Chf

Drugs UsedDrugs UsedIn In

Heart FailureHeart Failure

Heart Failure: When Co is inadequate to providethe Heart Failure: When Co is inadequate to providethe oxygen needed by the bodyoxygen needed by the body

Pathophysiology of Heart Failure:Pathophysiology of Heart Failure: Systolic failureSystolic failure Diastolic failureDiastolic failure

It may be It may be Chronic Heart Failure.Chronic Heart Failure. Acute Heart FailureAcute Heart Failure High output failure.High output failure.

Pathophysiology of cardiac performance:Pathophysiology of cardiac performance:Cardiac performance is a function of four primary sectors.Cardiac performance is a function of four primary sectors.

Preload.Preload. AfterloadAfterload ContractilityContractility Heart rate.Heart rate.

Compensatory Mechanism:Compensatory Mechanism:

Compensatory responses due to decreased CO:Compensatory responses due to decreased CO:

• Increased sympathetic ActivityIncreased sympathetic Activity

• Activation of Renin-Angiotensin Aldosterone System.Activation of Renin-Angiotensin Aldosterone System.

• Complex down regulatory changes in Complex down regulatory changes in ββ1 adrenoceptors G. Protein effector 1 adrenoceptors G. Protein effector

system , system , ββ3 not 3 not down regulated---ve inotropic effect. down regulated---ve inotropic effect.

• Myocardial Hypertrophy-- Myocardial Hypertrophy-- ↑in muscle, mass– initially better performance , ↑in muscle, mass– initially better performance ,

then ischemic changes & ↓ diastolic filling& alterations in diastolic filling, then ischemic changes & ↓ diastolic filling& alterations in diastolic filling,

• Remodeling: Remodeling: Dilation & slow structural changes in stressed myocardium:Dilation & slow structural changes in stressed myocardium:

--Proliferation of connective tissue & abnormal myocardial cells , like fetal myocytes--Proliferation of connective tissue & abnormal myocardial cells , like fetal myocytes

—die at accelerated rate—die at accelerated rate

• Release of natriuretic peptide , endothelin & vasopressinRelease of natriuretic peptide , endothelin & vasopressin

Approaches for the management of CHF:Approaches for the management of CHF:

ii. . Relief of symptoms and restoration of cardiac function. Relief of symptoms and restoration of cardiac function.

ii. Arrest/ reversal of disease progression & prolongation of ii. Arrest/ reversal of disease progression & prolongation of

survival.survival.

iii. Treatment of underlying cause.iii. Treatment of underlying cause.

i. Relief of symptoms and restoration of cardiac function. i. Relief of symptoms and restoration of cardiac function.

a) Unloading the stressed heart to a) Unloading the stressed heart to ↓↓ pre-load and after-load with drugs pre-load and after-load with drugs

without inotropic effect. without inotropic effect.

More valuable in long term treatment than positive inotropic drugsMore valuable in long term treatment than positive inotropic drugs

b) Use of positive inotropic drugs to b) Use of positive inotropic drugs to the force of contraction of the force of contraction of

myocardium. myocardium.

Very helpful in acute failure. Very helpful in acute failure.

Also reduce symptom of chronic failure. Also reduce symptom of chronic failure.

Drugs Used in Cardiac FailureDrugs Used in Cardiac Failure

A. A. Drugs With Positive Inotropic EffectsDrugs With Positive Inotropic Effects ( (Cardiotonic drugs)Cardiotonic drugs)

Cardiac glycosidesCardiac glycosides

Digoxin, Digitoxin, Ouabain, Strophanthin, Gitoxin.Digoxin, Digitoxin, Ouabain, Strophanthin, Gitoxin.

Phosphodiesterases inhibitors / Bipyridine derivativesPhosphodiesterases inhibitors / Bipyridine derivatives

Inamrinone (Amrinone), Milrinone.Inamrinone (Amrinone), Milrinone.

ββ11 Selective agonists Selective agonists

Dobutamine, Dopamine.Dobutamine, Dopamine.

Investigational agents: Investigational agents: IstaroximeIstaroxime

LevosimendanLevosimendan

Drugs Without Positive Inotropic EffectsDrugs Without Positive Inotropic Effects

ACE Inhibitors , ATACE Inhibitors , AT11 Antagonists: Antagonists:

ACE Inhibitors:ACE Inhibitors: Captopril, Enalapril, Lisinopril, Quinapril, Benazepril, Captopril, Enalapril, Lisinopril, Quinapril, Benazepril,

Fosinopril, Moexipril, Perinodopril, Trandolapril, Ramipril.Fosinopril, Moexipril, Perinodopril, Trandolapril, Ramipril.

ATAT11 Antagonists: Antagonists: Candesartan , Eprosartan , Irbesartan , Telmisartan , Losartan , Candesartan , Eprosartan , Irbesartan , Telmisartan , Losartan ,

Olmesartan & Valsatran. Olmesartan & Valsatran.

DiureticsDiuretics

Aldosterone Antagonists:Aldosterone Antagonists: Spironolactone , EplerenoneSpironolactone , Eplerenone

Thiazides:Thiazides: Bendrofluazide, Polythiazide, MetolazoneBendrofluazide, Polythiazide, Metolazone

Loop Diuretic: Loop Diuretic: Furosemide , Bumetanide Furosemide , Bumetanide

Vasodilators:Vasodilators:

Arteriolar dilators: Arteriolar dilators: HydralazineHydralazine

Venodilators: Venodilators: Isosorbide dinitrateIsosorbide dinitrate

Synthetic Brain Natriuretic Peptide:Synthetic Brain Natriuretic Peptide: Nesiritide Nesiritide

Competitive inhibitor of endothelin: Competitive inhibitor of endothelin: Bosentan& TezosentanBosentan& Tezosentan

Beta Adrenoceptor blockers: Beta Adrenoceptor blockers:

Carvedilol , Bisoprolol, Metoprolol.Carvedilol , Bisoprolol, Metoprolol.

Cardiac Glycosides (Cardinolides)Cardiac Glycosides (Cardinolides)

Digoxin is the prototype.Digoxin is the prototype.

Sources Sources Digitalis Lanata:Digitalis Lanata: Digoxin, Digitoxin, Gitoxin Digoxin, Digitoxin, Gitoxin Digitalis purpurea (purple fox glove):Digitalis purpurea (purple fox glove): Digitoxin, Gitoxin, GitalinDigitoxin, Gitoxin, Gitalin Strophanthus Kombe:Strophanthus Kombe: Strophanthin Strophanthin Strophanthus gratus:Strophanthus gratus: Ouabain Ouabain Chinese toad skin’s glands:Chinese toad skin’s glands: BufadienolidesBufadienolides

Cardiac Glycosides are called as cardiotonic agents Cardiac Glycosides are called as cardiotonic agents as they increase the mechanical efficiency of heart as as they increase the mechanical efficiency of heart as

a pumpa pump

Efficiency Of Heart: Work DoneEfficiency Of Heart: Work DoneOxygen consumedOxygen consumed

Epinephrine increases the work done alongwith oxygen Epinephrine increases the work done alongwith oxygen consumption so not labeled as cardiotonicconsumption so not labeled as cardiotonic

Cardiac Glycosides Cardiac Glycosides increase the mechanical efficiency of heart by increase the mechanical efficiency of heart by their positive ionotropic effect. There is no increase in oxygen their positive ionotropic effect. There is no increase in oxygen consumptionconsumption

ChemistryChemistry

The prototype of cardiac glycosides (cardenolides) is Digoxin The prototype of cardiac glycosides (cardenolides) is Digoxin – the most commonly used.– the most commonly used.

Chemically cardiac glycosides have a steroid nucleus linked to Chemically cardiac glycosides have a steroid nucleus linked to a lactone ring at 17 position& a series of sugars at carbon 3 of a lactone ring at 17 position& a series of sugars at carbon 3 of te nucleus.te nucleus.

Because they lack an ionizable group their solubility is not pH Because they lack an ionizable group their solubility is not pH

dependedependent.nt.

Chemistry of cardiac glycosidesChemistry of cardiac glycosides::

Pharmacokinetics of DigoxinPharmacokinetics of Digoxin

Oral availability: 65-80%Oral availability: 65-80% Widely distributed including CNS.Widely distributed including CNS.

Vd 6.3 L/kg, initial large dose (loading dose) is given.Vd 6.3 L/kg, initial large dose (loading dose) is given. PPB---20-40%PPB---20-40% Only 1/3 metabolized , 2/3 excreted unchanged by the Only 1/3 metabolized , 2/3 excreted unchanged by the

kidneys.kidneys.

Dosage adjustments in renal impairment.Dosage adjustments in renal impairment. Half-life in body36- 40 hoursHalf-life in body36- 40 hours

PharmacokineticsPharmacokinetics

DigoxinDigoxin DigitoxinDigitoxin11

Lipid solubility (oil/water coefficient)Lipid solubility (oil/water coefficient) MediumMedium HighHigh

Oral availability: 75% >90%>90%

Half-life in body (hours)Half-life in body (hours) 4040 168168

Plasma protein binding (%age bound)Plasma protein binding (%age bound) 20-4020-40 >90>90

Percentage metabolizedPercentage metabolized <40<40 >80>80

Volumes of distribution (L/kg)Volumes of distribution (L/kg) 6.36.3 0.60.6

Mode of Action of cardiac glycosidesMode of Action of cardiac glycosidesCardiac glycosides inhibit Na+/K+ ATPase (Sodium pump), the Cardiac glycosides inhibit Na+/K+ ATPase (Sodium pump), the

membrane bound transporter.membrane bound transporter.

A: Inhibition of Na+/K+ ATPase in heart---A: Inhibition of Na+/K+ ATPase in heart---positive inotropic effectpositive inotropic effect

B. The consequences of inhibition of Na+/K+ ATPase also affect the B. The consequences of inhibition of Na+/K+ ATPase also affect the Electrical function of the heart.Electrical function of the heart.

C. Cardiac glycosides also modify C. Cardiac glycosides also modify Autonomic OutflowAutonomic Outflow & this affects & this affects electrical properties of heartelectrical properties of heart

Inhibition of NaInhibition of Na++/K/K++ ATPase in CNS & GIT--- A/E ATPase in CNS & GIT--- A/E

A: A: Inhibition of Na+/K+ ATPase in heart produces positive Inhibition of Na+/K+ ATPase in heart produces positive inotropic effect, by inotropic effect, by ↑↑Calcium ions in vicinity of contractile Calcium ions in vicinity of contractile elements during systole.elements during systole.

This occurs in two stepsThis occurs in two steps i. Inhibition of Na+/K+ ATPase results in i. Inhibition of Na+/K+ ATPase results in ↑↑ in intracellular sodium in intracellular sodium

concentrationconcentration ii. ii. ↑↑ I/C Sodium alters the driving force for Na+/Ca+ exchanger (NCX). I/C Sodium alters the driving force for Na+/Ca+ exchanger (NCX). ↓↓ expulsion of Ca++ from the cell in exchange for Na+.expulsion of Ca++ from the cell in exchange for Na+. So a small but physiologically important So a small but physiologically important ↑in the free↑in the free Ca++ is available for Ca++ is available for

next contraction of cardiac muscle.next contraction of cardiac muscle. More Ca++ is stored in SR & upon release increases contractile force.More Ca++ is stored in SR & upon release increases contractile force.

TheThe↑↑ in contractility results in reversal of the compensatory in contractility results in reversal of the compensatory responses to heart failure:responses to heart failure:

↑↑ ventricular ejection…. ventricular ejection…. ↓↓ end diastolic & end systolic end diastolic & end systolic cardiac size.cardiac size.

↑↑ CO & CO & ↑↑ renal perfusion renal perfusion The above effects lead to a The above effects lead to a ↓↓ in sympathetic & renal in sympathetic & renal

responses.responses. ↑↑ renal perfusion -- no renin release--- no formation of Angiotensin---- renal perfusion -- no renin release--- no formation of Angiotensin----

no retention of sodium & water through Aldosteron no retention of sodium & water through Aldosteron TheThe↓↓ in sympathetic tone is beneficial…. in sympathetic tone is beneficial…. ↓↓ HR, preload & afterload HR, preload & afterload

improve the efficiency of heart.improve the efficiency of heart.

Pharmacological EffectsPharmacological EffectsA.A. CardiacCardiac B.B. Extra cardiacExtra cardiac

A.A. Cardaic Effects:Cardaic Effects:a. a. Mechanical effects ---Positive Inotropic EffectMechanical effects ---Positive Inotropic Effect

(as discussed in MOA)(as discussed in MOA)

b.b. Electrical effects may be: Direct Electrical effects Electrical effects may be: Direct Electrical effects

Autonomic effectsAutonomic effects

Autonomic effects Autonomic effects ::

a)a) At lower doses due to Parasympathomimetic Activity: At lower doses due to Parasympathomimetic Activity:

produce produce Negative Chronotropic EffectNegative Chronotropic Effect by by::

i)i) Sensitization of baroreceptors.Sensitization of baroreceptors.

ii)ii) Central vagal stimulation. Central vagal stimulation.

iii)iii) muscarinic transmission in Atria & AV node. muscarinic transmission in Atria & AV node.

b)b) At higher dose due to At higher dose due to sympathetic activity sympathetic activity ---- sensitization ---- sensitization

of myocardium ---- of myocardium ---- toxic effects of digitalis. toxic effects of digitalis.

Direct Electrical Cardiac Effects Direct Electrical Cardiac Effects

These effects follow a well defined progression.These effects follow a well defined progression.

At therapeutic concentration:At therapeutic concentration:

Early brief prolongation of action potential (AP).Early brief prolongation of action potential (AP).

Shortening of AP especially of plateau phase.Shortening of AP especially of plateau phase.

in RP of atria & ventricles , in RP of atria & ventricles , ↑↑ in RP of AV node in RP of AV node

At High concentration--- A/EAt High concentration--- A/E in resting membrane potential. in resting membrane potential.

Oscillatory delayed after depolarizing(DADs) due to Calcium overload.Oscillatory delayed after depolarizing(DADs) due to Calcium overload.

Premature ventricular depolarization / ectopic beats.Premature ventricular depolarization / ectopic beats.

Bigeminal rhythm in E.C.G---Ectopic beat after each normal sinus beat .Bigeminal rhythm in E.C.G---Ectopic beat after each normal sinus beat .

Ventricular tachycardiaVentricular tachycardia

Ventricular fibrillationVentricular fibrillation

Effects of Digoxin on electrical properties of cardiac tissuesEffects of Digoxin on electrical properties of cardiac tissues

Tissue or VariableTissue or Variable Effects at therapeutic Effects at therapeutic DosageDosage

Effects at Toxic DosageEffects at Toxic Dosage

Sinus nodeSinus node ↓ ↓ RateRate ↓ ↓ RateRate

Atrial muscleAtrial muscle ↓ ↓ RPRP ↓ ↓ RP, arrhythmiasRP, arrhythmias

Atrioventricular NodeAtrioventricular Node ↓↓conduction velocity , ↑RPconduction velocity , ↑RP ↑↑RP, arrhythmiasRP, arrhythmias

Purkinje system, ventricular Purkinje system, ventricular musclemuscle

Slight Slight ↓ RP↓ RP Extrasystoles, tachycardia, Extrasystoles, tachycardia, fibrillationfibrillation

ElectrocardiogramElectrocardiogram ↑ ↑ PR interval , ↓ QT PR interval , ↓ QT intervalinterval

Tachycardia, fibrillation, Tachycardia, fibrillation, arrest at extremely high arrest at extremely high dosagedosage

RP = Refractory periodRP = Refractory period

B. Effects on other OrgansB. Effects on other Organs (with A/E)(with A/E)

Smooth Muscles of GIT.Smooth Muscles of GIT.

CNS & EyeCNS & Eye

C.C. Interaction with Potassium, Magnesium, Calcium. Interaction with Potassium, Magnesium, Calcium.

Potassium: Potassium: K+ & K+ & cardiac glycosidescardiac glycosides interact in 2 ways: interact in 2 ways:

i.i. They inhibit each other’s binding to They inhibit each other’s binding to Na+/K+ ATPase— soNa+/K+ ATPase— so

Hyperkalemia Hyperkalemia ↓ the enzyme inhibiting action of cardiac glycosides.↓ the enzyme inhibiting action of cardiac glycosides.

Hypokalemia facilitates Hypokalemia facilitates enzyme inhibiting action --- ↑ toxicity. enzyme inhibiting action --- ↑ toxicity.

ii. Hyperkalemia ii. Hyperkalemia ↓ the abnormal automaticity --- ↓ toxicity. ↓ the abnormal automaticity --- ↓ toxicity.

Calcium:Calcium: It facilitates the toxic actions of cardiac glycosides--- It facilitates the toxic actions of cardiac glycosides---

By By ↑ overloading of I/C calcium stores--- ↑ abnormal ↑ overloading of I/C calcium stores--- ↑ abnormal

automaticity.automaticity.

So moderately So moderately ↑↑ extracellular Ca++ extracellular Ca++ --- ↑ risk of Digitalis --- ↑ risk of Digitalis

induced arrhythmias--- toxicity. induced arrhythmias--- toxicity.

Magnesium:Magnesium:The effects are opposite to CalciumThe effects are opposite to Calcium

Therapeutic Uses of DigoxinTherapeutic Uses of Digoxin i. Chronic Heart Failure: i. Chronic Heart Failure:

Only used if ACEIs & Diuretics have failedOnly used if ACEIs & Diuretics have failed Does not reduce mortality. Does not reduce mortality.

((55 years mortality rate in CHF is 50 % years mortality rate in CHF is 50 %)) It is useful in;It is useful in;

Chronic Heart Failure associated with atrial fibrillation: Drug of choice Chronic Heart Failure associated with atrial fibrillation: Drug of choice

Only 50% patients with normal sinus rhythm are relieved.Only 50% patients with normal sinus rhythm are relieved. Chronic Heart Failure with dilated heart & third heart sound.Chronic Heart Failure with dilated heart & third heart sound.

ii. ii. Atrial ArrhythmiasAtrial Arrhythmias:: Atrial Fibrillation & Flutter: To decrease ventricular rate Atrial Fibrillation & Flutter: To decrease ventricular rate because it because it

slows AV conductionslows AV conduction.. Paroxysmal Atrial & AV Nodal TachycardiaParoxysmal Atrial & AV Nodal Tachycardia

Used previously , Now DOC Adenosine & CCBs.Used previously , Now DOC Adenosine & CCBs.

C/I in Wolf-Parkinson White Syndrome with Atrial Fibrillation.C/I in Wolf-Parkinson White Syndrome with Atrial Fibrillation.

Toxicity: Toxicity: Digoxin has narrow therapeutic window.Digoxin has narrow therapeutic window. Therapeutic plasma conc.Therapeutic plasma conc.: 0.5-2 ng/ml: 0.5-2 ng/ml Toxic plasma conc:Toxic plasma conc: >2 ng/ml >2 ng/ml

1.1. GIT:GIT: Anorexia, nausea, vomiting & diarrhea– Anorexia, nausea, vomiting & diarrhea– the first signs of toxicitythe first signs of toxicity

2.2. CNS & Eye: CNS & Eye: Vagal & CTZ stimulation,Vagal & CTZ stimulation,

Fatigue headache , malaise ,confusion disorientation & hallucinations.Fatigue headache , malaise ,confusion disorientation & hallucinations.

Eye: blurred vision , halos on dark objectsEye: blurred vision , halos on dark objects

Changes in color perception ; chromotopsia– blindness for green color may Changes in color perception ; chromotopsia– blindness for green color may occuroccur

Rarely Gynaecomastia in males. Rarely Gynaecomastia in males.

3.3. Cardiac A/E: Cardiac A/E: Arrhythmias:Arrhythmias:• AV Junctional RhythmAV Junctional Rhythm• Ectopic BeatsEctopic Beats• Bigeminal Rhythm Bigeminal Rhythm • Second Degree AV BlockSecond Degree AV Block

• Ventricular TachycardiaVentricular Tachycardia

• Ventricular Fibrillation.Ventricular Fibrillation.

Drug Interactions:Drug Interactions: Thiazides/ Loop diuretics , corticoids --- Hypokalemia----- Thiazides/ Loop diuretics , corticoids --- Hypokalemia----- ↑ ↑

toxicitytoxicity Calcium: Hypercalcemia-- Calcium: Hypercalcemia-- ↑ Digoxin toxicity↑ Digoxin toxicity Quinidine Quinidine ↑ toxicity due to ↓renal clearance & ↑ toxicity due to ↓renal clearance &

displacement from PPB,.displacement from PPB,. Agents releasing catecholamines , sensitize the myocardium to Agents releasing catecholamines , sensitize the myocardium to

digitalis arrhythmias.digitalis arrhythmias.

Broad spectrum Antibiotics; alter GIT flora --- Broad spectrum Antibiotics; alter GIT flora --- ↑↑ bioavailability as bacterial metabolism of bioavailability as bacterial metabolism of Digoxin is reducedDigoxin is reduced

Cholestyramine decreases absorption of Cholestyramine decreases absorption of Digoxin Digoxin Propranolol, Verapamil, Diltiazem & DisopyramidePropranolol, Verapamil, Diltiazem & Disopyramide

depress AV conduction ,oppose inotropic effect.depress AV conduction ,oppose inotropic effect.

Management of Digitalis ToxicityManagement of Digitalis Toxicity Withdraw the drug.Withdraw the drug.

Run an ECG to judge the extent of toxicity & arrhythmias.Run an ECG to judge the extent of toxicity & arrhythmias.

Estimate serum KEstimate serum K+ + & digoxin level. & digoxin level.

Treatment of Hypokalaemia Treatment of Hypokalaemia Mild--- oral Potassium supplements, Potassium Chloride (KCl) TabletsMild--- oral Potassium supplements, Potassium Chloride (KCl) Tablets

If severe hypokalemia Potassium Chloride (KCl) by I/V injection is given.If severe hypokalemia Potassium Chloride (KCl) by I/V injection is given.

Stop Thiazide or Loop diuretics & give Spironolactone.Stop Thiazide or Loop diuretics & give Spironolactone.

Treatment of Arrhythmias –Treatment of Arrhythmias –

Phenytoin, Lignocaine (Drug of choice as they facilitate AV Phenytoin, Lignocaine (Drug of choice as they facilitate AV

conduction ,depressed by Digoxin)conduction ,depressed by Digoxin)

ββ- Blockers to counteract the sympathetic stimulation- Blockers to counteract the sympathetic stimulation

Do not use Quinidine it can increase Digoxin levels---- enhanced toxicity.Do not use Quinidine it can increase Digoxin levels---- enhanced toxicity.

Cholestyramine : Prevents further absorption of Cholestyramine : Prevents further absorption of unabsorbed Digoxin. unabsorbed Digoxin.

In severe toxicity: In severe toxicity:

The serum Potassium is already elevated at time of diagnosis (due to loss of K The serum Potassium is already elevated at time of diagnosis (due to loss of K

from skeletal muscles).from skeletal muscles).

The automaticity is depressed .The automaticity is depressed .

The anti-arrhythmic agents may lead to cardiac arrest; so the best treatment is:The anti-arrhythmic agents may lead to cardiac arrest; so the best treatment is:

Insertion of Insertion of temporary cardiac pace maker cathetertemporary cardiac pace maker catheter

Administration of Antibodies to Digoxin (Digoxin Immune fab ) which may be Administration of Antibodies to Digoxin (Digoxin Immune fab ) which may be

life saving .life saving .

Cardioversion Cardioversion only if there is only if there is ventricular fibrillation ventricular fibrillation ; otherwise Digoxin ; otherwise Digoxin

induced arrhythmia are made worse by cardioversioninduced arrhythmia are made worse by cardioversion

Other Positive Inotropic Drugs Used In Heart FailureOther Positive Inotropic Drugs Used In Heart Failure

Bipyridine derivatives:Bipyridine derivatives:

Inamrinone (Amrinone), Milrinone , Levosimendan (Investigational)Inamrinone (Amrinone), Milrinone , Levosimendan (Investigational)

MOA & effects: MOA & effects: They inhibit enzymes phosphodiesterase -3 found in cardiac & smooth They inhibit enzymes phosphodiesterase -3 found in cardiac & smooth

muscles, that inactivates cAMP & cGMP .muscles, that inactivates cAMP & cGMP .

Effects on Heart: Effects on Heart:

Positive inotropic effectsPositive inotropic effects. . Inhibition of PDEInhibition of PDE3 3 ---- ---- cAMP ---- cAMP ---- CaCa++++ influx influx --- ---

contraction of cardiac muscle, contraction of cardiac muscle,

May also May also CaCa++++ release from SR. release from SR.

Effects on B.V:Effects on B.V: Produce vasodilatationProduce vasodilatation. . Inhibition of PDEInhibition of PDE3 3 ---- ---- cGMP ---- relaxation of cGMP ---- relaxation of

SM.--- reduce preload & afterloadSM.--- reduce preload & afterload

Therapeutic use: Therapeutic use: usedused I/V forI/V for Acute decompensated heart failureAcute decompensated heart failure Exacerbation of chronic heart failure. Exacerbation of chronic heart failure.

Toxicity: Toxicity: ↑↑risk of mortality on long term userisk of mortality on long term use of both drugsof both drugs InamrinoneInamrinone: Nausea , : Nausea ,

vomiting ,arrhythmias ,thrombocytopenia, change in liver vomiting ,arrhythmias ,thrombocytopenia, change in liver enzymes,enzymes,

Milrinone:Milrinone: arrhythmias arrhythmias

Less likely to produce thrombocytopenia & liver toxicityLess likely to produce thrombocytopenia & liver toxicity

ββ11 Selective agonists: Selective agonists: Dobutamine (Synthetic catecholamine),Dobutamine (Synthetic catecholamine),

Role in HF: Role in HF: Improve cardiac performance by :Improve cardiac performance by :

Positive inotropic effect-- Positive inotropic effect-- ↑contractility, ↑ C O↑contractility, ↑ C O

Dobutamine Dobutamine is the most commonlyis the most commonly

Uses: Primarily in acute decompensated HF, due to MI & Surgery-- Uses: Primarily in acute decompensated HF, due to MI & Surgery--

controlled I/V infusion, DOA a few minutescontrolled I/V infusion, DOA a few minutes

May be used as intermittent infusion in CHF to reduce symptomsMay be used as intermittent infusion in CHF to reduce symptoms

Dopamine Dopamine ---Natural catecholamine.---Natural catecholamine.

Increases renal blood flow ,higher doses have Positive inotropic effect-- Increases renal blood flow ,higher doses have Positive inotropic effect--

↑contractility, ↑ C O, Also increase blood pressure.↑contractility, ↑ C O, Also increase blood pressure.

Therapeutic uses:Therapeutic uses:No role in CHF.No role in CHF.

Useful in acute decompensated HF & oliguric/ hypovolumic shock. Useful in acute decompensated HF & oliguric/ hypovolumic shock.

A/E: A/E: both can produce arrhythmia, additive effect with other both can produce arrhythmia, additive effect with other

sympatomimeticssympatomimetics

Drugs Without Positive Inotropic EffectsDrugs Without Positive Inotropic Effects

ACE Inhibitors , ATACE Inhibitors , AT11 Antagonists: Antagonists:

ACE Inhibitors:ACE Inhibitors: Captopril, Enalapril, Lisinopril, Quinapril, Captopril, Enalapril, Lisinopril, Quinapril,

Benazepril, Fosinopril, Moexipril, Perinodopril, Trandolapril, Benazepril, Fosinopril, Moexipril, Perinodopril, Trandolapril,

Ramipril.Ramipril.

ATAT11 Antagonists: Antagonists: Candesartan, Eprosartan, Irbesartan, Candesartan, Eprosartan, Irbesartan,

Telmisartan , Losartan, Olmesartan & Valsatran. Telmisartan , Losartan, Olmesartan & Valsatran.

M.O.A of ACE Inhibitors in heart failure:M.O.A of ACE Inhibitors in heart failure: ACEIs inhibit the converting enzyme peptidyl dipeptidase (ACE) ACEIs inhibit the converting enzyme peptidyl dipeptidase (ACE)

& prevent formation of Angiotensin II from Angiotensin I.& prevent formation of Angiotensin II from Angiotensin I. Inactivation of bradykinin by the same enzyme (plasma kininase) Inactivation of bradykinin by the same enzyme (plasma kininase)

is inhibited, so it accumulates.is inhibited, so it accumulates. Bradykinin produces vasodilation directly as well as through ↑ PG Bradykinin produces vasodilation directly as well as through ↑ PG

synthesis.synthesis.

So there is vasodilatation due to So there is vasodilatation due to ↓↓ Angiotensin II & ↑ Angiotensin II & ↑ bradykinin bradykinin ↓↓ PVR PVR Preload & after load. Preload & after load.

Due to Due to ↓↓ Angiotensin II, the release of aldosetrone & Angiotensin II, the release of aldosetrone & consequent retention of sodium & water is also consequent retention of sodium & water is also ↓ , ↓ ,

So ↓ blood volume also contributes to So ↓ blood volume also contributes to Preload & after load.Preload & after load. ↓↓ remodeling of Heart & BV.remodeling of Heart & BV.

Use of ACE Inhibitors in HF: Use of ACE Inhibitors in HF:

First line therapy in heart failure without edema.First line therapy in heart failure without edema. Useful in Useful in asymptomaticasymptomatic to those in to those in severe heart failuresevere heart failure..

By ↓By ↓ Preload & after load (Preload & after load (↓↓ PVR , PVR , ↓↓ salt retention ) . salt retention ) . ↓↓ sympathetic activity due to sympathetic activity due to ↓↓ Ang II , through inhibition of Ang II , through inhibition of

presynaptic effect on NE release. presynaptic effect on NE release. ↓↓ Mortality & Morbidity -----Mortality & Morbidity -----

↓↓ remodeling of Heart & BV.remodeling of Heart & BV. Slow the progress of ventricular dilation & delay the onset Slow the progress of ventricular dilation & delay the onset

of clinical heart failure. of clinical heart failure. ATAT11 Antagonists: Antagonists: Only used if patient can not tolerate ACEIsOnly used if patient can not tolerate ACEIs

DiureticsDiuretics

Aldosterone Antagonists:Aldosterone Antagonists: Spironolactone , Eplerenone Spironolactone , Eplerenone

Thiazides:Thiazides: Bendrofluazide, Polythiazide, MetolazoneBendrofluazide, Polythiazide, Metolazone

Loop Diuretic: Loop Diuretic: Furosemide , BumetanideFurosemide , Bumetanide

They are useful in CHF because they:They are useful in CHF because they: ↓↓ venous pressure & preload. venous pressure & preload. ↓↓ peripheral & pulmonary edema & relieve their symptomsperipheral & pulmonary edema & relieve their symptoms ↓↓ cardiac size--- better pump function.cardiac size--- better pump function. Do not influence the primary disease process in CHF.Do not influence the primary disease process in CHF.

..

Spironolactone & Eplerenone:Spironolactone & Eplerenone:

MOA: MOA: Block cytoplasmic aldosteron receptors in collecting tubules.Block cytoplasmic aldosteron receptors in collecting tubules.

Role in CHFRole in CHF In advanced HF, In advanced HF, ↑Aldosterone due to ↑ AngiotensinII.↑Aldosterone due to ↑ AngiotensinII. As they are direct receptor antagonists to As they are direct receptor antagonists to Aldosterone, Aldosterone, they they

prevent salt & water retention , myocardial hypertrophy & prevent salt & water retention , myocardial hypertrophy & Hypokalemia.Hypokalemia.

Monitor serum KMonitor serum K+.+.

Reserved for the most advanced casesReserved for the most advanced cases

Spironolactone & Eleprenone also reduce mortalitySpironolactone & Eleprenone also reduce mortality

Loop DiureticLoop Diuretic, I/V Furosemide ,DOC in acute HF specially , I/V Furosemide ,DOC in acute HF specially

with pulmonary edema.with pulmonary edema.

In CHF resistance may develop to Loop Diuretic so combined In CHF resistance may develop to Loop Diuretic so combined

with Thiazides Bendrofluazide, Polythiazide, Metolazone or with Thiazides Bendrofluazide, Polythiazide, Metolazone or

Spironolactone.Spironolactone.

Vasodilators:Vasodilators:

I/V Effective in acute heart failure. (Cardiogenic shock, MI).I/V Effective in acute heart failure. (Cardiogenic shock, MI).

Orally effective for long term therapy of chronic heart failure.Orally effective for long term therapy of chronic heart failure.

life expectancy in CHF----life expectancy in CHF---- reduce mortality:reduce mortality:

Long term use of Hydralazine & Isosorbide dinitrate also Long term use of Hydralazine & Isosorbide dinitrate also

damaging remodeling of the heart.damaging remodeling of the heart.

Selective Arteriolar dilator: Selective Arteriolar dilator: HydralazineHydralazine• Primarily Primarily afterload & relieve fatigue due to low CO afterload & relieve fatigue due to low CO

Selective Venodilator: Selective Venodilator: Isosorbide dinitrate Isosorbide dinitrate

Primarily Primarily preload. preload.

Useful in patients with high filling pressure & dyspneoaUseful in patients with high filling pressure & dyspneoa

Non-selective Vasodilators: Non-selective Vasodilators:

ACE inhibitorsACE inhibitors

Synthetic Brain Natriuretic Peptide (BNP) :Synthetic Brain Natriuretic Peptide (BNP) : Nesiritide Nesiritide

Competitive inhibitor of endothelin:Competitive inhibitor of endothelin: BosentanBosentan

Synthetic Brain Natriuretic Peptide (BNP) :Synthetic Brain Natriuretic Peptide (BNP) : Nesiritide NesiritidePrepared by, Recombinant DNA technique. Given I/V.Prepared by, Recombinant DNA technique. Given I/V.

MOA: MOA: Activates BNP receptors, Activates BNP receptors, cGMP in SM cells --- cGMP in SM cells --- vasodilation---- vasodilation---- preload & afterload. preload & afterload.Also causes diuresis.Also causes diuresis.

A/E: A/E: Renal damage & deaths, hypotension.Renal damage & deaths, hypotension.Competitive inhibitor of endothelin: Competitive inhibitor of endothelin: BosentanBosentan & tezosentan & tezosentanGiven orally.Given orally.Therapeutic use:Therapeutic use: Disappointing results in humans with CHF. Disappointing results in humans with CHF.Used in Pulmonary hypertensionUsed in Pulmonary hypertensionA/E:A/E: Teratogenic , hepatotoxic Teratogenic , hepatotoxic

Beta Adrenoceptor blockers: Beta Adrenoceptor blockers: Carvedilol , Bisoprolol, Carvedilol , Bisoprolol, Metoprolol.Metoprolol.

They They ↓ motility in selected patients with stable CHF.↓ motility in selected patients with stable CHF.Suggested mechanisms are:Suggested mechanisms are: Attenuation of the adverse effects of high concentration of Attenuation of the adverse effects of high concentration of

catecholamines includingcatecholamines including apoptosis. apoptosis. Up regulation of beta receptorsUp regulation of beta receptors ↓ ↓ Heart RateHeart Rate Prevent arrhythmias. Prevent arrhythmias. Inhibit vascular SM mitogenesis---↓ Remodeling. Inhibit vascular SM mitogenesis---↓ Remodeling.

Management of Acute Heart FailureManagement of Acute Heart Failure Acute heart failure occurs frequently in patients of CHF due to:Acute heart failure occurs frequently in patients of CHF due to:

exertion ,emotion, salt in diet.exertion ,emotion, salt in diet. Non-compliance with medical therapyNon-compliance with medical therapy Metabolic demand– high fever.Metabolic demand– high fever. AnemiaAnemia

Acute myocardial infarction is a common cause of acute heart failure_ with Acute myocardial infarction is a common cause of acute heart failure_ with or without CHF.or without CHF.

I/V therapy is the rule in acute heart failure. I/V therapy is the rule in acute heart failure.

Drug Therapy in Myocardial InfarctionDrug Therapy in Myocardial InfarctionDrug therapy includes:Drug therapy includes:

1.1. Relief of Pain, Anxiety and Apprehension:Relief of Pain, Anxiety and Apprehension: Opioid analgesics (morphine/ Opioid analgesics (morphine/ Pethidine) , diazepam.Pethidine) , diazepam.

2.2. OxygenationOxygenation

3.3. Maintenance of blood volumeMaintenance of blood volume

4.4. Correction of acidosisCorrection of acidosis

5.5. Prevention & treatment of arrhythmias-- BetablockersPrevention & treatment of arrhythmias-- Betablockers

6.6. Treatment of Pump failureTreatment of Pump failure

a)a) FurosemideFurosemide

b)b) VasodilatorsVasodilators

c)c) Inotropic agents– Dopamine & DobutamineInotropic agents– Dopamine & Dobutamine

7.7. Best treatment is Best treatment is emergency revasculization emergency revasculization using:using: Coronary angioplasty & a stent Coronary angioplasty & a stent Thrombolytic agents like streptokinase .Thrombolytic agents like streptokinase .

8. Prevention of thrombus extension, embolism, venous 8. Prevention of thrombus extension, embolism, venous thrombosis --- Anti-coagulants like heparin.thrombosis --- Anti-coagulants like heparin.

9. Prevention of remodeling & subsequent CHF—ACE 9. Prevention of remodeling & subsequent CHF—ACE inhibitorsinhibitors

10. Prevention of future attacks10. Prevention of future attacksa)a) Anti-platelet drugsAnti-platelet drugsb)b) ββ-Blockers -Blockers c)c) Control of hyperlipidaemiaControl of hyperlipidaemia

Subsets in acute MISubsets in acute MI TherapyTherapy

HypovolemiaHypovolemia Volume replacement Volume replacement

Pulmonary congestionPulmonary congestion Diuretic– I/V furosemide, NitratesDiuretic– I/V furosemide, Nitrates

Peripheral vasodilationPeripheral vasodilation None, or vasoactive drugsNone, or vasoactive drugs

Power failurePower failure Vasodilators, inotropic drugsVasodilators, inotropic drugs

Severe shockSevere shock Vasoactive drugs, inotropic drugs, vasodilators, circulatory assist devicesVasoactive drugs, inotropic drugs, vasodilators, circulatory assist devices

Right ventricular infractRight ventricular infract Provide volume replacement for LVFP, inotropic drugs. Avoid diuretics.Provide volume replacement for LVFP, inotropic drugs. Avoid diuretics.

Mitral regurgitation, Mitral regurgitation, ventricular septal defectventricular septal defect

Vasodilators, inotropic drugs, circulatory assistance , surgeryVasodilators, inotropic drugs, circulatory assistance , surgery