Cardiotonics
Tomáš Goněc 12.11.2012
Heart failure
Cardiomyocyte contraction
Therapy of heart failure:
inotropic agents
 cardioglycosides
 β-adrenergic agonists
 phosphodiesterase inhibitors
 Ca2+ channel senzitizers
Cardiac glycosides
 Aglycons:
Cardiac glycosides
Cardiac glycosides – mechanism of action
 Na+/K+-ATPase inhibitors
 Na+ ions intracelular retention
 due to ion substitution also Ca2+intracelular
retention
 positive inotropic effect
Cardiac glycosides used in therapy
 Lanatosides A, B, C; purpureaglycosides A, B
digitoxin, gitoxin, digoxin – secundary
glycosides with cleavaged terminal sugar
 Ouabain, k-strophantoside
 Proscillaridine, meproscillarine
(buffadienolides)
Cardiac glycosides
 narrow therapeutic-toxic window
 high plasma proteins binding
 monitoring during therapy necessary
 long-term administration increases mortality –
therapeutic use in future questionable
β1-adrenergic receptor agonists
 stimulation of adenylate-cyclase, increase of
intracelular cAMP, positive inotropic effect
OH
N
H
O
OH
N
H
OH
OMe
OMeoxyfedrine denopamine
Oxyfedrine synthesis
Denopamine synthesis
β1-adrenergic receptor agonists
OH
OH
NH2
OH
OH
N
H
OH
OH
OH
N
H
N
H
dopamine
dobutamine
dopexamine
Dopexamine synthesis
Dopamine synthesis
Dobutamine synthesis
Phosphodiesterase inhibitors
 xanthine derivatives
 bipyridine derivatives
 3-pyridazinone derivatives
 chinolin-2-one derivatives
Xanthine derivatives
 Theophyline
 Aminophyline
 Etophyline
* see coronary vasodilatators presentation
Bipyridine derivatives
N
H
NH2
O
N
N
H
O
N
N N
H
N
H
O
O
SCH3
Amrinon Milrinon Enoximon
Amrinon synthesis
3-pyridazinone derivatives
N
N
H
O
R
R N
H
N
OMe
N
H
N CN
CN
Pimobendan
Simendan
Pimobendan synthesis
Chinolin-2-one derivatives
N
H
O
N
N
O
MeO
OMe
Vesnarinone
Vesnarinone synthesis
Cardioprotectives
 detoxication of free radicals (NO, OO, OH)
OH
O
N N
P
OH
OH
O
NH2
N
NH
N
P
OH
OH
O
O
N
+
OH O
OH
phosphocreatin
phosphocreatinin
L-carnitin