage plasma concentrations o* ni*edipine increased 'J )
and 5>+ respecti$elJ+ compared Qith those o'ser$ed in Jounger adults"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
In one lactating Qoman Qho recei$ed !>+ &>+ and )> mg o* the drug e$erJ 6
hours as con$entional capsules+ peaG milG concentrations o* ni*edipine occurred
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Qithin ! hour a*ter a dose and ranged *rom a'out !)79) ng?mL0 the drug
generallJ Qas not detecta'le during the hour prior to a dose"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
/apidlJ and *ullJ a'sor'ed *olloQing oral administration"
*rom DrugBanG
/oute o* Elimination
Ni*edipine is e8tensi$elJ meta'oli(ed to highlJ Qater7solu'le+ inacti$e
meta'olites accounting *or > to 6> o* the dose e8creted in the urine" Theremainder is e8creted in the *eces in meta'oli(ed *orm+ most liGelJ as a result o*
'iliarJ e8cretion"
*rom DrugBanG
3eta'olism?3eta'olites
The drug is e8tensi$elJ meta'oli(ed in the li$er #to highlJ Qater7solu'le+ inacti$e
meta'olites% 'J the cJtochrome 27,9> microsomal en(Jme sJstem+ including
CV2)A"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
.epatic meta'olism $ia cJtochrome 2,9> sJstem" 2redominantlJ meta'oli(ed 'J
CV2)A,+ 'ut also 'J CV2!A& and CV2&A iso(Jmes"
*rom DrugBanG
Biological .al*7Li*e
In patients Qith normal renal and hepatic *unction+ the plasma hal*7li*e o*
ni*edipine is a'out & hours Qhen administered as con$entional capsules+ and
a'out 5 hours Qhen administered as e8tended7release ta'lets #Adalat CC%"
American SocietJ o* .ealth SJstem 2harmacists0 A.1S Drug In*ormation &>>"
Bethesda+ 3D" #&>>%
*rom .SDB
& hours
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A3LODI2INA
2u'Chem CID &!&
Chemical Names Amlodipine0 66!9>7,&70 Amlocard0 Amlodis0 Coro$al0Nor$asc0 3ore"""
3olecular 1ormulaC&>.&9ClN&O9
3olecular Weight ,>6"659 g?mol
InChI eJ .TIXEAX4CVTUBY7U.111AOVSA7N
Sa*etJ SummarJ La'oratorJ Chemical Sa*etJ SummarJ #LCSS%
3odi*J Date&>!97!>7>)
Create Date&>>97>)7&9
Amlodipine is a long7acting dihJdropJridine calcium channel 'locGer" It is eecti$e
in the treatment o* AN6"659 g?mol
3olecular 1ormula C&>.&9ClN&O9E8perimental 2roperties
3elting 2oint
!567!5 [C
*rom DrugBanG
Solu'ilitJ
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In Qater+ 59") mg?L at &9 deg C #est%
US E2A0 Estimation 2rogram Inter*ace #E2I% Suite" 4er" ,"!" Ran+ &>!!" A$aila'le
*rom+ as o* No$ )+ &>!! http??QQQ"epa"go$?oppt?e8posure?pu's?episuitedl"htm
*rom .SDB
Water Solu'ilitJ
59") mg?L
*rom DrugBanG
4apor 2ressure
!"!Y!>7 mm .g at &9 deg C #est%
US E2A0 E
Dissociation Constants
pa = 6"5 #amine% #est%
S2A/C0 pa?propertJ ser$er" 4er ,"9"+ Sept+ &>>" A$aila'le *rom+ as o* No$ )+
&>!! http??archemcalc"com?sparc?
2harmacologJ
Amlodipine 'elongs to the dihJdropJridine #D.2% class o* calcium channel
'locGers #CCBs%+ the most QidelJ used class o* CCBs" There are at least f$e
dierent tJpes o* calcium channels in .omo sapiens L7+ N7+ 2?X7+ /7 and T7tJpe" It
Qas QidelJ accepted that D.2 CCBs target L7tJpe calcium channels+ the maor
channel in muscle cells that mediate contraction0 hoQe$er+ some studies ha$e
indicated that amlodipine also 'inds to and inhi'its N7tJpe calcium channels #see
re*erences in Targets section%" Similar to other D.2 CCBs+ amlodipine 'inds
directlJ to inacti$e L7tJpe calcium channels sta'ili(ing their inacti$e
con*ormation" Since arterial smooth muscle depolari(ations are longer in durationthan cardiac muscle depolari(ations+ inacti$e channels are more pre$alent in
smooth muscle cells" Alternati$e splicing o* the alpha7! su'unit o* the channel
gi$es amlodipine additional arterial selecti$itJ" At therapeutic su'7to8ic
concentrations+ amlodipine has little eect on cardiac mJocJtes and conduction
cells"
*rom DrugBanG
Amlodipine is a sJnthetic dihJdropJridine and a calcium channel 'locGer Qith
antihJpertensi$e and antianginal properties" Amlodipine inhi'its the in-u8 o*
e8tracellular calcium ions into mJocardial and peripheral $ascular smooth musclecells+ there'J pre$enting $ascular and mJocardial contraction" This results in a
http://archemcalc.com/sparc/http://archemcalc.com/sparc/
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dilatation o* the main coronarJ and sJstemic arteries+ decreased mJocardial
contractilitJ+ increased 'lood -oQ and o8Jgen deli$erJ to the mJocardial tissue+
and decreased total peripheral resistance" This agent maJ also modulate multi7
drug response #3D/% acti$itJ through inhi'ition o* the p7glJcoprotein eZu8
pump"
*rom NCIt
Amlodipine 3aleate is the maleate salt o* amlodipine+ a sJnthetic phenJlpJridine
$asodilator Qith antihJpertensi$e and antianginal eects" Amlodipine inhi'its the
in-u8 o* e8tracellular calcium ions into mJocardial and peripheral $ascular
smooth muscle cells+ there'J pre$enting $ascular and mJocardial contraction"
1urthermore+ decreased mJocardial contractilitJ and dilation o* the main coronarJ
and sJstemic arteries lead to increased 'lood -oQ and o8Jgen deli$erJ to the
mJocardial tissue and decreases total peripheral resistance" This agent maJ also
modulate multi7drug response acti$itJ through inhi'ition o* the p7glJcoprotein
eZu8 pump"
*rom NCIt
3eS. 2harmacolo3eS. 2harmacological Classifcation
Calcium Channel BlocGers
A class o* drugs that act 'J selecti$e inhi'ition o* calcium in-u8 through cellular
mem'ranes" See a list o* 2u'Chem compounds matching this categorJ"
*rom 3eS.
AntihJpertensi$e Agents
Drugs used in the treatment o* acute or chronic $ascular .V2E/TENSION
regardless o* pharmacological mechanism" Among the antihJpertensi$e agents
are DIU/ETICS0 #especiallJ DIU/ETICS+ T.IAIDE%0 AD/ENE/
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*rom 3eS.
ATC Code
C>6CA>! 7 Amlodipine @ C>6CA 7 DihJdropJridine deri$ati$es @ C>6C 7 Selecti$e
calcium channel 'locGers Qith mainlJ $ascular eects @ C>6 7 Calcium channel
'locGers @ C 7 Cardio$ascular sJstem 3ore in*ormation"""
*rom W.OCC
A'sorption+ Distri'ution and E8cretion
Amlodipine is a dihJdropJridine that has sloQ a'sorption and a prolonged
eect" ?Salt not specifed?
.ardman+ R">!+ p" )5,
*rom .SDB
/enal e8cretion accounts *or > Qith a'out 9 amlodipine unchanged and &>
to &9 is e8creted in 'ile and *eces" ?Amlodipine? is not remo$ed *rom the 'odJ
'J hemodialJsis"
1ord 3D+ DelaneJ A+ Ling LR+ EricGson T0 Clinical To8icologJ" W"B" Saunders
CompanJ"+ 2hiladelphia+ 2A" &>>!+ 1olloQing oral administration the 'ioa$aila'ilitJ
is a'out 9> to 66" 1ood has no eect on to8icoGinetic parameters" 2eaG plasma
concentrations o* to 5 ng?ml occur in to 5 hours" Amlodipine is 5 to
protein 'ound" It is su'ected to e8tensi$e hepatic meta'olism"
Ellenhorn+ 3"R"+ S" SchonQald+
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Less than 9 o* an oral dose is e8creted unchanged in the urine" The remainder
is meta'oli(ed to a num'er o* inacti$e meta'olites e8creted in the urine and
*eces"
Ellenhorn+ 3"R"+ S" SchonQald+ 76'5>7da&6)ded&
*rom .SDB
SteadJ7state plasma le$els o* amlodipine are reached a*ter 5 to 6 daJs o*
consecuti$e dailJ dosing" """ E8 $i$o studies ha$e shoQn that appro8imatelJ )
o* the circulating drug is 'ound to plasma proteins in hJpertensi$e patients"
US Natl Inst .ealth0 DailJ3ed" Current 3edication In*ormation *or A3LODI2INE
BESVLATE #amlodipine 'esJlate% ta'let #No$em'er &>!>%" A$aila'le *rom+ as o*Septem'er &+ &>!! http??dailJmed"nlm"nih"go$?dailJmed?looGup"c*m
setid=)*,5>)c>7>'e7,!a>76'5>7da&6)ded&
*rom .SDB
Amlodipine is a dihJdropJridine calcium antagonist drug Qith distincti$e
pharmacoGinetic characteristics Qhich appear to 'e attri'uta'le to a high degree
o* ioni(ation" 1olloQing oral administration+ 'ioa$aila'ilitJ is > to 9 and
plasma concentrations rise graduallJ to peaG to 6 hr a*ter administration"
Amlodipine is e8tensi$elJ meta'olised in the li$er #'ut there is no signifcant
presJstemic or frst7pass meta'olism% and is sloQlJ cleared Qith a terminalelimination hal*7li*e o* ,> to 9> hr" 4olume o* distri'ution is large #&! L?Gg% and
there is a high degree o* protein 'inding #6%" There is some e$idence that age+
se$ere hepatic impairment and se$ere renal impairment in-uence the
pharmacoGinetic profle leading to higher plasma concentrations and longer hal*7
li$es" There is no e$idence o* pharmacoGinetic drug interactions" Amlodipine
shoQs linear dose7related pharmacoGinetic characteristics and+ at steadJ7state+
there are relati$elJ small -uctuations in plasma concentrations across a dosage
inter$al" Thus+ although structurallJ related to other dihJdropJridine deri$ati$es+
amlodipine displaJs signifcantlJ dierent pharmacoGinetic characteristics and is
suita'le *or administration in a single dailJ dose"
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3eredith 2A et al0 Clin 2harmacoGinet &!% p"&&7)! #!&%
*rom .SDB
Amlodipine+ a dihJdropJridine calcium antagonist+ Qas sJnthesi(ed in an attempt
to de$elop a compound Qith a pharmacoGinetic profle characteristic o* this class+
Qhich Qould also ha$e an increased oral 'ioa$aila'ilitJ and e8tended clearance
time" A single intra$enous dose o* !> mg resulted in an a'solute 'ioa$aila'ilitJ o*
, and a calculated elimination hal*7li*e o* ), hours" The pharmacoGinetic
profle o* oral doses shoQed similar changes" These results Qere signifcantlJ
dierent *rom those seen Qith most other dihJdropJridines #elimination hal*7li*e o*
) to !> hours and a'solute 'ioa$aila'ilitJ o* !> to )>% and nondihJdropJridine
calcium antagonists #elimination hal*7li*e ) to hours and loQ a'solute
'ioa$aila'ilitJ%" With chronic oral dosing o* amlodipine once dailJ *or !, daJs+
support Qas pro$ided *or the linearitJ o* amlodipine\s pharmacoGinetics and
a'sence o* such Qith chronic oral dosing Qith $erapamil+ diltia(em+ and
ni*edipine" In the elderlJ population+ elimination hal*7li*e o* 9 mg oral doses is
signifcantlJ prolonged #,6 $s )9 hours0 p less than >">&9% suggesting decreased
oral clearance or increased 'ioa$aila'ilitJ" Comparison o* the pharmacoGinetics o*
amlodipine in patients Qith chronic sta'le angina pectoris Qith the profle in
healthJ $olunteers suggested that clearance is not altered in patients Qith
chronic sta'le angina+ steadJ state 'eing reached to !& hours a*ter
administration o* the drug" In patients Qith cirrhosis+ elimination hal*7li*e is
signifcantlJ prolonged #> $s ), hours0 p less than >">!% suggesting that there is
a greater accumulation o* amlodipine in patients Qith se$ere li$er disease than in
indi$iduals Qith normal hepatic *unction"
A'ernaethJ D/0 Am .eart R !!6#9% p"!!>>7!!>) #!6%
*rom .SDB
""" A randomi(ed+ &7QaJ crosso$er studJ Qas conducted in !6 healthJ male
$olunteers to compare the pharmacoGinetics and pharmacodJnamics o* these
tQo *orms+ i"e" amlodipine nicotinate #test% and amlodipine 'esJlate #re*erence%+
a*ter administration o* a single dose o* 9 mg o* each drug and a Qashout period
'etQeen doses o* , QeeGs" Blood samples *or the pharmacoGinetic analJsis o*
amlodipine Qere o'tained o$er the !,,7hour period a*ter administration" SJstolic
and diastolic 'lood pressures and pulse rates Qere recorded immediatelJ prior toeach 'lood sampling" All participants completed 'oth treatment periods+ and no
serious ad$erse e$ents occurred during the studJ period" A*ter administering a
single dose o* each *ormulation+ mean AUC>7infnitJ and Cma8 $alues Qere
!>"!?7>", ng 8 hr?mL and )"65?7!">, ng?mL *or the test *ormulation and
&>)"!9?79&">9 ng 8 hr?mL and ,">!?7>"> ng?mL *or the re*erence *ormulation+
respecti$elJ" The > confdence inter$als o* test?re*erence mean ratios *or
AUC>7 infnitJ and Cma8 *ell Qithin the predetermined eui$alence range o* 6> 7
!&9" 2harmacodJnamic profles including sJstolic and diastolic 'lood pressures
and pulse rates e8hi'ited no signifcant dierences 'etQeen the tQo
*ormulations" The tQo amlodipine *ormulations shoQed similar pharmacoGineticand pharmacodJnamic characteristics and the neQ amlodipine *ormulation+
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amlodipine nicotinate+ Qas *ound to 'e eui$alent *or pharmacoGinetics to the
currentlJ a$aila'le amlodipine 'esJlate Qith respect to the rate and e8tent o*
amlodipine a'sorption" A'stract 2u'3ed
2arG RV et al0 Int R Clin 2harmacol Ther ,, #!&% ,!75 #&>>%
*rom .SDB
Amlodipine is sloQlJ and almost completelJ a'sor'ed *rom the gastrointestinal
tract" 2eaG plasma concentrations are reached 7!& hour *olloQing oral
administration" Its estimated 'ioa$aila'ilitJ is ,7>" A'sorption is not aected
'J *ood"
*rom DrugBanG
/oute o* Elimination
Amlodipine is e8tensi$elJ #a'out >% con$erted to inacti$e meta'olites $ia
hepatic meta'olism Qith !> o* the parent compound and > o* the
meta'olites e8creted in the urine"
*rom DrugBanG
3eta'olism?3eta'olites
Amlodipine is e8tensi$elJ #a'out >% con$erted to inacti$e meta'olites $ia
hepatic meta'olism Qith !> o* the parent compound and > o* themeta'olites e8creted in the urine"
US Natl Inst .ealth0 DailJ3ed" Current 3edication In*ormation *or A3LODI2INE
BESVLATE #amlodipine 'esJlate% ta'let #No$em'er &>!>%" A$aila'le *rom+ as o*
Septem'er &+ &>!! http??dailJmed"nlm"nih"go$?dailJmed?looGup"c*m
setid=)*,5>)c>7>'e7,!a>76'5>7da&6)ded&
*rom .SDB
?Amlodipine undergoes? minimal presJstemic meta'olism" SloQ 'ut e8tensi$e
hepatic meta'olism0 meta'olites lacG signifcant acti$itJ"
1ord 3D+ DelaneJ A+ Ling LR+ EricGson T0 Clinical To8icologJ" W"B" Saunders
CompanJ"+ 2hiladelphia+ 2A" &>>!+ p" )5,
*rom .SDB
There are no acti$e meta'olites" The rate o* o8idati$e meta'olism is relati$elJ
sloQ and so amlodipine dose not e8hi'it e8tensi$e frst7pass or presJstemic
meta'olism a*ter oral administration"
Ellenhorn+ 3"R"+ S" SchonQald+
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*rom .SDB
In the present studJ+ the meta'olic profle o* amlodipine+ a Qell7GnoQn calcium
channel 'locGer+ Qas in$estigated emploJing liuid chromatographJ7mass
spectrometric #LC?3S% techniues" TQo dierent tJpes o* mass spectrometers 7 a
triple7uadrupole #XX% and a uadrupole time7o*7-ight #X7TO1% massspectrometer 7 Qere utili(ed to acuire structural in*ormation on amlodipine
meta'olites" The meta'olites Qere produced 'J incu'ation o* amlodipine Qith
primarJ cultures o* rat hepatocJtes" Incu'ations *rom rat hepatocJtes Qere
analJ(ed Qith LC73S?3S+ and &! phase I and phase II meta'olites Qere detected"
Their product ion spectra Qere acuired and interpreted+ and structures Qere
proposed" Accurate mass measurement using LC7X7TO1 Qas used to determine
the elemental composition o* meta'olites and thus to confrm the proposed
structures o* these p" meta'olites" 3ainlJ phase I meta'olic changes Qere
o'ser$ed including dehJdrogenation o* the dihJdropJridine core+ as Qell as
reactions o* side chains+ such as hJdrolJsis o* ester 'onds+ hJdro8Jlation+ N7acetJlation+ o8idati$e deamination+ and their com'inations" The onlJ phase II
meta'olite detected Qas the glucuronide o* a dehJdrogenated+ deaminated
meta'olite o* amlodipine" ?In$estigators? propose se$eral in $itro meta'olic
pathQaJs o* amlodipine in rat+ 'ased on our analJsis o* th )5,
1. Hepatic. Metabolized extensively (90%) to inactive metabolites via the cytochrome P450 3A4 isozyme.
from DrugBank
2. Biological Half-Life
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours.
US Natl Inst Health; DailyMed. Current Medication Information for AMLODIPINE BESYLATE (amlodipine besylate) tablet
(November 2010). Available from, as of September 26, 2011:http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-
0b9e-41a0-8b70-da26683d9ed2
from HSDB
The total body clearance is 7 mL/min/kg.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human
Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 564
from HSDB
/Amlodipine/ elimination takes 35 hours in healthy volunteers; may be prolonged to 65 hours in elderly, 60 hours in
hepatic function impairment; not affected by renal function impairment.
Ford MD, Delaney KA, Ling LJ, Erickson T; Clinical Toxicology. W.B. Saunders Company., Philadelphia, PA. 2001, p. 374
from HSDB
30-50 hours
from DrugBank
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2
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3. Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that
inhibits the transmembrane influx ofcMechanism of Action
Amlodipine is a dihydropyridine calcium antagonist(calcium ion antagonist or slow-channel blocker) that inhibits
the transmembrane influx ofcalcium ions into vascular smooth muscle and cardiac muscle. Experimental data
suggest thatamlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile
processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of
extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibitscalcium ion influx
across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle
cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at
therapeutic doses. Serumcalcium concentration is not affected by amlodipine. Within the physiologic pH
range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with thecalcium channel receptor
is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a
gradual onset of effect.
US Natl Inst Health; DailyMed. Current Medication Information for AMLODIPINE BESYLATE (amlodipine besylate) tablet
(November 2010). Available from, as of September 26, 2011:http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-
0b9e-41a0-8b70-da26683d9ed2
from HSDB
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload)
against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any
given level of exercise.
US Natl Inst Health; DailyMed. Current Medication Information for AMLODIPINE BESYLATE (amlodipine besylate) tablet
(November 2010). Available from, as of September 26, 2011:http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-
0b9e-41a0-8b70-da26683d9ed2
from HSDB
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary
arteries and arterioles in response to calcium,potassium epinephrine, serotonin, and thromboxane A2 analog in
experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is
responsible for the effectiveness ofamlodipine in vasospastic (Prinzmetal's or variant) angina.
US Natl Inst Health; DailyMed. Current Medication Information for AMLODIPINE BESYLATE (amlodipine besylate) tablet
(November 2010). Available from, as of September 26, 2011:http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2
from HSDB
Recent studies have suggested that cytokines are capable of modifying cardiovascular function and that drugs
used in the treatment of heart failure have various modulating properties on the production of cytokines. More
recently, we have found that ouabain induces the production of cytokines. This study was performed to examine
the effects of calcium channel blockers on the production of cytokines induced by a cardiac glycoside. Human
peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured in 0.1, 1,
10, and 30 micromol/l amlodipine,diltiazem, andnifedipine in presence of 1 micromol/louabain. After 24 h of
incubation, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were measured in the culture supernatants by enzyme-linked
immunosorbent assay.Ouabain induced the production of IL-1alpha, IL-1beta and IL-6, but not of TNF-alpha.
https://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/oxygenhttps://pubchem.ncbi.nlm.nih.gov/compound/oxygenhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/potassiumhttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttps://pubchem.ncbi.nlm.nih.gov/compound/serotoninhttps://pubchem.ncbi.nlm.nih.gov/compound/serotoninhttps://pubchem.ncbi.nlm.nih.gov/compound/thromboxane%20A2https://pubchem.ncbi.nlm.nih.gov/compound/thromboxane%20A2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/Ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium%20ionhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/oxygenhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/potassiumhttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttps://pubchem.ncbi.nlm.nih.gov/compound/serotoninhttps://pubchem.ncbi.nlm.nih.gov/compound/thromboxane%20A2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3f4703c0-0b9e-41a0-8b70-da26683d9ed2https://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/ouabainhttps://pubchem.ncbi.nlm.nih.gov/compound/Ouabain
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Induction of IL-1beta was most prominent. The production of IL-1alpha, and IL-6 was inhibited by amlodipine in a
concentration-dependent manner and was significantly decreased at a concentration of 10 micromol/l. IL-1beta
production was also inhibited by 30 micromol/l amlodipine. In contrast, neitherdiltiazem nor nifedipineinhibited the
production of these cytokines. The unique property of amlodipine to inhibit the production of IL-1alpha, IL-1beta
and IL-6 may contribute to its beneficial effects in heart failure patients.
Matsumori A et al; Cytokine 12(3): p.294-297 (2000)
from HSDB
Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic
plaques. Calciumchannel blockers have been shown to reduce VSMC proliferation, but the underlying molecular
mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, /investigators/
demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro.
/Investigators/ show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the
glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-
activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of
intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by
C/EBP-alpha antisense oligonucleotide or by the GR antagonistRU486. Amlodipine-dependent inhibition of cell
proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting
C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled
antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-
proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain
beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a
vascular relaxant. Abstract:PubMed
Ziesche R et al; FASEB J 18 (13): 1516-23 (2004)
from HSDB
The effects of long-acting calcium channel blockers on pressure overload-induced cardiac hypertrophy have been
little studied in experimental animals and the underlying mechanisms are not fully understood. /Investigators/
previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of the epidermal growth
factor receptor (EGFR). In this study, /the authors/ investigated whether amlodipine attenuates cardiac
hypertrophy by inhibiting EGFR phosphorylation. /Investigators/ found that amlodipine dose-dependently
inhibitedepinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat
cardiomyocytes. /This/ in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by
transverse aortic constriction (TAC) in C57/B6 mice. One week after TAC, amlodipinetreatment (3 mg/kg/day)significantly reduced the heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC
mice, P < 0.01). These results indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of
EGFR phosphorylation. Abstract:PubMed
Liao Y et al; Biochem Biophys Res Commun 327 (4): 1083-7 (2005)
from HSDB
/Investigators/ examined whether amlodipine, an L-typecalcium channel blocker (CCB), has an inhibitory effect on
oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient (ApoEKO)
mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with orwithout oral administration ofamlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After
https://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/RU486https://pubchem.ncbi.nlm.nih.gov/compound/RU486https://pubchem.ncbi.nlm.nih.gov/compound/RU486https://pubchem.ncbi.nlm.nih.gov/compound/RU486http://www.ncbi.nlm.nih.gov/pubmed/15466360?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttp://www.ncbi.nlm.nih.gov/pubmed/15652507?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttps://pubchem.ncbi.nlm.nih.gov/compound/diltiazemhttps://pubchem.ncbi.nlm.nih.gov/compound/nifedipinehttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/RU486https://pubchem.ncbi.nlm.nih.gov/compound/RU486http://www.ncbi.nlm.nih.gov/pubmed/15466360?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/epinephrinehttp://www.ncbi.nlm.nih.gov/pubmed/15652507?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterol
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HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine
dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions
ofNADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular
adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with
immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10
weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the
proximal aorta. In the atherosclerotic lesion,superoxide production, the expression ofNADPH oxidase subunits,
andNADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were
increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant
with HCD administration, with no significant change in blood pressure and plasmacholesterol level. /Investigators/
also observed that treatment withamlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a
decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area
in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and
the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic
lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of
oxidative stress and inflammatory response. Abstract:PubMed
Yoshii T et al; Hypertens Res 29 (6): 457-66 (2006)
from HSDB
Calcium channel blockers (CCBs) are widely used in the therapy of cardiovascular diseases. Recent studies have
shown that several CCBs exerted distinct anti-inflammatory effect in myocardial dysfunction models. The purpose
of the present study was to evaluate therapeutic effect and possible mechanism of action of amlodipine, one of the
widely used CCBs, on rat cardiac dysfunction during sepsis induced bylipopolysaccharide (LPS). Pretreatment of
the rats with amlodipine (10 or 30 mg/kg, i.v.) delayed the fall of mean arterial blood pressure caused by
LPS. Amlodipine also significantly inhibited the elevation of plasma tumor necrosis factor alpha (TNF-alpha) and
decreased levels of inducible nitric oxide synthase (iNOS) in response to LPS challenge. To investigate the
mechanism of the action of amlodipine, neonatal rat cardiomyocytes were used as a
model. Amlodipine concentration-dependently decreased the release of TNF-alpha and iNOS protein expression,
and suppressed the degradation and phosphorylation of inhibitor of kappaB-alpha (IkappaB-alpha) in LPS-
activated neonatal rat cardiomyocytes. Further studies revealed that amlodipine markedly activated
phosphatidylinositiol 3-kinase (PI3K) and Akt, downstream of the PI3K signal cascade. Application of PI3K
inhibitors,wortmannin and LY294002 attenuated the depression of TNF-alpha and iNOS expression
by amlodipine in LPS-induced cardiomyocytes. These findings may explain some cardioprotective effects
of amlodipine in LPS-mediated sepsis and suggest that the inhibition of TNF-alpha and iNOS expression
by amlodipine is, at least in part, dependent on PI3K/Akt signaling pathway. Abstract:PubMed
Li XQ et al; Int Immunopharmacol 9 (9): 1032-41 (2009)
from HSDB
Amlodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx
ofcalciumions through L-typecalcium channels.Calcium ions entering the cell through these channels bind to
calmodulin.Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated
MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle
contraction. Signal amplification is achieved bycalcium-induced calcium release from the sarcoplasmic reticulum
throughryanodine receptors. Inhibition of the initial influx ofcalcium decreases the contractile activity of arterialsmooth muscle cells and results in vasodilation. The vasodilatory effects of amlodipine result in an overall
https://pubchem.ncbi.nlm.nih.gov/compound/superoxidehttps://pubchem.ncbi.nlm.nih.gov/compound/superoxidehttps://pubchem.ncbi.nlm.nih.gov/compound/nicotinamide-adenine%20dinucleotide%20phosphatehttps://pubchem.ncbi.nlm.nih.gov/compound/nicotinamide-adenine%20dinucleotide%20phosphatehttps://pubchem.ncbi.nlm.nih.gov/compound/nicotinamide-adenine%20dinucleotide%20phosphatehttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/superoxidehttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttp://www.ncbi.nlm.nih.gov/pubmed/16940709?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/lipopolysaccharidehttps://pubchem.ncbi.nlm.nih.gov/compound/nitric%20oxidehttps://pubchem.ncbi.nlm.nih.gov/compound/nitric%20oxidehttps://pubchem.ncbi.nlm.nih.gov/compound/nitric%20oxidehttps://pubchem.ncbi.nlm.nih.gov/compound/wortmanninhttps://pubchem.ncbi.nlm.nih.gov/compound/wortmanninhttps://pubchem.ncbi.nlm.nih.gov/compound/LY294002https://pubchem.ncbi.nlm.nih.gov/compound/LY294002https://pubchem.ncbi.nlm.nih.gov/compound/LY294002http://www.ncbi.nlm.nih.gov/pubmed/19393774?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/superoxidehttps://pubchem.ncbi.nlm.nih.gov/compound/nicotinamide-adenine%20dinucleotide%20phosphatehttps://pubchem.ncbi.nlm.nih.gov/compound/nicotinamide-adenine%20dinucleotide%20phosphatehttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/superoxidehttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/NADPHhttps://pubchem.ncbi.nlm.nih.gov/compound/cholesterolhttp://www.ncbi.nlm.nih.gov/pubmed/16940709?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/lipopolysaccharidehttps://pubchem.ncbi.nlm.nih.gov/compound/nitric%20oxidehttps://pubchem.ncbi.nlm.nih.gov/compound/wortmanninhttps://pubchem.ncbi.nlm.nih.gov/compound/LY294002http://www.ncbi.nlm.nih.gov/pubmed/19393774?dopt=Abstracthttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/calcium
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decrease in blood pressure. Amlodipine is a long-acting CCB that may be used to treat mild to moderate essential
hypertension and exertion-related angina (chronic stable angina). Another possible mechanism is
that amlodipine inhibits vascular smooth muscle carbonic anhydrase I activity causing cellular pH increases which
may be involved inregulating intracelluarcalcium influx through calcium channels.
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are alsoinvolved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter
release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type
calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They
are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA
(omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-
agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in
excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to
DHP compounds
Gene Name CACNA1C
1ELODI2INA
Chemical Names 1elodipine0 2lendil0 5&9>757)0 /enedil0 Splendil0 1elodaJ0
3ore"""
3olecular 1ormulaC!6.!Cl&NO,
3olecular Weight )6,"&9)5 g?mol
1elodipine is a dihJdropJridine calcium antagonist Qith positi$e inotropic eects"
It loQers 'lood pressure 'J reducing peripheral $ascular resistance through a
highlJ selecti$e action on smooth muscle in arteriolar resistance $essels"
*rom 3eS.
1elodipine is a dihJdropJridine calcium channel 'locGing agent" 1elodipine inhi'its
the in-u8 o* e8tracellular calcium ions into mJocardial and $ascular smooth
muscle cells+ causing dilatation o* the main coronarJ and sJstemic arteries and
decreasing mJocardial contractilitJ" This agent also inhi'its the drug eZu8 pump
27glJcoprotein Qhich is o$ere8pressed in some multi7drug resistant tumors andmaJ impro$e the e]cacJ o* some antineoplastic agents" #NCI>,%
IUPAC Name
5-O-ethyl 3-O-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
3olecular Weight )6,"&9)5 g?mol
3olecular 1ormula
E8perimental 2roperties
3elting 2oint
https://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calcium
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!,9 [C
*rom DrugBanG
Solu'ilitJ
Water Solu'ilitJ
!"5 mg?L
2harmacologJ
1elodipine 'elongs to the dihJdropJridine #D.2% class o* calcium channel 'locGers
#CCBs%+ the most QidelJ used class o* CCBs" There are at least f$e dierent tJpes
o* calcium channels in .omo sapiens L7+ N7+ 2?X7+ /7 and T7tJpe" It Qas QidelJ
accepted that CCBs target L7tJpe calcium channels+ the maor channel in musclecells that mediates contraction0 hoQe$er+ some studies ha$e shoQn that
*elodipine also 'inds to and inhi'its T7tJpe calcium channels" T7tJpe calcium
channels are most commonlJ *ound on neurons+ cells Qith pacemaGer acti$itJ
and on osteocJtes" The pharmacologic signifcance o* T7tJpe calcium channel
'locGade is unGnoQn" 1elodipine also 'inds to calmodulin and inhi'its calmodulin7
dependent calcium release *rom the sarcoplasmic reticulum" The eect o* this
interaction appears to 'e minor" Another studJ demonstrated that *elodipine
attenuates the acti$itJ o* calmodulin7dependent cJclic nucleotide
phosphodiesterase #Ca32DE% 'J 'inding to the 2DE7!B! and 2DE7!A& en(Jme
su'units" Ca32DE is one o* the GeJ en(Jmes in$ol$ed in cJclic nucleotides andcalcium second messenger sJstems" 1elodipine also acts as an antagonist to the
mineralcorticoid receptor 'J competing Qith aldosterone *or 'inding and 'locGing
aldosterone7induced coacti$ator recruitment o* the mineralcorticoid receptor"
1elodipine is a'le to 'ind to sGeletal and cardiac muscle iso*orms o* troponin C+
one o* the GeJ regulatorJ proteins in muscle contraction" Though *elodipine
e8hi'its 'inding to manJ endogenous molecules+ its $asodilatorJ eects are still
thought to 'e 'rought a'out primarilJ through inhi'ition o* $oltage7gated L7tJpe
calcium channels" Similar to other D.2 CCBs+ *elodipine 'inds directlJ to inacti$e
calcium channels sta'ili(ing their inacti$e con*ormation" Since arterial smooth
muscle depolari(ations are longer in duration than cardiac muscledepolari(ations+ inacti$e channels are more pre$alent in smooth muscle cells"
Alternati$e splicing o* the alpha7! su'unit o* the channel gi$es *elodipine
additional arterial selecti$itJ" At therapeutic su'7to8ic concentrations+ *elodipine
has little eect on cardiac mJocJtes and conduction cells"
*rom DrugBanG
1elodipine is a dihJdropJridine calcium channel 'locGing agent" 1elodipine inhi'its
the in-u8 o* e8tracellular calcium ions into mJocardial and $ascular smooth
muscle cells+ causing dilatation o* the main coronarJ and sJstemic arteries and
decreasing mJocardial contractilitJ" This agent also inhi'its the drug eZu8 pump
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27glJcoprotein Qhich is o$ere8pressed in some multi7drug resistant tumors and
maJ impro$e the e]cacJ o* some antineoplastic agents" #NCI>,%
A'sorption+ Distri'ution and E8cretion
Is completelJ a'sor'ed *rom the gastrointestinal tract0 hoQe$er+ e8tensi$e frst7
pass meta'olism through the portal circulation results in a loQ sJstemic
a$aila'ilitJ o* !9" Bioa$aila'ilitJ is unaected 'J *ood"
*rom DrugBanG
/oute o* Elimination
Although higher concentrations o* the meta'olites are present in the plasma due
to decreased urinarJ e8cretion+ these are inacti$e" Animal studies ha$e
demonstrated that *elodipine crosses the 'lood7'rain 'arrier and the placenta"
*rom DrugBanG
4olume o* Distri'ution
!> L?Gg
*rom DrugBanG
Clearance
>"6 L?min :Voung healthJ su'ects;
*rom DrugBanG
3eta'olism?3eta'olites
.epatic meta'olism primarilJ $ia cJtochrome 2,9> )A," Si8 meta'olites Qith no
apprecia'le $asodilatorJ eects ha$e 'een identifed"
*rom DrugBanG
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1. Biological .al*7
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1.Life
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17.5-31.5 hours in hypertensive
patients; 19.1-35.9 hours in elderly
hypertensive patients; 8.5-19.7 in
healthy volunteers.
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from DrugBank
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2.Mechanism of Action
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Felodipine decreases arterial smooth
muscle contractility and subsequent
vasoconstriction by inhibiting the influx
ofcalciumions through voltage-gated
L-type calcium channels. It reversibly
competes against nitrendipine and
other DHP CCBs for DHP binding
sites in vascular smooth muscle and
cultured rabbit atrial
cells.Calcium ions entering the cell
through these channels bind to
calmodulin.Calcium-bound
calmodulin then binds to and activates
myosin light chain kinase (MLCK).
Activated MLCK catalyzes the
phosphorylation of the regulatory light
chain subunit of myosin, a key step in
muscle contraction. Signal
amplification is achieved by calcium-
inducedcalcium release from the
sarcoplasmic reticulum
throughryanodine receptors. Inhibition
of the initial influx
ofcalcium decreases the contractile
activity of arterial smooth muscle cells
and results in vasodilation. The
vasodilatory effects of felodipine result
in an overall decrease in blood
pressure. Felodipine may be used to
treat mild to moderate essential
hypertension.
https://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/nitrendipinehttps://pubchem.ncbi.nlm.nih.gov/compound/nitrendipinehttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/nitrendipinehttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/Calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/calciumhttps://pubchem.ncbi.nlm.nih.gov/compound/ryanodinehttps://pubchem.ncbi.nlm.nih.gov/compound/calcium
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from DrugBank
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2.Toxicity
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1.Toxicological Information
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1.Toxicity Summary
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Symptoms of overdose include
excessive peripheral vasodilation with
marked hypotension and possibly
bradycardia. Oral rat LD50 is 1050
mg/kg.
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from DrugBank
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2.Protein Binding
+ primarilJ to the al'umin *raction"
NI3ODI2INA
Chemical Names Nimodipine0 2eriplum0 Nimotop0 >69797,0 Admon0
Nimodipino0 3ore"""
3olecular 1ormulaC&!.&N&O5
3olecular Weight ,!6",,>), g?mol
InChI eJ Nimodipine is a calcium channel 'locGader Qith pre*erential
cere'ro$ascular acti$itJ" It has marGed cere'ro$ascular dilating eects andloQers 'lood pressure"
*rom 3eS.
Nimodipine is a dihJdropJridine deri$ati$e and an analogue o* the calcium
channel 'locGer ni*edipine+ Qith antihJpertensi$e acti$itJ" Nimodipine inhi'its the
transmem'rane in-u8 o* calcium ions in response to depolari(ation in smooth
muscle cells+ there'J inhi'iting $ascular smooth muscle contraction and inducing
$asodilatation" Nimodipine has a greater eect on cere'ral arteries than on
peripheral smooth muscle cells and mJocardial cells+ pro'a'lJ 'ecause this agent
can cross the 'lood 'rain 'arrier due to its lipophilic nature" 1urthermore+ thisagent also inhi'its the drug eZu8 pump 27glJcoprotein+ Qhich is o$ere8pressed in
some multi7drug resistant tumors+ and maJ impro$e the e]cacJ o* some
antineoplastic agents"
IU2AC Name
)7O7#&7metho8JethJl% 97O7propan7&7Jl &+7dimethJl7,7#)7nitrophenJl%7!+,7
dihJdropJridine7)+97dicar'o8JlateE8perimental 2roperties
3elting 2oint
!&9 [C
2harmacologJ
Nimodipine 'elongs to the class o* pharmacological agents GnoQn as calcium
channel 'locGers" Nimodipine is indicated *or the impro$ement o* neurological
outcome 'J reducing the incidence and se$eritJ o* ischemic defcits in patients
Qith su'arachnoid hemorrhage *rom ruptured congenital aneurJsms Qho are in
good neurological condition post7ictus #e"g"+ .unt and .ess
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inhi'its contractions o* $ascular smooth muscle" In animal e8periments+
nimodipine had a greater eect on cere'ral arteries than on arteries elseQhere in
the 'odJ perhaps 'ecause it is highlJ lipophilic+ alloQing it to cross the 'lood
'rain 'arrier"
*rom DrugBanG
Nimodipine is a dihJdropJridine deri$ati$e and an analogue o* the calcium
channel 'locGer ni*edipine+ Qith antihJpertensi$e acti$itJ" Nimodipine inhi'its the
transmem'rane in-u8 o* calcium ions in response to depolari(ation in smooth
muscle cells+ there'J inhi'iting $ascular smooth muscle contraction and inducing
$asodilatation" Nimodipine has a greater eect on cere'ral arteries than on
peripheral smooth muscle cells and mJocardial cells+ pro'a'lJ 'ecause this agent
can cross the 'lood 'rain 'arrier due to its lipophilic nature" 1urthermore+ this
agent also inhi'its the drug eZu8 pump 27glJcoprotein+ Qhich is o$ere8pressed in
some multi7drug resistant tumors+ and maJ impro$e the e]cacJ o* some
antineoplastic agents"
A'sorption+ Distri'ution and E8cretion
In humans+ nimodipine is rapidlJ a'sor'ed a*ter oral administration+ and peaG
concentrations are generallJ attained Qithin one hour" Bioa$aila'ilitJ is !>>
*olloQing intra$enous administration and )7)> *olloQing oral administration due
to e8tensi$e frst7pass meta'olism"
*rom DrugBanG
/oute o* Elimination
Nimodipine is eliminated almost e8clusi$elJ in the *orm o* meta'olites and less
than ! is reco$ered in the urine as unchanged drug" Numerous meta'olites+ all
o* Qhich are either inacti$e or considera'lJ less acti$e than the parent
compound+ ha$e 'een identifed"
*rom DrugBanG
3eta'olism?3eta'olites
.epatic meta'olism $ia CV2 )A,"
*rom DrugBanG
Biological .al*7Li*e
!"57 hours
3echanism o* Action
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Although the precise mechanism o* action is not GnoQn+ nimodipine 'locGs
intracellular in-u8 o* calcium through $oltage7dependent and receptor7operated
sloQ calcium channels across the mem'ranes o* mJocardial+ $ascular smooth
muscle+ and neuronal cells" Nimodipine 'inds specifcallJ to L7tJpe $oltage7gated
calcium channels" The inhi'ition o* calcium ion trans*er results in the inhi'ition o*
$ascular smooth muscle contraction" E$idence suggests that the dilation o* smallcere'ral resistance $essels+ Qith a resultant increase in collateral circulation+
and?or a direct eect in$ol$ing the pre$ention o* calcium o$erload in neurons
maJ 'e responsi'le *or nimodipine\s clinical eect in patients Qith su'arachnoid
hemorrhage"
*rom DrugBanG
To8icitJ
To8icological In*ormation
To8icitJ SummarJ
SJmptoms o* o$erdosage Qould 'e e8pected to 'e related to cardio$ascular
eects such as e8cessi$e peripheral $asodilation Qith marGed sJstemic
hJpotension"
*rom DrugBanG
2rotein Binding
9 'ound to plasma protein
,"DI1ENIL2I2E/AINE # 1LUNA/IINA %
!+,7di*enilpipera(ina
1LUNA/IINA
olecular 1ormula C&.&1&N&
3olecular Weight ,>,",,6, g?mol
1lunari(ine is a selecti$e calcium entrJ 'locGer Qith calmodulin 'inding properties
and histamine .! 'locGing acti$itJ" 1lunari(ine is eecti$e in the prophJla8is o*
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migraine+ occlusi$e peripheral $ascular disease+ $ertigo o* central and peripheral
origin+ and as an adu$ant in the therapJ o* epilepsJ"
*rom 3eS.
1lunari(ine is a selecti$e calcium entrJ 'locGer Qith calmodulin 'inding properties
and histamine .! 'locGing acti$itJ" It is eecti$e in the prophJla8is o* migraine+
occlusi$e peripheral $ascular disease+ $ertiIU2AC Name
!7:'is#,7-uorophenJl%methJl;7,7:#E%7)7phenJlprop7&7enJl;pipera(inego o* central
and peripheral origin+ and as an adu$ant in the therapJ o* epilepsJ"
E8perimental 2roperties
3elting 2oint2harmacologJ
1lunari(ine is a selecti$e calcium entrJ 'locGer Qith calmodulin 'inding properties
and histamine .! 'locGing acti$itJ"
*rom DrugBanG
3eS. 2harmacological Classifcation
Calcium Channel BlocGers
A class o* drugs that act 'J selecti$e inhi'ition o* calcium in-u8 through cellularmem'ranes" See a list o* 2u'Chem compounds matching this categorJ"
*rom 3eS.
4asodilator Agents
Drugs used to cause dilation o* the 'lood $essels" See a list o* 2u'Chem
compounds matching this categorJ"
*rom 3eS.
.istamine .! Antagonists
Drugs that selecti$elJ 'ind to 'ut do not acti$ate histamine .! receptors+ there'J
'locGing the actions o* endogenous histamine" Included here are the classical
antihistaminics that antagoni(e or pre$ent the action o* histamine mainlJ in
immediate hJpersensiti$itJ" TheJ act in the 'ronchi+ capillaries+ and some other
smooth muscles+ and are used to pre$ent or allaJ motion sicGness+ seasonal
rhinitis+ and allergic dermatitis and to induce somnolence" The eects o* 'locGing
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central ner$ous sJstem .! receptors are not as Qell understood" See a list o*
2u'Chem compounds matching this categorJ"
*rom 3eS.
Anticon$ulsants
Drugs used to pre$ent SEIU/ES or reduce their se$eritJ" See a list o* 2u'Chem
compounds matching this categorJ" A'sorption+ Distri'ution and E8cretion
69 *olloQing oral administration"
*rom DrugBanG
3eta'olism?3eta'olites
.epatic+ to tQo meta'olites $ia N7dealJlation and hJdro8Jlation"
*rom DrugBanG
Biological .al*7Li*e
!6 daJs
*rom DrugBanG
3echanism o* Action
1lunari(ine inhi'its the in-u8 o* e8tracellular calcium through mJocardial and
$ascular mem'rane pores 'J phJsicallJ plugging the channel" The decrease in
intracellular calcium inhi'its the contractile processes o* smooth muscle cells+
causing dilation o* the coronarJ and sJstemic arteries+ increased o8Jgen deli$erJ
to the mJocardial tissue+ decreased total peripheral resistance+ decreased
sJstemic 'lood pressure+ and decTo8icitJ
To8icological In*ormation
To8icitJ SummarJ
71lunari(ine should 'e used Qith care in patients Qith depression or those 'eing
prescri'ed other agents+ such as phenothia(ines+ concurrentlJ+ Qhich maJ cause
e8trapJramidal side7eects" 7Acute o$erdosage has 'een reported and the
o'ser$ed sJmptoms Qere sedation+ agitation and tachJcardia" 7Treatment o*
acute o$erdosage consists o* charcoal administration+ induction o* emesis or
gastric la$age+ and supporti$e measures" No specifc antidote is GnoQn"
*rom DrugBanG
2rotein Binding
'ound to plasma proteinsreased a*terload"
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&9!"9
Ranssen+ 2"A"R"0 U"S" 2atent )+55)+)0 No$em'er &>+ !5)0 assigned to Ranssen2harmaceutica N"4"