clase de blocante de canale de calciu

8/19/2019 Clase de Blocante de Canale de Calciu

1/42

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


2/42

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


3/42

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


6/42

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"


7/42

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


8/42

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"


9/42


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"


Bethesda+ 3D" #&>>%

*rom .SDB

Ni*edipine is distri'uted into milG"


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"


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"


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"


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


10/42

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"


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"


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%"


Bethesda+ 3D" #&>>%

*rom .SDB

& hours


11/42

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


12/42

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/


13/42

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/


14/42

*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


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+


15/42

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"


16/42

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+


17/42

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


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


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+


18/42

*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


19/42

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.



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.



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.


(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


20/42

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


21/42

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


22/42

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


23/42

!,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


24/42

27glJcoprotein Qhich is o$ere8pressed in some multi7drug resistant tumors and

maJ impro$e the e]cacJ o* some antineoplastic agents" #NCI>,%


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


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


.epatic meta'olism primarilJ $ia cJtochrome 2,9> )A," Si8 meta'olites Qith no

apprecia'le $asodilatorJ eects ha$e 'een identifed"

*rom DrugBanG


25/42

1. Biological .al*7


26/42

1.Life


27/42

17.5-31.5 hours in hypertensive

patients; 19.1-35.9 hours in elderly

hypertensive patients; 8.5-19.7 in

healthy volunteers.


28/42

from DrugBank


29/42

2.Mechanism of Action


30/42

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


31/42

from DrugBank


32/42

2.Toxicity


33/42

1.Toxicological Information


34/42

1.Toxicity Summary


35/42

Symptoms of overdose include

excessive peripheral vasodilation with

marked hypotension and possibly

bradycardia. Oral rat LD50 is 1050

mg/kg.


36/42

from DrugBank


37/42

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


38/42

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"


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


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


.epatic meta'olism $ia CV2 )A,"

*rom DrugBanG


!"57 hours

3echanism o* Action


39/42

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*


40/42

migraine+ occlusi$e peripheral $ascular disease+ $ertigo o* central and peripheral

origin+ and as an adu$ant in the therapJ o* epilepsJ"

*rom 3eS.


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


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


41/42

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


.epatic+ to tQo meta'olites $ia N7dealJlation and hJdro8Jlation"

*rom DrugBanG


!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"


42/42

&9!"9

Ranssen+ 2"A"R"0 U"S" 2atent )+55)+)0 No$em'er &>+ !5)0 assigned to Ranssen2harmaceutica N"4"

clase de blocante de canale de calciu

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