1. Drugs UsedDrugs Used
InIn
Heart FailureHeart Failure

2. Heart Failure: When Co is inadequate to providetheHeart 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 beIt may be
 Chronic Heart Failure.Chronic Heart Failure.
 Acute Heart FailureAcute Heart Failure
 High output failure.High output failure.

3. 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.

4. Compensatory Mechanism:Compensatory Mechanism:

6. 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 inComplex down regulatory changes in ββ1 adrenoceptors G. Protein effector1 adrenoceptors G. Protein effector
system ,system , ββ3 not3 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

7. 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 ofii. Arrest/ reversal of disease progression & prolongation of
survival.survival.
iii. Treatment of underlying cause.iii. Treatment of underlying cause.

8. i. Relief of symptoms and restoration of cardiac function.i. Relief of symptoms and restoration of cardiac function.
a) Unloading the stressed heart toa) Unloading the stressed heart to ↓↓ pre-load and after-load with drugspre-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 tob) Use of positive inotropic drugs to  the force of contraction ofthe 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.

9. 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 agonistsSelective agonists
Dobutamine, Dopamine.Dobutamine, Dopamine.
Investigational agents:Investigational agents: IstaroximeIstaroxime
LevosimendanLevosimendan

10. 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 ,Candesartan , Eprosartan , Irbesartan , Telmisartan ,
Losartan , Olmesartan & Valsatran.Losartan , Olmesartan & Valsatran.
 DiureticsDiuretics
Aldosterone Antagonists:Aldosterone Antagonists: Spironolactone , EplerenoneSpironolactone , Eplerenone
Thiazides:Thiazides: Bendrofluazide, Polythiazide, MetolazoneBendrofluazide, Polythiazide, Metolazone
Loop Diuretic:Loop Diuretic: Furosemide , BumetanideFurosemide , Bumetanide

11.  Vasodilators:Vasodilators:
Arteriolar dilators:Arteriolar dilators: HydralazineHydralazine
Venodilators:Venodilators: Isosorbide dinitrateIsosorbide dinitrate
Synthetic Brain Natriuretic Peptide:Synthetic Brain Natriuretic Peptide: NesiritideNesiritide
Competitive inhibitor of endothelin:Competitive inhibitor of endothelin: Bosentan& TezosentanBosentan& Tezosentan
 Beta Adrenoceptor blockers:Beta Adrenoceptor blockers:
Carvedilol , Bisoprolol, Metoprolol.Carvedilol , Bisoprolol, Metoprolol.

12. Cardiac Glycosides (Cardinolides)Cardiac Glycosides (Cardinolides)
Digoxin is the prototype.Digoxin is the prototype.
SourcesSources
 Digitalis Lanata:Digitalis Lanata: Digoxin, Digitoxin, GitoxinDigoxin, Digitoxin, Gitoxin
 Digitalis purpurea (purple fox glove):Digitalis purpurea (purple fox glove):
 Digitoxin, Gitoxin, GitalinDigitoxin, Gitoxin, Gitalin
 Strophanthus Kombe:Strophanthus Kombe: StrophanthinStrophanthin
 Strophanthus gratus:Strophanthus gratus: OuabainOuabain
 Chinese toad skin’s glands:Chinese toad skin’s glands: BufadienolidesBufadienolides

13. Cardiac Glycosides are called as cardiotonic agentsCardiac Glycosides are called as cardiotonic agents
as they increase the mechanical efficiency of heart asas they increase the mechanical efficiency of heart as
a pumpa pump
 Efficiency Of Heart: Work DoneEfficiency Of Heart: Work Done
Oxygen consumedOxygen consumed
 Epinephrine increases the work done alongwith oxygenEpinephrine increases the work done alongwith oxygen
consumption so not labeled as cardiotonicconsumption so not labeled as cardiotonic
 Cardiac GlycosidesCardiac Glycosides increase the mechanical efficiency of heart byincrease the mechanical efficiency of heart by
their positive ionotropic effect. There is no increase in oxygentheir positive ionotropic effect. There is no increase in oxygen
consumptionconsumption

14. ChemistryChemistry
 The prototype of cardiac glycosides (cardenolides) is DigoxinThe prototype of cardiac glycosides (cardenolides) is Digoxin
– the most commonly used.– the most commonly used.
 Chemically cardiac glycosides have a steroid nucleus linked toChemically cardiac glycosides have a steroid nucleus linked to
a lactone ring at 17 position& a series of sugars at carbon 3 ofa 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 pHBecause they lack an ionizable group their solubility is not pH
dependedependent.nt.

15. Chemistry of cardiac glycosidesChemistry of cardiac glycosides::

16. 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 theOnly 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

17. 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

20. Mode of Action of cardiac glycosidesMode of Action of cardiac glycosides
Cardiac glycosides inhibit Na+/K+ ATPase (Sodium pump), theCardiac 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 theB. 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 modifyC. 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/EATPase in CNS & GIT--- A/E

21. A:A: Inhibition of Na+/K+ ATPase in heart produces positiveInhibition of Na+/K+ ATPase in heart produces positive
inotropic effect, byinotropic effect, by ↑↑Calcium ions in vicinity of contractileCalcium 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 ini. Inhibition of Na+/K+ ATPase results in ↑↑ in intracellular sodiumin 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 importantSo a small but physiologically important ↑in the free↑in the free Ca++ is available forCa++ 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.

24. TheThe↑↑ in contractility results in reversal of the compensatoryin contractility results in reversal of the compensatory
responses to heart failure:responses to heart failure:
 ↑↑ ventricular ejection….ventricular ejection…. ↓↓ end diastolic & end systolicend diastolic & end systolic
cardiac size.cardiac size.
 ↑↑ CO &CO & ↑↑ renal perfusionrenal perfusion
 The above effects lead to aThe above effects lead to a ↓↓ in sympathetic & renalin 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 Aldosteronno retention of sodium & water through Aldosteron
 TheThe↓↓ in sympathetic tone is beneficial….in sympathetic tone is beneficial…. ↓↓ HR, preload & afterloadHR, preload & afterload
improve the efficiency of heart.improve the efficiency of heart.

26. Pharmacological EffectsPharmacological Effects
A.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 effectsElectrical effects may be: Direct Electrical effects
Autonomic effectsAutonomic effects

27. Autonomic effectsAutonomic effects ::
a)a) At lower doses due to Parasympathomimetic Activity:At lower doses due to Parasympathomimetic Activity:
produceproduce Negative Chronotropic EffectNegative Chronotropic Effect byby::
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 toAt higher dose due to  sympathetic activitysympathetic activity ---- sensitization---- sensitization
of myocardium ----of myocardium ----  toxic effects of digitalis.toxic effects of digitalis.

28. Direct Electrical Cardiac EffectsDirect 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 nodein RP of AV node

29. 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

32. Effects of Digoxin on electrical properties of cardiac tissuesEffects of Digoxin on electrical properties of cardiac tissues
Tissue or VariableTissue or Variable Effects at therapeuticEffects 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, ventricularPurkinje system, ventricular
musclemuscle
SlightSlight ↓ RP↓ RP Extrasystoles, tachycardia,Extrasystoles, tachycardia,
fibrillationfibrillation
ElectrocardiogramElectrocardiogram ↑↑ PR interval , ↓ QTPR interval , ↓ QT
intervalinterval
Tachycardia, fibrillation,Tachycardia, fibrillation,
arrest at extremely higharrest at extremely high
dosagedosage
RP = Refractory periodRP = Refractory period

33. 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 toThey inhibit each other’s binding to Na+/K+ ATPase— soNa+/K+ ATPase— so
 HyperkalemiaHyperkalemia ↓ the enzyme inhibiting action of cardiac glycosides.↓ the enzyme inhibiting action of cardiac glycosides.
 Hypokalemia facilitatesHypokalemia facilitates enzyme inhibiting action --- ↑ toxicity.enzyme inhibiting action --- ↑ toxicity.
ii. Hyperkalemiaii. Hyperkalemia ↓ the abnormal automaticity --- ↓ toxicity.↓ the abnormal automaticity --- ↓ toxicity.

34. Calcium:Calcium: It facilitates the toxic actions of cardiac glycosides---It facilitates the toxic actions of cardiac glycosides---
 ByBy ↑ overloading of I/C calcium stores--- ↑ abnormal↑ overloading of I/C calcium stores--- ↑ abnormal
automaticity.automaticity.
 So moderatelySo 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

35. 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 choiceChronic 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.

36. ii.ii. Atrial ArrhythmiasAtrial Arrhythmias::
 Atrial Fibrillation & Flutter: To decrease ventricular rateAtrial Fibrillation & Flutter: To decrease ventricular rate because itbecause 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.

37. 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 mayChanges in color perception ; chromotopsia– blindness for green color may
occuroccur
Rarely Gynaecomastia in males.Rarely Gynaecomastia in males.

38. 3.3. Cardiac A/E:Cardiac A/E: Arrhythmias:Arrhythmias:
• AV Junctional RhythmAV Junctional Rhythm
• Ectopic BeatsEctopic Beats
• Bigeminal RhythmBigeminal Rhythm
• Second Degree AV BlockSecond Degree AV Block
• Ventricular TachycardiaVentricular Tachycardia
• Ventricular Fibrillation.Ventricular Fibrillation.

39. Drug Interactions:Drug Interactions:
 Thiazides/ Loop diuretics , corticoids --- Hypokalemia-----Thiazides/ Loop diuretics , corticoids --- Hypokalemia----- ↑↑
toxicitytoxicity
 Calcium: Hypercalcemia--Calcium: Hypercalcemia-- ↑ Digoxin toxicity↑ Digoxin toxicity
 QuinidineQuinidine ↑ toxicity due to ↓renal clearance &↑ toxicity due to ↓renal clearance &
displacement from PPB,.displacement from PPB,.
 Agents releasing catecholamines , sensitize the myocardium toAgents releasing catecholamines , sensitize the myocardium to
digitalis arrhythmias.digitalis arrhythmias.

40.  Broad spectrum Antibiotics; alter GIT flora ---Broad spectrum Antibiotics; alter GIT flora --- ↑↑
bioavailability as bacterial metabolism ofbioavailability as bacterial metabolism of Digoxin is reducedDigoxin is reduced
 Cholestyramine decreases absorption ofCholestyramine decreases absorption of DigoxinDigoxin
 Propranolol, Verapamil, Diltiazem & DisopyramidePropranolol, Verapamil, Diltiazem & Disopyramide
depress AV conduction ,oppose inotropic effect.depress AV conduction ,oppose inotropic effect.

42. 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 HypokalaemiaTreatment 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.

43.  Treatment of Arrhythmias –Treatment of Arrhythmias –
 Phenytoin, Lignocaine (Drug of choice as they facilitate AV conductionPhenytoin, Lignocaine (Drug of choice as they facilitate AV conduction
,depressed by Digoxin),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 ofCholestyramine : Prevents further absorption of unabsorbed Digoxin.unabsorbed Digoxin.

44. In severe toxicity:In severe toxicity:
 The serum Potassium is already elevated at time of diagnosis (due to loss of KThe 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 ofInsertion of temporary cardiac pace maker cathetertemporary cardiac pace maker catheter
 Administration of Antibodies to Digoxin (Digoxin Immune fab ) which may beAdministration of Antibodies to Digoxin (Digoxin Immune fab ) which may be
life saving .life saving .
 CardioversionCardioversion only if there isonly if there is ventricular fibrillationventricular fibrillation ; otherwise Digoxin; otherwise Digoxin
induced arrhythmia are made worse by cardioversioninduced arrhythmia are made worse by cardioversion

45. 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 & smoothThey 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 PDE33 -------- cAMP ----cAMP ----  CaCa++++
influxinflux ------ 
contraction of cardiac muscle,contraction of cardiac muscle,
May alsoMay also  CaCa++++
release from SR.release from SR.
Effects on B.V:Effects on B.V: Produce vasodilatationProduce vasodilatation.. Inhibition of PDEInhibition of PDE33 -------- cGMP ---- relaxation ofcGMP ---- relaxation of
SM.--- reduce preload & afterloadSM.--- reduce preload & afterload

46.  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 , vomiting ,arrhythmias: Nausea , vomiting ,arrhythmias
,thrombocytopenia, change in liver enzymes,,thrombocytopenia, change in liver enzymes,
 Milrinone:Milrinone: arrhythmiasarrhythmias
Less likely to produce thrombocytopenia & liver toxicityLess likely to produce thrombocytopenia & liver toxicity

47. 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
DobutamineDobutamine 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

48. DopamineDopamine ---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 otherboth can produce arrhythmia, additive effect with other
sympatomimeticssympatomimetics

49. 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.

50. 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 ↑ PGBradykinin produces vasodilation directly as well as through ↑ PG
synthesis.synthesis.

51.  So there is vasodilatation due toSo there is vasodilatation due to ↓↓ Angiotensin II & ↑Angiotensin II & ↑
bradykininbradykinin  ↓↓ PVRPVR  Preload & after load.Preload & after load.
 Due toDue to ↓↓ Angiotensin II, the release of aldosetrone &Angiotensin II, the release of aldosetrone &
consequent retention of sodium & water is alsoconsequent retention of sodium & water is also ↓ ,↓ ,
 So ↓ blood volume also contributes toSo ↓ blood volume also contributes to Preload & after load.Preload & after load.
 ↓↓ remodeling of Heart & BV.remodeling of Heart & BV.

52. 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 inUseful in asymptomaticasymptomatic to those into those in severe heart failuresevere heart failure..
By ↓By ↓ Preload & after load (Preload & after load (↓↓ PVR ,PVR , ↓↓ salt retention ) .salt retention ) .
 ↓↓ sympathetic activity due tosympathetic activity due to ↓↓ Ang II , through inhibition ofAng 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 onsetSlow 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

55. DiureticsDiuretics
Aldosterone Antagonists:Aldosterone Antagonists: Spironolactone , EplerenoneSpironolactone , 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.
..

56. 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 toAs they are direct receptor antagonists to Aldosterone,Aldosterone, theythey
prevent salt & water retention , myocardial hypertrophy &prevent salt & water retention , myocardial hypertrophy &
Hypokalemia.Hypokalemia.
 Monitor serum KMonitor serum K+.+.
 ReservedforthemostadvancedcasesReservedforthemostadvancedcases
 Spironolactone & Eleprenone also reduce mortalitySpironolactone & Eleprenone also reduce mortality

57. 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 combinedIn CHF resistance may develop to Loop Diuretic so combined
with Thiazides Bendrofluazide, Polythiazide, Metolazone orwith Thiazides Bendrofluazide, Polythiazide, Metolazone or
Spironolactone.Spironolactone.

58. 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 alsoLong term use of Hydralazine & Isosorbide dinitrate also 
damaging remodeling of the heart.damaging remodeling of the heart.

59. Selective Arteriolar dilator:Selective Arteriolar dilator: HydralazineHydralazine
• PrimarilyPrimarily  afterload & relieve fatigue due to low COafterload & relieve fatigue due to low CO
Selective Venodilator:Selective Venodilator: Isosorbide dinitrateIsosorbide dinitrate
 PrimarilyPrimarily  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) : NesiritideNesiritide
 Competitive inhibitor of endothelin:Competitive inhibitor of endothelin: BosentanBosentan

60. Synthetic Brain Natriuretic Peptide (BNP) :Synthetic Brain Natriuretic Peptide (BNP) : NesiritideNesiritide
Prepared 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& tezosentan
Given 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 hypertension
A/E:A/E: Teratogenic , hepatotoxicTeratogenic , hepatotoxic

61. Beta Adrenoceptor blockers:Beta Adrenoceptor blockers: Carvedilol , Bisoprolol,Carvedilol , Bisoprolol,
Metoprolol.Metoprolol.
TheyThey ↓ 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 ofAttenuation 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.

65. 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_ withAcute 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.

66. Drug Therapy in Myocardial InfarctionDrug Therapy in Myocardial Infarction
Drug 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

67. 7.7. Best treatment isBest treatment is emergency revasculizationemergency revasculization using:using:
 Coronary angioplasty & a stentCoronary angioplasty & a stent
 Thrombolytic agents like streptokinase .Thrombolytic agents like streptokinase .
8. Prevention of thrombus extension, embolism, venous8. Prevention of thrombus extension, embolism, venous
thrombosis --- Anti-coagulants like heparin.thrombosis --- Anti-coagulants like heparin.
9. Prevention of remodeling & subsequent CHF—ACE9. Prevention of remodeling & subsequent CHF—ACE
inhibitorsinhibitors
10. Prevention of future attacks10. Prevention of future attacks
a)a) Anti-platelet drugsAnti-platelet drugs
b)b) ββ-Blockers-Blockers
c)c) Control of hyperlipidaemiaControl of hyperlipidaemia

68. Subsets in acute MISubsets in acute MI TherapyTherapy
HypovolemiaHypovolemia Volume replacementVolume 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