DRUGS FOR DRUGS FOR ССONGESTIVE ONGESTIVE HEART FAILURE (CHF)HEART FAILURE (CHF)

2 MAIN TYPES of CHF2 MAIN TYPES of CHF

SYSTOLIC CHFSYSTOLIC CHF – insufficiency – insufficiency

of output (of output (decrease of systolic contractiondecrease of systolic contraction))

DIASTOLIC CHFDIASTOLIC CHF - insufficiency of - insufficiency of input (input (calcium overload of myocardium, calcium overload of myocardium,

decrease of dilatation during diastoledecrease of dilatation during diastole))

Treatment of CHFTreatment of CHF

Cardiac glycosidesCardiac glycosidesNonglycoside cardiotonic drugsNonglycoside cardiotonic drugsInhibitors of angiotensine transforming Inhibitors of angiotensine transforming (converting) enzyme(converting) enzyme ( (IATEIATE, , IACEIACE))Antagonists of angiotensine II receptorsAntagonists of angiotensine II receptors (А (АRRА А IIII))Diuretics Diuretics Peripheral vasodilatorsPeripheral vasodilatorsBeta-adrenoblockersBeta-adrenoblockersDrugs of metabolic actionDrugs of metabolic action

DRUGS FOR DRUGS FOR ССONGESTIVE HEART ONGESTIVE HEART FAILURE (CHF)FAILURE (CHF)

CARDIOTONIC CARDIOTONIC DRUGSDRUGS

CARDIOTONIC DRUGSCARDIOTONIC DRUGS

CARDIAC GLYCOSIDESCARDIAC GLYCOSIDES

NONGLYCOSIDE NONGLYCOSIDE CARDIOTONIC DRUGSCARDIOTONIC DRUGS Beta-Beta-

adrenergic agonists adrenergic agonists

((DobutamineDobutamine))Phosphodiesterase inhibitorsPhosphodiesterase inhibitors

(Amrinone, Milrinone)(Amrinone, Milrinone)

CARDIAC GLYCOSIDESCARDIAC GLYCOSIDES

Purple FoxglovePurple Foxglove

FoxgloveFoxglove

Lily of the valleyLily of the valley

LychnisLychnis

StrophantusStrophantus

Chemical structure of cardiac Chemical structure of cardiac glycosidesglycosides

PharmacodynamicsPharmacodynamics

Cardiac actionCardiac action

Extra cardiac actionExtra cardiac action

Cardiac actionCardiac action

Positive inotropicPositive inotropic

Positive bathmotropicPositive bathmotropic

Negative chronotropicNegative chronotropic

Negative dromotropicNegative dromotropic

Changes which correlate Changes which correlate to positive inotropic actionto positive inotropic action Narrowing QRS complexNarrowing QRS complex

Decreasing ST Decreasing ST T-blip – double-phasedT-blip – double-phased, ,

negativenegative Changes which correlate Changes which correlate to negative dromotropic to negative dromotropic

actionaction Prolongation of PQ intervalProlongation of PQ interval

Changes which correlate Changes which correlate to negative chronotropic to negative chronotropic

actionaction Increase of RR intervalIncrease of RR interval

ECG changes under the influence of CGchanges under the influence of CGVvvvvvvvvvvvvvvvvvvvvvvv

vvvvvvvvvvvvvvv

MECHANISM OF CARDIOTONIC (POSITIVE MECHANISM OF CARDIOTONIC (POSITIVE

INOTROPICINOTROPIC) ) ACTION Of CGACTION Of CG

Promote increasing of Promote increasing of Calcium Calcium ions ions concentration in myocardiocytes cytoplasm concentration in myocardiocytes cytoplasm

-- Transport of Transport of Са Са ++++ inside the cellinside the cell

- Stimulate exit of - Stimulate exit of СаСа++++ from sarcoplasmic from sarcoplasmic reticulumreticulum

- - Block Block К,К, Na- Na-ААTPTP--asease ( (braking repolarizationbraking repolarization))

Improve usage of macroergic substances by Improve usage of macroergic substances by cells, decrease myocardium demand in cells, decrease myocardium demand in oxygenoxygen

Increase tone of sympathetic nervous systemIncrease tone of sympathetic nervous system

Ion Channels and Ionic Movements in the Myocardial CellIon Channels and Ionic Movements in the Myocardial Cell

Extracardiac action of CGExtracardiac action of CG

DiureticDiuretic

SedativeSedative (Inf. herbae Adonidis vernalis, (Inf. herbae Adonidis vernalis,

T-ra Convallariae)T-ra Convallariae)

Stimulating influence on Stimulating influence on smooth muscles smooth muscles (toxic doses)(toxic doses)

Pharmacokinetics of CGPharmacokinetics of CG

Absorption of CG in gastro-intestinal Absorption of CG in gastro-intestinal tracttract

DigitoxinDigitoxin – – 95-95-100 %100 %

DigoxinDigoxin – 60-80 % – 60-80 %

CelanidCelanid – 15-40 % – 15-40 %

StrophanthinStrophanthin – 3-5 % – 3-5 %

ADMINISTRATION OF CARDIAC ADMINISTRATION OF CARDIAC GLYCOSIDESGLYCOSIDES

They are drugs of choice for patients with They are drugs of choice for patients with systolicsystolic CHF, accompanied by CHF, accompanied by tachysystolic form of atria tachysystolic form of atria fibrillationfibrillationPatients withPatients with III andIII and IV FCIV FC ( (according toaccording to NYHANYHA) ) of of CHF, in a case of transferring of II FC into III FC CHF, in a case of transferring of II FC into III FC (functional class)(functional class)SupraventricularSupraventricular tachycardia and tachyarrhythmia tachycardia and tachyarrhythmia

Improve disease currency, life quality, Improve disease currency, life quality, increase tolerance towards physical loads, increase tolerance towards physical loads, but but dondon’t affect’t affect level of mortality level of mortality in patients in patients

with CHFwith CHF

THERAPEUTICS TARGETS OF CG IN THERAPEUTICS TARGETS OF CG IN TACHYARRHITHMIAS OF SUPRAVENTRICULAR ORIGINTACHYARRHITHMIAS OF SUPRAVENTRICULAR ORIGIN

DigoxinDigoxin

MODE of ACTION of CG IN CASE OF CHFMODE of ACTION of CG IN CASE OF CHF

Increasing of systolic and minute volumes Increasing of systolic and minute volumes of heart activity (enhancing cardiac muscle of heart activity (enhancing cardiac muscle contractility, thus contractility, thus increasing outputincreasing output))

Improving of circulation in lungs and Improving of circulation in lungs and peripheral organs, decreasing volume of peripheral organs, decreasing volume of blood circulation, excretion of surplus liquid blood circulation, excretion of surplus liquid out of the organismout of the organism

Elimination of hypoxia and metabolic Elimination of hypoxia and metabolic acidosis in tissuesacidosis in tissues

The following manifestations testify about The following manifestations testify about

therapeutic actiontherapeutic action of CG of CG

1.1. Improving of general state of the Improving of general state of the patientpatient ( (decreasing of weakness, short decreasing of weakness, short

breath, sleep normalizationbreath, sleep normalization, , disappearing of edema, cyanosis, etc.)disappearing of edema, cyanosis, etc.)

2.2. Tachycardia transforms into Tachycardia transforms into normo (brady)cardianormo (brady)cardia

3.3. Increasing of diuresisIncreasing of diuresis 4.4. Typical changes in ECGTypical changes in ECG

Schemes of digitalizationSchemes of digitalization

FastFast (1-2 (1-2 daysdays))Medium Medium (3-4 (3-4 daysdays))SlowSlow ( (more than more than 5 5 daysdays))

Nowadays rather oftenNowadays rather often cardiac glycosides are cardiac glycosides are administered from the beginning of treatment in administered from the beginning of treatment in supportive dosessupportive doses: :

digoxindigoxin – 0,125-0,75 – 0,125-0,75 mg daily mg daily ( (digitalization lasts digitalization lasts forfor 5-7 5-7 daysdays), ),

digitoxindigitoxin – 0,1-0,15 – 0,1-0,15 mg dailymg daily ( (digitalizationdigitalization lasts forlasts for 25-30 25-30 daysdays))

Contraindications for Contraindications for CG administration CG administration

1. 1. Absolute contraindicationAbsolute contraindication – – ііntoxication ntoxication with CGwith CG

2. 2. Other contraindicationsOther contraindications

- - diastolic CHFdiastolic CHF

- - sinus tachycardiasinus tachycardia based on thyrotoxicosis, based on thyrotoxicosis, anemia, increased temperature, anemia, increased temperature, hypoxiahypoxia

- - insufficiency of aortal valves, isolated insufficiency of aortal valves, isolated mitral stenosismitral stenosis, , diffuse myocarditisdiffuse myocarditis

Intoxication with CGIntoxication with CG

Frequency -Frequency -

6-23 %6-23 %

Mortality - Mortality -

overover 40 % 40 %

Factors which promote Factors which promote INTOXICATION WITH CGINTOXICATION WITH CG

DECREASING OF TOLERANCE TOWARDS CGDECREASING OF TOLERANCE TOWARDS CG – – in in case of considerable damage of myocardium with case of considerable damage of myocardium with pathological processpathological process ( (acute MI, myocarditis, chronic acute MI, myocarditis, chronic lung heartlung heart)): : ““Patients which need CG the most are the Patients which need CG the most are the most sensitive to themmost sensitive to them””HYPOPOTASSIUMEMIA, HYPOMAGNESIUMEMIAHYPOPOTASSIUMEMIA, HYPOMAGNESIUMEMIA

- administration of diuretics- administration of diuretics ( (furosemid, dichlothiazide)furosemid, dichlothiazide), , glucocorticoid hormonesglucocorticoid hormones, , glucose with insulin, glucose with insulin,

amphoterricine Bamphoterricine B - secondary hyperaldosteronism, vomiting, diarrhea- secondary hyperaldosteronism, vomiting, diarrhea

HYPERCALCIUMEMIAHYPERCALCIUMEMIAKIDNEY and LIVER INSUFFICIENCYKIDNEY and LIVER INSUFFICIENCY

Intoxication with CGIntoxication with CGCardiac symptomsCardiac symptoms

Worsening of contractile function of Worsening of contractile function of myocardiummyocardium, , increasing of circulation increasing of circulation insufficiencyinsufficiency (18(18--26 %)26 %)Disturbance of heart rhythmDisturbance of heart rhythm(90(90--95 %, 65 % 95 %, 65 % -- single symptom of single symptom of intoxicationintoxication))

-- tachyarrhythmiastachyarrhythmias ((increasing of automatismincreasing of automatism))-- blockadesblockades-- combined disorders of rhythmcombined disorders of rhythm

Intoxication with CGIntoxication with CGIntoxication with CGIntoxication with CG

ExtracardiacExtracardiac symptomssymptoms

GastroGastro--intestinalintestinal (40(40--50 %)50 %)

Neurological and psychical Neurological and psychical (25 %)(25 %)

Eye symptomsEye symptoms (65 %)(65 %)

Worsening of kidneys functionWorsening of kidneys function

Treatment of intoxication with CGTreatment of intoxication with CG

Immediate abolition of CG introductionImmediate abolition of CG introductionCorrection of hypopotassiumemiaCorrection of hypopotassiumemia (KCl, panangin)(KCl, panangin)Introduction of unithiolumIntroduction of unithiolum (1 (1 mlml of of 5 % 5 % solutionsolution / / kg of kg of body weight i. m. body weight i. m. 2-3-5 2-3-5 times per daytimes per day))Cleaning of GI tract (vaseline oil, cholestyraminCleaning of GI tract (vaseline oil, cholestyramin, , magnesium sulfatemagnesium sulfate))Treatment of arrhythmiasTreatment of arrhythmias ( (anaprilin, verapamil, difenin, anaprilin, verapamil, difenin, lidokain, atropine)lidokain, atropine)Na Na ЕЕDTADTA ( (trilontrilon B)B), , Na citrateNa citrateCalcitrin Calcitrin Antibodies towards digoxinAntibodies towards digoxin ( (Digibind)Digibind)Oxygen therapy Oxygen therapy

NONGLYCOSIDE CARDITONIC NONGLYCOSIDE CARDITONIC DRUGSDRUGS

Xantins, derivatives of isoquinolineXantins, derivatives of isoquinoline ( (ethophilineethophiline))Pyridines, and bipyridinesPyridines, and bipyridines ( (amrinon, milrinonamrinon, milrinon))Derivatives of imidazoleDerivatives of imidazole ( (vardaxvardax))Derivatives of piperidineDerivatives of piperidine ( (buquineran, buquineran, carbazerancarbazeran))Polypeptides Polypeptides ((glucagonglucagon))Carboxyl antibioticsCarboxyl antibiotics ( (lasolacid, calcimycinlasolacid, calcimycin))Derivatives of other chemical groupsDerivatives of other chemical groups: : LL--carnitin, heptaminol, creatinol-o-phosphate, carnitin, heptaminol, creatinol-o-phosphate, trapidil, etc.trapidil, etc.

POSITIVE INOTROPIC AGENTSPOSITIVE INOTROPIC AGENTS1.1. Beta Receptor AgonistsBeta Receptor Agonists

2.2. Phosphodiesterase inhibitorsPhosphodiesterase inhibitors

3.3. Na+,K+-ATPase InhibitorsNa+,K+-ATPase Inhibitors

NONGLYCOSIDE CARDIOTONIC NONGLYCOSIDE CARDIOTONIC DRUGSDRUGS

DobutaminDobutamin – – betabeta11--adrenomimeticadrenomimetic - - in case of in case of

acute and chronic CHF acute and chronic CHF – – intravenously dropply intravenously dropply – 2,5-5-10 – 2,5-5-10 mcgmcg/(/(kgkg..minmin); ); in case of constant in case of constant infusion tolerance develops after infusion tolerance develops after 3-4 3-4 daysdays; ; in in case of increasing of dosecase of increasing of dose – – cardiac cardiac arrhythmiasarrhythmias

Amrinon, milrinonAmrinon, milrinon – – inhibitors of inhibitors of phosphodiesterasephosphodiesterase – – for temporary for temporary improvement of patient’s condition in terminal improvement of patient’s condition in terminal stages of CHFstages of CHF

INHIBITORS OF ANGIOTENSINE INHIBITORS OF ANGIOTENSINE CONVERTING ENZYMECONVERTING ENZYME ( (IACE)IACE)

Captopril, enalapril, ramipril, Captopril, enalapril, ramipril, lysinorpillysinorpil

In case of CHF they brake pathological In case of CHF they brake pathological consequences of activation of renin-angiotensine consequences of activation of renin-angiotensine

system by inhibiting ACEsystem by inhibiting ACE:: production of angiotensineproduction of angiotensine IIII decreases decreases ((vasoconstrictorvasoconstrictor, , inductor of aldosterone, norepinephrine, endothelin inductor of aldosterone, norepinephrine, endothelin secretion, myocardium hypertrophysecretion, myocardium hypertrophy))

Accumulation of bradikininAccumulation of bradikinin ( (inductor of prostacycline and inductor of prostacycline and nitrogen oxide synthesisnitrogen oxide synthesis))

captopril captopril ((capotencapoten)), ramipril, , ramipril, enalapril etc.enalapril etc.

CAPTOPRILCAPTOPRIL ( (CAPOTENCAPOTEN))

Dose titrationDose titration: : fromfrom 6,25-12,5 6,25-12,5 mg per day tomg per day to 12,5-50 12,5-50 mgmg 3 3 times a day until appearance times a day until appearance of effectof effectSide effectsSide effects: : dry coughdry cough ( (can be decreased can be decreased by NSAIDsby NSAIDs), ), considerable decreasing of considerable decreasing of APAP, , worsening of kidneys’ functionworsening of kidneys’ function, , hyperpotassiumemia, tachycardia, hyperpotassiumemia, tachycardia, neutropenia, aphtose stomatitisneutropenia, aphtose stomatitisContraindicated Contraindicated in case of bilateral stenosis in case of bilateral stenosis of kidney arteries, should not be combined of kidney arteries, should not be combined with potassium drugswith potassium drugs

INHIBITORS OF ANGIOTESINE CONVERTING ENZYMEINHIBITORS OF ANGIOTESINE CONVERTING ENZYME

((IACEIACE)) captopril captopril ((capotencapoten)), ramipril, , ramipril, enalapril etc.enalapril etc.

ANTAGONISTS OF ANTAGONISTS OF ANGIOTENSINE II RECEPTORS ANGIOTENSINE II RECEPTORS (А(АRRА А

IIII))

LOSARTANLOSARTAN ( (COZAAR)COZAAR)

Blocks receptors of angiotensineBlocks receptors of angiotensine IIIIDecreases mortality of patients with CHFDecreases mortality of patients with CHF

onon 50 % 50 %Breaks development of myocardium Breaks development of myocardium

hypertrophy hypertrophy

It is approved to combine IACE with It is approved to combine IACE with ААRRА А IIII

Losartan Losartan ((Cozaar), Irbesartan (Avapro)Cozaar), Irbesartan (Avapro)etc.etc.

DIURETICSDIURETICS

DichlotiazideDichlotiazide, , hygrotonehygrotone

((oxodolineoxodoline),), clopamide clopamide ( (brinaldixbrinaldix))

FurosemidFurosemid, , etacrinic acidetacrinic acid

Spironolacton Spironolacton

improve currency of the disease, increase improve currency of the disease, increase tolerance of patients towards physical loadstolerance of patients towards physical loads, ,

spironolactonspironolacton decreases quantity of decreases quantity of relapses and mortalityrelapses and mortality

BETA-ADRENOBLOCKERSBETA-ADRENOBLOCKERS

CarvedilolCarvedilol, methoprolol, bisoprolol, nebivolol, methoprolol, bisoprolol, nebivolol They decrease mortality, improve disease currency They decrease mortality, improve disease currency

and quality of patients’ lives in case of and quality of patients’ lives in case of stabile CHFstabile CHF

Mechanism of action in case of CHFMechanism of action in case of CHFRenewing of quantity and sensitivity of beta-Renewing of quantity and sensitivity of beta-adrenoreceptors in heart, which leads to increasing adrenoreceptors in heart, which leads to increasing of systolic volume after of systolic volume after 8-10 8-10 weeks of regular weeks of regular administration administration ((paradox of beta-adrenoblockadeparadox of beta-adrenoblockade))Prevent calcium overload of myocardium, improve Prevent calcium overload of myocardium, improve coronary blood circulationcoronary blood circulationDecrease production of reninDecrease production of reninPrevent arrhythmias Prevent arrhythmias

Carvedilol Carvedilol – – αα11--adrenoblocking and antioxidant adrenoblocking and antioxidant actionaction

BETABETA--ADRENOBLOCKERSADRENOBLOCKERSScheme of administration of beta-Scheme of administration of beta-

adrenoblockers in a case of CHFadrenoblockers in a case of CHF The treatment is started from a small doseThe treatment is started from a small dose

(3,175-6,25 (3,175-6,25 mg carvedilolmg carvedilol), ), everyevery 2-4 2-4 weeks it is doubled weeks it is doubled until obtaining the effectuntil obtaining the effect ( (usually develops afterusually develops after 2-3 2-3 monthsmonths))..

Average effective dosesAverage effective doses: :

carvedilolcarvedilol – 50 – 50 mgmg

metoprolol metoprolol – 100 – 100 mgmg

bisoprololbisoprolol – 5 – 5 mgmg

Administration of beta-blockers is possible Administration of beta-blockers is possible only in a only in a case of constant condition of the patientcase of constant condition of the patient, , before before development of stabile improvement of condition development of stabile improvement of condition temporary worsening may developtemporary worsening may develop

DRUGS OF DRUGS OF METABOLICMETABOLIC ACTION ACTION

VitaminsVitamins: Е, С, В: Е, С, В group group

Ryboxin Ryboxin

Mildronate Mildronate

PhosphadenPhosphaden, , ATPATP

Creatinphosphate Creatinphosphate

Potassium orotatePotassium orotate, , anabolic steroidsanabolic steroids

TrimetazidineTrimetazidine

Drugs manifest cardiocytoprotective action, Drugs manifest cardiocytoprotective action, improve energetic metabolism in improve energetic metabolism in

myocardiummyocardium

ААtptp--longlong 0.010.01

Drugs of metabolic influenceDrugs of metabolic influence

PECULIARITIES OF TREATMENT OF PECULIARITIES OF TREATMENT OF DIASTOLIC DISFUNCTION OF DIASTOLIC DISFUNCTION OF

MYOCARDIUMMYOCARDIUM

IndicatedIndicated::

IACEIACE, А, АRRА А IIII, ,

BetaBeta--adrenoblockers, calcium ions adrenoblockers, calcium ions antagonistsantagonists

ContraindicatedContraindicated::

NitratesNitrates, , diuretics, cardiac glycosidesdiuretics, cardiac glycosides