HEART

FAILURE
 CARDIATONICS (1940)

 cardiac output RBF

ACEI
preload (1970)

Diuretics BV RААS

(1950)

AАТII
(1990)
afterload
TPR SAS

Vasodilators BB
(2000)
(1960)
 EFFECTS of SAS activation
аdrenoreceptors
bеtа1 bеtа2 аlfa

hypertrophy of cardiomyocites, vasoconstriction

intensification of apoptosis, ischemia sodium retention

development of arrhythmias,
myocardial fibrosis, increase in О2
 EFFECTS of ALDOSTERONE

• Retention - Na+   act. of the

myocardial fibroblasts

• Excretion - К+   activity of SAS

• Excretion - Mg2+ • Arrhythmias

•
 REMODELING

VENTRICULE(S) STRUCTURE
ALTERATION, THAT IS
ACCOMPANIED BY INCREASE IN
END-DIASTOLIC VOLUM, END-
SISTOLIC VOLUM, LEFT VENTRICULE
MASS AND ITS GEOMETRICAL FORM
 BETA-ADRENOBLOCKERS
EFFECTS
ADRENORECEPTORS
BETA1 BETA2 АLFA1

nebivolol

МЕТОPRОLОL cuccinate
BISОPRОLОL

CARVЕDILОL

CARDIOTOXICITY
 BETA-ADRENOBLOCKERS
PHARMACOKINETICS
BAV Т1/2 EXCRETION PROTEIN B.
% h. %
МЕТОPRОLОL 50 3.5 KIDNEY 10

FOOD 20-40%

BISОPRОLОL ABOUT 90 9-12 KIDNEY 33

CARVЕDILОL 25 6-10 LIVER 99

nebivolola racemate consisting of two enantiomers: D-nebivolol and L-nebivolol. D-nebivolol is a competitive
and highly selective β1-adrenergic receptor blocker; L-nebivolol has a mild vasodilator effect by modulating the
release of vasodilating factor (NO) from the vascular endothelium.
KIDNEY (38%) LIVER (48%)
 BETA-ADRENOBLOCKERS
PHARMACOKINETICS
nebivolol-
racemate consisting of two enantiomers: D-nebivolol and L-nebivolol. D-nebivolol is a competitive and highly
selective β1-adrenergic receptor blocker; L-nebivolol has a mild vasodilator effect by modulating the
release of vasodilating factor (NO) from the vascular endothelium.

 Bioavailability- 12% in individuals with a fast metabolism (the "first pass" effect through the liver) and is
almost complete in individuals with a slow metabolism.
 In blood plasma, both enantiomers predominantly bind to albumin.
Plasma protein binding of D-nebivolol is 98.1%, L-nebivolol - 97.9%.
 Metabolized by acyclic and aromatic hydroxylation and partial N-dealkylation. The resulting hydroxy and
amino derivatives are conjugated with glucuronic acid and excreted in the form of O- and N-glucuronides.
 It is excreted by the kidneys (38%) and through the intestines (48%).
 In persons with a rapid metabolism T1 / 2 of hydroxymetabolites - 24 hours, nebivolol enantiomers - 10
hours;
 in persons with a slow metabolism: hydroxymetabolites - 48 hours, nebivolol enantiomers - 30-50 hours.
 BETA-ADRENOBLOCKERS USES

• Systolic disfunction of myocardium

• In stabilization of CHF clinical signs with

ACE inhibitors and/or diuretics
EFFECTS OF ACE INHIBITORS
AND АТII ANTAGONISTS
NORMA ACEI ААТII
angiotensinogen

renin

angiotensin I

ACE bradykinin

angiotensin II

АТР1 АТР2
 ACE INHIBITORS
• DRUG • PRODRUG
• Enalapril
Captopril • Fosinopril
Lisinopril • Perindopril
• Ramipril
• Trandolapril
 АТII receptors antagonists
pharmacokinetics
DRUG Т1/2(h) BAV -% Vd(l/kg) D (mg) Protein bind.-%

candesartan 9-12 15 0,13 8-32 Noncompetitive

eprosartan 5-7 13 13 400-800 Compet.

irbesartan 11-15 60-80 53-93 75-300 Compet.

losartan 2 33 34 25-100 Noncom.

telmisartan 24 24-58 500 20-80 Noncompetitive

valsartan 6 25 17 80-320 Compet.

 NATRIURETIC PEPTIDES

• ATRIAL NP (ANP) – is released from the

right atria during its strain
• BRAIN NP (BNP) - is released from the
ventricles during encrease in filling pressure
• С-NP (CNP) – is in the kidney, takes part in
regulation of the RAAS
 EFFECTS OF NP
АNTАGОNISМ with
SАS

АNTАGОNISМ
with RААS
NP vasodilatation

neu
natriuresis end tral
ope
pti
das
e
NE INHIBITORS
 INHIBITORS of neprilysin
(neutral endopeptidase)

Sacubitril effects of Natriuretic peptides - Atrial

Natriuretic Peptide (ANP), B-type Natriuretic Peptide (BNP), and C-type
Natriuretic Peptide (CNP)

•Promote renal excretion of fluid and sodium

•Promote myocardial relaxation and inhibit
hypertrophy and fibrosis
•Suppress sympathetic outflow in the brain
•Stimulate vasodilation
ARNI =AII receptor blocker+INHIBITORS
of neprilysin(neutral endopeptidase)

Entresto® is a combination pill that contains

sacubitril and valsartan
•Valsartan
– Valsartan is an angiotensin II receptor blocker (ARB)
– ARBs work by decreasing the effects of the renin-
angiotensin-aldosterone-system (RAAS)
– Angiotensin promotes fluid and sodium retention,
vasoconstriction, sympathetic outflow, and cardiac
hypertrophy and fibrosis. ARBs block angiotensin
receptors.
 ENDOTHELIN EFFECTS
ENDOTHELIN (ET )-1

ETА ET В

- vasoconstriction - vasodilatation
- prolipheration of vascular (NO and/or prostacyclin)
wall smooth muscles - antiprolipheration

- myocardial cells hypertrophy - antithrombotic

 ENDOTHELIN RECEPTOR
ANTAGONISTS

• NONSELECTIVE • SELECTIVE

BОSЕNТАN DАRUSЕNТАN
 Peripheral vasodilators
• Direct myotropic action
• venous: isosorbide dinitrate, molsidomine
• arteriolar: hydralazine, minoxidil
• mixed: Na nitroprusside
• Ca- channel blockers
nifedipine, аmlodipine
• Adrenoblockers
prazosin, doxazosin;
Nicorandil
Nesiritid
 Metabolic agents
• Trimethazidine
• Inozitol
• Pyridoxine
• Anabolic steroids
 Cytokines
Cytokinesinhibitors
inhibitors
Cytokines inhibitors
• Monoclonal antibodies to TNF–
аlpha
Cytokines inhibitors
pentoxyphilline
• Synthetic antagonist to TNF-L
etanersept
 CARDIATONICS (1940)

• Cardiac glycosides
• Adrenomimetics: DOBUTAMINE,
DOPAMINE, ADRENALINE,
DOPEXAMINE
• Inhibitors of phosphodiesterase:
AMRINONE, MILRENONE,
ENOXIMONE
• Ca sensitizers: LEVOSIMBENDANE
 LEVOSIMBENDANE
(levosimendane 2,5 mg-5 ml)
Mechanism of action:
• Blocks phosphodiesterase III, up troponine bond
with Са
- activation of cytoplasm Са utilization
- opening of КАТpase –channels
• Effects:
• “+” inotropic action
• vasodilation
• Therapeutic uses: аlternative drug to
dobutamine i/v
• 12-24 mkgm/kg during first 10 minute, then 0.1-0.2
mkgm/kg/min. during 6 hrs (24 hrs)
 LEVOSIMBENDANE
(levosimendane)
-T1/2 more 1 hrs
-More then 95% is excreted in unactive
metabolites during 1 week
-can cause hypokaliemia,
Hypotension, tachycardia
• Contraindicated:
- in children up to 18,
- -Pregnancy,
- BP systolic -less 90 Hg
 Cardiac glycosides

• Digitalis der.: DIGOXIN(tab/0,25; 0,1 mg №

50, sol. 0,025%-1ml, DIGITOXIN
• Strophanthus der.: STROPHANTHINE-K, G
(ouabain)
• Lily of the valley der.:CONVALLOTOXIN,
CORGLYCONE
• Semisynthetic: ACETYL-DIGOXIN,
LANATOSIDE
 DIGOXIN
• Enhances LV function, normalizes baroreceptor-mediated
reflexes and increases cardiac output at rest and during
exercise
• Recommended to improve clinical status of patients with
heart failure due to LV dysfunction and should be used in
complex with diuretics, ACE inhibitors and beta-blockers
• Also recommended in patients with heart failure who have
atrial fibrillation
• Digoxin initiated and maintained at a dose of 0.25 mg daily
• Adverse effects include cardiac arrhythmias (bradycardia,
AV block, GI symptoms and neurological complaints (eg.
visual disturbances, confusion)
• Intoxication: extrasystolia, CNS delusion, depression
Summary of drug treatment for CHF
Asymptomatic Mild to moderate Moderate (III f.c.)to
LV dysfunction (II f.class). Severe (IV f.c.)
(I functional class) CHF CHF

ACE inhibitor Digoxin Digoxin

Beta blocker
(torasemide) Diuretics (2-3) Diuretics (3-4)
ACE inhibitor ACE inhibitor
Beta blocker Beta blocker
Spironolactone