Cardiac glycosides. Modern Cardiac glycosides. Modern cardiotonic drugs and other cardiotonic drugs and other agents used in the treatment agents used in the treatment of congestive heart failureof congestive heart failure

Lector prof. Posokhova K.A.Lector prof. Posokhova K.A.

Treatment of chronic heart Treatment of chronic heart insufficiencyinsufficiency

Heart glycosidesHeart glycosidesNonglycoside cardiotonic drugsNonglycoside cardiotonic drugsInhibitors of angiotensine transforming Inhibitors of angiotensine transforming enzymeenzyme ( (IATEIATE, , IACEIACE))Antagonists of angiotesine II receptorsAntagonists of angiotesine II receptors (А (АRRА А IIII))Diuretics Diuretics Peripheral vasodilatorsPeripheral vasodilatorsBeta-adrenoblockersBeta-adrenoblockersDrugs of metabolic actionDrugs of metabolic action

CARDIOTONIC CARDIOTONIC DRUGSDRUGS

CARDIOTONIC DRUGSCARDIOTONIC DRUGS

HEART GLYCOSIDESHEART GLYCOSIDES

NONGLYCOSIDE NONGLYCOSIDE CARDIOTONIC DRUGSCARDIOTONIC DRUGS

((DobutaminDobutamin))

HEART HEART GLYCOSIDESGLYCOSIDES

Purple Foxglove Purple Foxglove

FoxgloveFoxglove

Lily of the valleyLily of the valley

LychnisLychnis

Chemical structure of heart glycosidesChemical structure of heart glycosides

PharmacodynamicsPharmacodynamics

Cardiac actionCardiac action

Extracardiac actionExtracardiac action

Cardiac actionCardiac action

Positive inotropicPositive inotropic

Positive bathmotropicPositive bathmotropic

Negative chronotropicNegative chronotropic

Negative dromotropicNegative dromotropic

ECG changes under the ECG changes under the influence of HGinfluence of HG

Changes which correlate to positive Changes which correlate to positive innotropic actioninnotropic action

Narrowing QRS complexNarrowing QRS complex Decreasing ST Decreasing ST

T-blip – double-phasedT-blip – double-phased, , negativenegative Changes which correlate to negative Changes which correlate to negative

dromotropic actiondromotropic action Prolongation of PQ intervalProlongation of PQ interval

Changes which correlate to negative Changes which correlate to negative chronotropic actionchronotropic action

Increasing of RR intervalIncreasing of RR interval

MECHANISM OF CARDIOTONIC (POSITIVE MECHANISM OF CARDIOTONIC (POSITIVE

INOTROPICINOTROPIC) ) ACTION OG HGACTION OG HG HGHG

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

1.1. Stimulate exit of Stimulate exit of Са Са from sarcoplasmic reticulumfrom sarcoplasmic reticulum2.2. 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 need in oxygencells, decrease myocardium need in oxygenIncrease tone of sympatic nervous systemIncrease tone of sympatic nervous system

Extracardiac action of Extracardiac action of HGHG

DiureticDiuretic SedativeSedative

Stimulating influence on Stimulating influence on smooth musclessmooth muscles

Pharmacokinetics of HGPharmacokinetics of HGAbsorption of HG in gastro-intestinal Absorption of HG in gastro-intestinal

tracttract

DigitoxinDigitoxin – 100 % – 100 % DigoxinDigoxin – 60-80 % – 60-80 % CelanidCelanid – 15-40 % – 15-40 %

StrophanthinStrophanthin – 3-5 % – 3-5 %

Pharmacokinetics of HGPharmacokinetics of HGHG of short actionHG of short action ( (strophanthin, corglyconstrophanthin, corglycon))

- - latent periodlatent period – 5-10 – 5-10 minmin, , - - action durationaction duration – 8-12 – 8-12 hourshours ( (corglyconcorglycon), 1-3 ), 1-3 daysdays

((strophanthinstrophanthin), ), - - slow intravenous introductionslow intravenous introduction

HG of medium action durationHG of medium action duration ( (digpoxin, celaniddigpoxin, celanid))- latent periodlatent period – 5-30 – 5-30 min.min. ( (i.v.i.v.), 30-60 ), 30-60 min.min. ( (orallyorally))- action duration –action duration – 3 3--6 6 daysdays- slow intravenous, oral introductionslow intravenous, oral introduction

HG of long lasting actionHG of long lasting action ( (digitoxindigitoxin))- latentlatent periodperiod – 4-12 – 4-12 hourshours- action durationaction duration – 2-3 – 2-3 weeksweeks- oral introductionoral introduction

INDICATIONS FOR INTRODUCTION INDICATIONS FOR INTRODUCTION OF HEART GLYCOSIDESOF HEART GLYCOSIDES

They are drugs of choice for patients with systolic They are drugs of choice for patients with systolic dysfunction of dysfunction of myocardium, accompanied by myocardium, accompanied by tachysystolic form of atria fibrilationtachysystolic form of atria fibrilationPatients withPatients with III andIII and IV FCIV FC ( (according toaccording to NYHANYHA) ) of of chronic heart insufficiency, in case of transferring chronic heart insufficiency, in case of transferring of II FC into III FCof II FC into III FCSupraventricular tachycardia and tachyarrhythmiaSupraventricular tachycardia and tachyarrhythmia

Improving of disease currency, life quality, increasing of Improving of disease currency, life quality, increasing of tolerance towards physical loads, but absence of tolerance towards physical loads, but absence of influence on mortality level in patients with CHIinfluence on mortality level in patients with CHI

MECHANISM OF TREATMENT ACTION MECHANISM OF TREATMENT ACTION OF HG IN CASE OF HEART OF HG IN CASE OF HEART

INSUFFICIENCYINSUFFICIENCYIncreasing of systolic and minute Increasing of systolic and minute volumes of heart activityvolumes of heart activityImproving of circulation in lung and Improving of circulation in lung and organic circulation circles, decreasing of organic circulation circles, decreasing of CBV, excretion of surplus liquid from the CBV, excretion of surplus liquid from the organismorganismElimination 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 HG of HG::

1.1. Improving of general condition of Improving of general condition of the patientthe patient ( (decreasing of weakness, decreasing of weakness, short breath, sleep normalizationshort breath, sleep normalization, , disappearing of edema, cyanosis, disappearing of edema, cyanosis, etc.)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

TREATMENT WITH HEART GLYCOSIDESTREATMENT WITH HEART GLYCOSIDES – 2 – 2 stagesstages

STARTING DIGITALIZATION STARTING DIGITALIZATION ((PERIOD OF PERIOD OF SATURATION OF THE ORGANISM WITH THE SATURATION OF THE ORGANISM WITH THE

DRUGDRUG)) The aim is to reach full dose of action in the The aim is to reach full dose of action in the

organism of the patientorganism of the patient (effective therapeutic (effective therapeutic dose)dose) of HGof HG

SUPPORTIVE THERAPYSUPPORTIVE THERAPY The aim is to support the full dose in the The aim is to support the full dose in the

organism of the patientorganism of the patient

AVERAGE FULL DOSES OF AVERAGE FULL DOSES OF ACTION OF HGACTION OF HG

StrophantinStrophantin – 0,6-0,7 – 0,6-0,7 mgmg Celanid Celanid – 2 мг (– 2 мг (i.v.i.v.), 5 ), 5 mgmg ( (orallyorally)) DigoxinDigoxin – 2 – 2 mgmg ( (i.v.i.v.), 3 ), 3 mgmg ( (orallyorally)) DigitoxinDigitoxin – 2 – 2 mgmg

Real full doses of action in certain Real full doses of action in certain patients can differ from the average full patients can differ from the average full

dose of action fordose of action for 50-200 % 50-200 %

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 heart glycosides are heart 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 mgmg//dayday ( (digitalization lasts fordigitalization lasts for 5-7 5-7 daysdays), ),

digitoxindigitoxin – 0,1-0,15 – 0,1-0,15 mgmg//dayday ( (digitalizationdigitalization lasts forlasts for 25- 25-30 30 daysdays))

HG according to level of HG according to level of positive inotropicpositive inotropic actionaction

strophantinstrophantin > celanid> celanid > digoxin> digoxin > > digitoxindigitoxin

according to level ofaccording to level of negative negative chronotropicchronotropic actionaction

digitoxin >digitoxin > digoxin >digoxin > celanid >celanid > strophantinstrophantin

Contraindications for Contraindications for administration of HGadministration of HG

1. 1. Absolute contraindicationAbsolute contraindication – – ііntoxication ntoxication with HGwith HG

2. 2. Other contraindicationsOther contraindications - - diastolic dysfunction ofdiastolic dysfunction of myocardiummyocardium- - sinus tachycardia based on thyrotoxicosis, sinus tachycardia based on thyrotoxicosis,

anemia, increased temperature, hypoxiaanemia, increased temperature, hypoxia- - insufficiency of aortal valves, isolated insufficiency of aortal valves, isolated

mitral stenosismitral stenosis, , diffuse myocarditisdiffuse myocarditis

Intoxication with heart Intoxication with heart glycosidesglycosides

Cardiac symptomsCardiac symptomsWorsening of contractive action of Worsening of contractive action of

myocardium, increasing of myocardium, increasing of circulation insufficiencycirculation insufficiency

Disturbance of heart rhythmDisturbance of heart rhythm

Extracardiac symptomsExtracardiac symptoms

Gastro-intestinalGastro-intestinalNeurological and psychical Neurological and psychical Eye symptomsEye symptomsDisturbance of kidney functionDisturbance of kidney function Allergic reactionsAllergic reactions Gynecomastia Gynecomastia

Treatment of intoxicationTreatment of intoxicationImmediate quitting of HG introductionImmediate quitting of HG introductionAcceleration of HG excretion from GI Acceleration of HG excretion from GI

tracttractCorrection of hypopotassiumemiaCorrection of hypopotassiumemiaIntroduction of unitiolIntroduction of unitiolTreatment of arrhythmiaTreatment of arrhythmiaOxygen therapyOxygen therapy

Factors which promote developmentFactors which promote developmentINTOXICATION WITH HEART INTOXICATION WITH HEART

GLYCOZIDESGLYCOZIDES

DigitoxinDigitoxin is a choice drugis a choice drug when HI is combined when HI is combined with with kidney insufficiencykidney insufficiency, , but contraindicated if but contraindicated if liver is damagedliver is damaged ( (it is metabolized by liverit is metabolized by liver))Digoxin Digoxin is not contraindicated even in case of is not contraindicated even in case of liver cirrhosis liver cirrhosis (it is not metabolized in liver(it is not metabolized in liver), ), but but contraindicated in case of kidney insufficiencycontraindicated in case of kidney insufficiency ((it is excreted by kidneysit is excreted by kidneys) )

Intoxication with heart Intoxication with heart gkycozidesgkycozidesCardiac symptomsCardiac symptoms

Worsening of contractive function of Worsening of contractive function of myocardiummyocardium, , increasing of circulation increasing of circulation insufficiencyinsufficiency –– relapserelapse of HIof HI (18(18--26 %)26 %)Disturbance of heart rhythmDisturbance of heart rhythm(90(90--95 %, у 65 % 95 %, у 65 % -- single symptom of single symptom of intoxicationintoxication))

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

Intoxication with heart glycosidesIntoxication with heart glycosides

ExtracardiacExtracardiac symptomssymptomsGastroGastro--intestinalintestinal (40(40--50 %)50 %)Neurological and psychicalNeurological and psychical(25 %)(25 %)Eye symptomsEye symptoms (65 %)(65 %)Worsening of kidneys functionWorsening of kidneys function

Treatment of intoxication Treatment of intoxication with heart glycosideswith heart glycosides

Immediate quitting of HG introductionImmediate quitting of HG introductionCorrection of hypopotassiumemiaCorrection of hypopotassiumemia (KCl, panangin)(KCl, panangin)Introduction of unitiolIntroduction of unitiol (1 (1 mlml of of 5 % 5 % solutionsolution / / kg of kg of weight i.m. weight i.m. 2-3-5 2-3-5 times per daytimes per day))Clearing of GI tract (vaseline oil, cholestyraminClearing 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, carnitin, heptaminol, creatinol-o-phosphate, trapidil, etc.heptaminol, creatinol-o-phosphate, trapidil, etc.

NONGLYCOSIDE CARDIOTONIC NONGLYCOSIDE CARDIOTONIC DRUGSDRUGS

DobutaminDobutamin – – betabeta11--adrenomimeticadrenomimetic - - in case of in case of acute and chronic heart insufficiency acute and chronic heart insufficiency – – intravenously dropping intravenously dropping – 2,5-5-10 – 2,5-5-10 mcgmcg/(/(kgkg..minmin); ); in case of constant infusion in case of constant infusion tolerance develops after tolerance develops after 3-4 3-4 daysdays; ; in case of in case of increasing of doseincreasing of dose – – heart arrhythmiasheart arrhythmiasAmrinon, 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 stage of HIstage of HI

INHIBITORS OF ANGIOTENSINE INHIBITORS OF ANGIOTENSINE TRASFORMING ENZYMETRASFORMING ENZYME ( (IATE)IATE)

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

In case of HI they brake pathological consequences In case of HI they brake pathological consequences of activation of renin-angiotesine system by of activation of renin-angiotesine system by

inhibiting ATEinhibiting ATE:: 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 bradikinAccumulation of bradikin ( (inductor of prostacycline and inductor of prostacycline and nitrogen oxide synthesisnitrogen oxide synthesis))

INHIBITORS OF ANGIOTESINE INHIBITORS OF ANGIOTESINE TRANSFORMING ENZYMETRANSFORMING ENZYME ( (IATEIATE))

Increase duration and improve Increase duration and improve quality of life of patients with HIquality of life of patients with HIIncrease tolerance towards physical Increase tolerance towards physical loadsloadsDecrease risk of recurring MIDecrease risk of recurring MIBrake development of miocardium Brake development of miocardium hypertrophy hypertrophy

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 nonsteroid antiinflammatoryby nonsteroid antiinflammatory), ), considerable decreasing of APconsiderable decreasing of AP, , worsening worsening of kidneys’ functionof kidneys’ function, , hyperpotassiumemia, hyperpotassiumemia, tachycardia, neutropenia, aphtose stomatitistachycardia, neutropenia, 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

CAPTOPRIL CAPTOPRIL ((CAPOTENCAPOTEN))

ANTAGONISTS OF ANTAGONISTS OF ANGIOTESINE II RECEPTOS ANGIOTESINE II RECEPTOS (А(АRRА А IIII))

LOSARTANLOSARTAN ( (cosaar)cosaar)Blocks receptors of angiotensineBlocks receptors of angiotensine IIII

Decreases mortality of patients with HIDecreases mortality of patients with HI onon 50 % 50 %

Breaks development of myocardium Breaks development of myocardium hypertrophy hypertrophy

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

Losartan Losartan ((cosaar)cosaar)

DIURETICSDIURETICSDichlotiazideDichlotiazide, , hyhrotonehyhrotone ( (oxodolineoxodoline), ),

clopamideclopamide ( (brinaldixbrinaldix))FurosemidFurosemid, , etacrine acidetacrine 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, ,

spironolacton decreases quantity of relapses spironolacton decreases quantity of relapses and mortalityand mortality

PERIPHERAL PERIPHERAL VASODILATORSVASODILATORS

ArterialArterial:: hydralasin, calcium ions antagonists, hydralasin, calcium ions antagonists, minoxydilminoxydilVenousVenous:: nitrates, molsidominnitrates, molsidominOf mixed actionOf mixed action ( (influence on tone of arterioles influence on tone of arterioles and venulesand venules): ): sodium nitroprusidesodium nitropruside, , prasosine, prasosine, inhibitors of ATE, ARA IIinhibitors of ATE, ARA II

Isosorbide dinitrateIsosorbide dinitrate (30-160 (30-160 mgmg//dayday) + ) + hydralasinhydralasin (50-300 (50-300 mgmg//dayday) – ) – for patients which for patients which

have contraindications towards administration of have contraindications towards administration of IATEIATE

PERIPHERAL PERIPHERAL VASODILATORSVASODILATORS

Unfavorable action in case of HIUnfavorable action in case of HI::

They activate sympatic-adrenalsystem and They activate sympatic-adrenalsystem and intermediately renin-aldosterone system intermediately renin-aldosterone system

BETA-ADRENOBLOCKERSBETA-ADRENOBLOCKERSCarvedili, methoprolol, bisoprololCarvedili, methoprolol, bisoprolol

They decrease mortality, improve disease currency and They decrease mortality, improve disease currency and quality of patients’ lives in case of stagnant HIquality of patients’ lives in case of stagnant HIMechanism of treatment action in case of HIMechanism of treatment action in case of HIRenewing of quantity and sensitivity of beta-Renewing of quantity and sensitivity of beta-adrenoreceptors in heart, which leads to increasing of adrenoreceptors in heart, which leads to increasing of systolic volume after systolic volume after 8-10 8-10 weeks of regular administration weeks of regular 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 – – alphaalpha11--adrenoblocking and antioxidant actionadrenoblocking and antioxidant action

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

adrenoblockers in case of HIadrenoblockers in case of HI The treatment is started from a small doseThe treatment is started from a small dose (3,175-6,25 (3,175-6,25 carvedilolcarvedilol), ), everyevery 2-4 2-4 weeks it is doubled until weeks it is doubled until

obtaining the effectobtaining the effect ( (usually develops afterusually develops after 2-3 2-3 monthsmonths)).. Average effective dosesAverage effective doses: :

carvedilolcarvedilol – 50 – 50 mgmgmetoprolol metoprolol – 100 – 100 mgmg

bisoprololbisoprolol – 5 – 5 mgmg Administration of beta-blockers is possible only in case of Administration of beta-blockers is possible only in case of

constant condition of the patientconstant condition of the patient, , before development of before development of stabile improvement of condition temporary worsening may stabile improvement of condition temporary worsening may developdevelop

DRUGS OF METABOLIC ACTIONDRUGS OF METABOLIC ACTIONVitaminsVitamins: Е, С, В: Е, С, В group groupRyboxin Ryboxin Mildronate Mildronate PhosphadenPhosphaden, , ATPATPCreatinphosphate Creatinphosphate Potassium orotatePotassium orotate, , anabolic steroidsanabolic steroids

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::

IATEIATE, А, АRRА А IIII, , BetaBeta--adrenoblockers, calcium ions adrenoblockers, calcium ions

antagonistsantagonists

ContraindicatedContraindicated::

NitratesNitrates, , diuretics, heart glycosidesdiuretics, heart glycosides