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ThThee ef

effefects

cts of

of ddigo

igoxin

xin anandd dodopam

pamine

ine onon tthhee

ooxyxygen gen con consum sumppttioion, n, lactat lactatee pprroodduction uction and and

hhaem aemododynynamic amic perf perfoorman rmancece ooff anan iisosolat lateed, d,

pperf erfuused, sed, workin workingg gguuinea-pig inea-pig hheaeart. rt.

digoxin

digoxin imimpr

provoveses tthehe hhaaememodynam

odynamicic

perfor performmance ance ooff tthehe hheear artt wwithout ithout alter altering ing iitsts

mmetaboli etabolismsm and and ther therefor eforee iincr ncreases eases itsits

effici

efficiency….

ency…. dopam

odynamiicc per

dopamiinene imimpr

perform

provoveses the

the

of the

haemodynam

haem

expense of

expense

formaancncee of

aerobic

the heart

heart aatt ththee

of iinnccrreaeasseded aero

bic and

and anaer

anaerobic

obic

mmetaboli etabolismsm..

 ThThee ef effefects cts of of ddigo anandd dodopam onon tthhee ooxyxygen gen con consum

ZZannad

annad EE,, EEur

ur JJ PPhar

harmmacol

acol ((1982

1982 ) )

Jul 9;

Jul 9;

 ThThee ef effefects cts of of ddigo anandd dodopam onon tthhee ooxyxygen gen con consum

8181((22))::263-71

263-71

 ThThee ef effefects cts of of ddigo anandd dodopam onon tthhee ooxyxygen gen con consum

Car

Cardiov

diovasc

ascular

ular PPhaharmrmacacoollogy

ogy

Dru

Druggss aanndd bblolooodd vveesssseelsls

Dru

Druggss aanndd ththee heheaartrt

Ma

Majojorr cclinliniiccaall iinnddicaicatiotionsns::

HHypypeerrtensi tensionon

AAngina ngina pec pecttor oriiss

CCar ardiac diac fail failuurree

AAtheros theroscleclerosi rosiss

CCar ardiac diac arr arrythm ythmiiasas

Car Car diov diov asc asc ular ular P P ha ha rm rm ac ac
Car Car diov diov asc asc ular ular P P ha ha rm rm ac ac
Car Car diov diov asc asc ular ular P P ha ha rm rm ac ac
Car Car diov diov asc asc ular ular P P ha ha rm rm ac ac

Drugug aacti

Dr

ctionon onon

bbloo

loodd vveessssel

elss

PProroff JJoohnhn FFinb

inbeergrg

PhPhaarmrmacacoolog

logyy DeDeppaartrtmmeenntt

Dr ug ug a a cti Dr cti on on on on b b loo v

Rappaport Faculty of Medicine

Rappaport Faculty of Medicine

Dr ug ug a a cti Dr cti on on on on b b loo v
Dr ug ug a a cti Dr cti on on on on b b loo v

Car

Cardi

dioovvasc

ascular

ular phar

pharmmacacolog

ologyy

CoConntrol

trol ooff inintrtraacceellula

llularr cacalclciumium

coconncceennttraratitioonn isis aa mmaajjoorr ttaargrgeett inin ddrruugg

aactio

ctionn oonn the

the CCVV ssyysstetemm

Car Car di di o o v v asc asc ular ular phar phar m m
Car Car di di o o v v asc asc ular ular phar phar m m
Car Car di di o o v v asc asc ular ular phar phar m m

Determination of contraction of vascular

smooth muscle in vitro

Determination of contraction of vascular smooth muscle in vitro

Endothelium dependent and independent vascular effects

Endothelium dependent and independent vascular effects Blood vessel without endothelium Blood vessel with endothelium

Blood vessel without endothelium

Blood vessel with endothelium

Endothelium dependent and independent vascular effects Blood vessel without endothelium Blood vessel with endothelium
Endothelium dependent and independent vascular effects Blood vessel without endothelium Blood vessel with endothelium

E Endndotheli

otheliuumm depen

dependen

dentt and

and

iindndepend

ependenentt vas

vascucullarar eff

effects

ects

Lumen

Endothelial cell

Vascular smooth muscle cell Extracellular space
Vascular smooth muscle cell
Extracellular space

EnEndodotthhel

eliumium-depe

-dependen

ndentt

vasodil

vaso

dilators

ators

AAcecetyl

tylcchhoolilinnee

HHiisstatamin

minee

EEndndooththelin

elin

55-HT

-HT

BBrraaddykin

ykininin

SSububsstan

tanccee PP

En En do do t t h h el el ium ium -depe -depe nden nden
En En do do t t h h el el ium ium -depe -depe nden nden
En En do do t t h h el el ium ium -depe -depe nden nden
En En do do t t h h el el ium ium -depe -depe nden nden

Shear stress; Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, ATII

Endothelial cell

GPCR

GPCR

Shear stress; Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, AT II Endothelial cell GPCR

[Ca++]i

Shear stress; Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, AT II Endothelial cell GPCR

eeNNOSOS

Shear stress; Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, AT II Endothelial cell GPCR

eNOS

L-Arg

NO

Vascular s mooth muscle cell
Vascular s mooth muscle cell

Agonist, shear stress

Endothelial cell

Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction

NOS

EDHF

Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction
Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction

COX

Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction
PGI 2 NO Hyper- contraction relaxation
PGI 2
NO
Hyper-
contraction
relaxation
Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction

Gap junction

polarisation

Agonist, shear stress Endothelial cell NOS EDHF COX PGI 2 NO Hyper- contraction relaxation Gap junction
mooth muscle
mooth muscle

Direct agonist

Vascular s

cell

Vascular smooth muscle cell direct contractants

Ligand-gated cationic channel

NA, AII, TP, ET1, 5-HT

agonist ++ Ca L-type voltage- gated channel GPCR PLC ATP IP3 P2X [Ca ++ ] i
agonist
++
Ca
L-type voltage-
gated channel
GPCR
PLC
ATP
IP3
P2X
[Ca ++ ] i
++
Ca
SR
contraction

Smooth muscle contraction mechanism

++ Ca [Ca ++ ] i SR Ca ++ Calmodulin MLCK MLCK* Myosin LC Myosin LC-P*
++
Ca
[Ca ++ ] i
SR
Ca ++ Calmodulin
MLCK MLCK*
Myosin LC Myosin LC-P*
Actin-myosin crossbridges
contraction
MLCK = Myosin light chain kina se
Myosin LC = myosin light c hains

Smooth muscle relaxation: NO

NO

GC GGCC** PDE cGMP GMP MLCP MMLCLCP* P* MMyosin yosin LC-P* LC-P* Myosin LC relaxation MLCP
GC
GGCC**
PDE
cGMP
GMP
MLCP
MMLCLCP*
P*
MMyosin
yosin LC-P*
LC-P*
Myosin LC
relaxation
MLCP = Myosin light chain pho sphatase

Smooth muscle relaxation: agonists

+ K PGI 2 Adren ANP IP, 2 GC GGCC** cGMP cAMP MLCK MLCP MMLCLCP* P*
+
K
PGI 2
Adren
ANP
IP, 2
GC
GGCC**
cGMP
cAMP
MLCK
MLCP
MMLCLCP*
P*
MMyosin
yosin LC-P*
LC-P*
Myosin LC
relaxation
MLCP = Myosin light chain pho sphatase

Vasodil

Vas

odilators:

ators: OOrrgganic

anic NNiitrates

trates

AAmyl

myl nnitri

itritete:: Bru

Brunnttoonn fofounundd iitt eeffffeecctivtivee for

for

aanngin

ginaa

Nitro

Nitroglyc

glycerin

erin:: ccoonnvveertertedd eennzzyymmaatiticcaallylly aanndd

n-ennzymzymaatticicaallylly toto NNOO;;

nnoon-e

vveeinins>s>aarrteteririeess

SSododiuiumm nnitrop

itroprurussssididee:: ccoonnvveertertedd ddirireecctlytly

Vas odil Vas odil ators: ators: O O r r g g anic anic N N

(n(nonon-e-enznzymymaatticicaalllly)y) toto NNO;

O;

vveeins

ins == aartrteerieriess

Vas odil Vas odil ators: ators: O O r r g g anic anic N N
Vas odil Vas odil ators: ators: O O r r g g anic anic N N
Vas odil Vas odil ators: ators: O O r r g g anic anic N N
Alfred Nobel 1833-1896 Discoverer of DYNAMITE (nitroglycerin + kieselguhr) Suffered from angina pectoris but refused to

Alfred Nobel 1833-1896

Discoverer of DYNAMITE

(nitroglycerin + kieselguhr)

Suffered from angina pectoris

but refused to take nitroglycerin

Alfred Nobel 1833-1896 Discoverer of DYNAMITE (nitroglycerin + kieselguhr) Suffered from angina pectoris but refused to
Alfred Nobel 1833-1896 Discoverer of DYNAMITE (nitroglycerin + kieselguhr) Suffered from angina pectoris but refused to
Alfred Nobel 1833-1896 Discoverer of DYNAMITE (nitroglycerin + kieselguhr) Suffered from angina pectoris but refused to

Sodium nitroprusside (SNP)

Organic nitrates R-NO 2

Non-enzymatic Enzymatic + non-enzymatic Thiols SH RSNO NO R-SNO
Non-enzymatic
Enzymatic + non-enzymatic
Thiols SH
RSNO
NO
R-SNO
Sodium nitroprusside (SNP) Organic nitrates R-NO Non-enzymatic Enzymatic + non-enzymatic Thiols SH RSNO NO R-SNO
Sodium nitroprusside (SNP) Organic nitrates R-NO Non-enzymatic Enzymatic + non-enzymatic Thiols SH RSNO NO R-SNO
Sodium nitroprusside (SNP) Organic nitrates R-NO Non-enzymatic Enzymatic + non-enzymatic Thiols SH RSNO NO R-SNO

Calc

Calciumium channe

channellss

1: 1: vvooltaltagege-o-opeperaratetedd

BBlocke

lockedd byby dihy

dihyddrop

ropyryridines

idines et

etcc

Opene

Openedd byby CaCa++++ aagonist

gonist drugs

drugs egeg Bay

BayK-864

K-86444

BBlocka

lockadede sho

showwss use-

use-depend

dependence

ence

2: 2: rerececepptor-o

tor-opeperaratetedd

Opene

Incom

BBlocka

Openedd byby aagonist

Incomplet

pletel

gonist egeg ATP

ATP

Calc Calc ium ium channe channe l l s s  1: vvooltaltagege-o-opeperaratetedd BBlocke lockedd byby

elyy blocked

blocked bbyy BBaayyKK--8644

8644

not show

endence nce
endence
nce

lockadede doe

doess not

show uussee-dep

-depende

Calc Calc ium ium channe channe l l s s  1: vvooltaltagege-o-opeperaratetedd BBlocke lockedd byby
Calc Calc ium ium channe channe l l s s  1: vvooltaltagege-o-opeperaratetedd BBlocke lockedd byby

Voltage dependent Ca 2+ channels

L-type (long-conducting, cardiac,

smooth and striated muscle, neuronal)

T-type (Transient)

N-type (neuronal)

P/Q-type (Cerebral Purkinje cell)

R-type (rat brain)

Voltage dependent Ca channels • L-type (long-conducting, cardiac, smooth and striated muscle, neuronal) • T-type (Transient)
Voltage dependent Ca channels • L-type (long-conducting, cardiac, smooth and striated muscle, neuronal) • T-type (Transient)
Voltage dependent Ca channels • L-type (long-conducting, cardiac, smooth and striated muscle, neuronal) • T-type (Transient)
L-t L-type ype calcium calcium cchahannnnel el st struct ructure ure
L-t
L-type
ype calcium
calcium cchahannnnel
el st
struct
ructure
ure

VVolt

oltaagege gated

gated ccalc

alciiuumm cchhannels

annels

αα11 sub

subununitsits coconfe

nferr pphaharmrmaaccoollooggica

icall

cchahararacte

cterisristicticss

αα1S1S skskeelleetatall mmuuscscllee

αα1C1C ccaarrddiaiac,

c, smsmoooothth mmuuscscllee,, nneueuroronnaall

αα1D1D eenndodoccrine

rine/n/neueuroronnaall

αα11sub

subuunniitsts hhaavvee II –– IVIV ddoommaains,

ins, eeaachch dodomain

main

V V olt olt a a ge ge gated gated c c alc alc i i

has S1-S6 segments with SS1 and

has S1-S6 segments with SS1 and

llooooppss

V V olt olt a a ge ge gated gated c c alc alc i i

SS2 short

SS2 short

V V olt olt a a ge ge gated gated c c alc alc i i

Calc

Calciiuumm cchhannel

annel bl

block

ocker

erss

PhPheennyylalalkyla

lkylamin

mineess,, eegg vveerarapapammilil

Dih

Dihydro

ydroppyyridridine

iness,, egeg nniifefeddiippininee

BeBennzzootthhiaiazziinneess,, eegg dilti

diltiaazzeemm

HeHeaarrtt

bblolooodd vveesssseelsls

VVera

erappamamilil >>

diltiaz

diltiazeemm

Calc Calc i i u u m m c c h h annel annel bl bl

>> nnifeifedip

dipininee

Calc Calc i i u u m m c c h h annel annel bl bl
Calc Calc i i u u m m c c h h annel annel bl bl

CaCa ++++ cchhannel

annel bloc

blockkade

ade

ChChann

annels

els cycle

cycle bbetwetweeeenn resting

resting,,

en, ina

inact

ctiivvated

ated

opopen,

Af

Affinfinityity for

for bl

blockin

ockingg dru

drugg ddepepend

endss oonn

staattee

st

Blocke

Blockersrs show

show ggreatest

reatest af

affinfinityity for

for

ininactiv

activaattiionon st

staatete

Ca Ca c c h h annel annel bloc bloc k k ade ade  ChChann
Ca Ca c c h h annel annel bloc bloc k k ade ade  ChChann
Ca Ca c c h h annel annel bloc bloc k k ade ade  ChChann

L-t

L-type

ype channels:

channels: ssub-unit

ub-unit st

struc

ructure

ture

and CCCCBB bi

and

binding

nding sit

siteses

D

B

P

L-t L-t ype ype channels: channels: s s ub-unit ub-unit st st ruc ruc ture ture
L-t L-t ype ype channels: channels: s s ub-unit ub-unit st st ruc ruc ture ture
L-t L-t ype ype channels: channels: s s ub-unit ub-unit st st ruc ruc ture ture

EEndothelins

ndothelins

E E ndothelins COX ET PGI ET1 NOS ET1 ET B NO contraction ET A seful
COX
COX

ET B

PGI 2

ET1

NOS

E E ndothelins COX ET PGI ET1 NOS ET1 ET B NO contraction ET A seful

ET1

ET B NO contraction ET A
ET B
NO
contraction
ET A
E E ndothelins COX ET PGI ET1 NOS ET1 ET B NO contraction ET A seful
seful i n , but hepatotoxic
seful i n
, but hepatotoxic

Bosentan: ET A,B antagonist: u

E E ndothelins COX ET PGI ET1 NOS ET1 ET B NO contraction ET A seful
E E ndothelins COX ET PGI ET1 NOS ET1 ET B NO contraction ET A seful

pulmonary hypertension

NNeutral

eutral end

endope

opepti

ptiddaasese (N(NEPEP))

inhiibitors

inh

bitors

AActi

ctioonsns of

of NENEPPss ::

Meta

Metabolism

bolism of

of at

atrial

rial nat

natriure

riuretictic pep

peptitiddee ((AANPNP)),,

Meta

Metabolism

bolism of

of AAIIII

SSimimililaarr fufunction

nction ttoo Endoth

Endotheli

elinn conv

conver

erting

ting enenzyzymmee (b(biigg

EETT

EETT1)

1)

NNEEPP iinhibito

nhibitorsrs iincr

ease AANPNP

ncrease

vvasasodilat

odilation;

ion;

reducee EETT

reduc

vvaasodil

sodilation;

ation; can

can incr

increase

ease AAIIII

vvasasoocconstr

onstriciction

tion

N N eutral eutral end end ope ope pti pti d d a a se se

Candoxatril, orally active NEPI, reduces BP

Candoxatril, orally active NEPI, reduces B

unpredictable

unpredi

ctable res

respoponnsese

N N eutral eutral end end ope ope pti pti d d a a se se
P but but
P but
but

PPhosphodies

hosphodiester

terasasee inhi

inhibbiitor

torss

CaCaffein

ffeinee,, amamininopophhyll

yllininee:: ggeennera

erall PDPDEE--II

AmAmrino

rinonnee,, milri

milrinnoonnee,, PPDEDE33--II,, vvaassododilato

ilatorr

aandnd pposositiv

itivee ininotro

otropepess

Sild

Sildeenanafil fil (V(Viiaaggaara):

ra): PPDEDE55 ccyclic

yclic GMGMPP

inh inhibibititoor:r:

Incr

Increases

eases ppenenileile er

erecti

ection,

on, affects

affects ccolor

olor vviisiosionn,,

P P hosphodies hosphodies ter ter as as e e inhi inhi b b i i

PPotential

otential fafattal

al com

combi

bination

nation wwithith nit

nitrates

rates

P P hosphodies hosphodies ter ter as as e e inhi inhi b b i i
P P hosphodies hosphodies ter ter as as e e inhi inhi b b i i

Ischemic heart

Ischemic

heart disease

disease

Ischemic heart Ischemic heart disease disease Cardiac work µ VO VO µ blood flow Increased work

Cardiac work µ VO 2

VO 2

µ

blood flow

Increased work

increased

demand for blood flow.

Demand cannot be met, so get

Ischemic heart Ischemic heart disease disease Cardiac work µ VO VO µ blood flow Increased work

anaerobic metabolism, increased

Ischemic heart Ischemic heart disease disease Cardiac work µ VO VO µ blood flow Increased work
toris)
toris)

lactic acid production, and

Ischemic heart Ischemic heart disease disease Cardiac work µ VO VO µ blood flow Increased work

ischemic pain

(angina pec

IsIscchem

hemicic hear

heartt dis

disease

ease

InIn norm

normaall condi

conditions

tions,, tthehe incr

increased

eased ccoronar

oronaryy BBFF

inin rrespons

esponsee toto incr

increased

eased ccardi

ardiacac wwoorrkk isis

mmediated

ediated byby NONO

InIn cor

formmatio

coronary

onary aarrter

teryy dis

disease

ease wwithith plaque

plaque for

ationn,,

this mmechani

this

echanismsm iiss non-

non-fufuncnctional

tional

AAss aa rresult

esult,, ddiirrect

ect vvasasodila

odilatotorr dr

drugs,

ugs, egeg

dipyridam

dipyr

idamole,

ole, wwiillll nnot

ot iincr

ease bl

blood

ood flow

ncrease

flow toto

ischem

isc

hemicic are

a, bbut

ut wwor

sen the

the si situation

tuation byby

area,

orsen

Is Is c c hem hem ic ic hear hear t t dis dis ease ease

causingng “i“iscschem

causi

hemicic steal”

steal”

Is Is c c hem hem ic ic hear hear t t dis dis ease ease
Is Is c c hem hem ic ic hear hear t t dis dis ease ease
Stenosis of branch
Stenosis of
branch

of coronary artery

Rang et al Pharmacology, 5 th Edition, p280

Stenosis of branch of coronary artery Rang et al Pharmacology, 5 Edition, p280

“Ischemic steal”

“Ischemic steal”
“Ischemic steal”
“Ischemic steal”

Effect of nitrates

Effect of nitrates
Effect of nitrates
Effect of nitrates

AAngngiinana pect

pector

orisis

Sta

Stabbllee aanngin

ginaa,, tretreaatteedd wwithith bbeeta-b

ta-blolockckeersrs,,

CaCa++++ aanntag

tagoonnisisttss oorr nnitrate

itratess

CaCalclciumium aanta

ntaggoonniisststs,, uussee vveerap

rapaammilil typ

type,

e,

reduuccee VVOO 22 ddurin

red

uringg eeffofforrtt

vvaarian

riantt aanngin

ginaa,, uussee vvaassododilailator

tor ccaallcciuiumm

bblloocckkeerrss,, eegg nnifed

ifedipipine

ine,, amamloloddipin

ipinee (lo(lonngg

aactin ctingg))

A A ng ng i i na na pect  Sta aanngin tretreaatteedd wwithith bbeeta-b CaCa++++

Additional treatments include as

Additional treatments include aspirin, ,

sta statins tins,, ddiieett

A A ng ng i i na na pect  Sta aanngin tretreaatteedd wwithith bbeeta-b CaCa++++

pirin

A A ng ng i i na na pect  Sta aanngin tretreaatteedd wwithith bbeeta-b CaCa++++

PPhar

harmac

macoologic

logicaall ttreatm

reatment

ent of

of

angina

angina pec

pector

toriiss

Org

Orgaanniicc nniitratrates

tes:: NTG

NTG s/l,

s/l, or

or isisososoorbrbiiddee

ddiinnitritraatete,, isisoossorb

orbidide-5

e-5-- mmononoonnititraratete

s/l

s/l

pp.o.o..

oorr

TThheerap

rapeeuutiticc ddoosse,

e, rereduduccee pprereloa

loadd ++

ddiilalatitioonn ooff ccoollate

llateral

ral vveesssseelsls

Exc

Excesesssivivee ddososee,, red

reduucceess pprerellooaadd ++

aaffteterloa rloadd hhypypootteennssiioonn aandnd tatachchycycard ardiaia

(de (detri trimmeenntatall))

P P har har mac mac o o logic logic a a l l t t
ga tio n gation
ga tio n
gation

Nitrates also reduce platelet aggre

Nitrates also reduce platelet aggre

P P har har mac mac o o logic logic a a l l t t
P P har har mac mac o o logic logic a a l l t t
P P har har mac mac o o logic logic a a l l t t

Nit

Nitrrates

ates,, sside-

ide-eff

effeeccttss

RRel

elaxation

axation of

of other

other smsmooth

ooth mmuscl

uscle,

can rrelie

e, can

elievvee

chest papaiinn caus

chest

causeded byby esophageal

esophageal spasm

spasm

CCanan potenti

potentiate

ate or

preci

ecipitate

pitate esop

esophhagageeal

al rreeflfluxux

or pr

HHeadac

eadache;

he; toler

tolerance

ance dev

deveelops

lops

TTol

olerance

erance toto ththeerrapeuti

apeuticc effect

effect mminiminimiised

sed byby

intermmittent

inter

ittent dos

dosing

ing rregim

egimee

NNBBBB:: ni

nitrates

trates are

are ccontrai

ontraindic

ndicaatetedd iiff patient

patient iiss

Nit Nit r r ates ates , , s s ide- ide- eff eff e e

taking phosphodiesterase inhibitor eg sildenafil

taking phosphodiesterase inhibitor eg sildenafil

(V(Viiagra) agra)!!!!

Nit Nit r r ates ates , , s s ide- ide- eff eff e e
Nit Nit r r ates ates , , s s ide- ide- eff eff e e

Ni Nittrates rates

VVasasoodi

dilators

lators

BBeeta-ad ta-adren renocepto oceptorr ago agonists nists

AAlpha lpha-1-1 adre adrenocept noceptor or anantagon tagoniisststs

AAnngi

giootensin

tensin aantago

ntagonists

nists ((AATT11 ant

antagon

agoniists

sts,, ACACEE

iinnhibitors)

hibitors)

Calc Calciumium cchhanne annell bl bloockers ckers

PPootassium tassium chann channel el open openers ers

EEnndothe

dothellinin aantag

ntagonists

onists

PPDEDE inhibitor

inhibitorss

 Ni Nittrates rates V V as as o o di di lators lators  BBeeta-ad

Hydralazine (mixed K+ opener and Ca++ antagonism)

Hydralazine (mixed K+ opener and Ca++ antagonism)

 Ni Nittrates rates V V as as o o di di lators lators  BBeeta-ad
 Ni Nittrates rates V V as as o o di di lators lators  BBeeta-ad

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