HEART FAILUREAbnormality of cardiac contraction &/or

relaxation result in common symptoms of shortness of breath and tiredness, so the heart became unable to meet body requirement.

HF classificationAcute & chronicLeft & right sidedSystolic & diastolic

Main causes

I. Coronary artery disease

II. Hypertension

III. Valvular heart disease

IV.Cardiomyopathy

V. Corpulmonale

Factors aggravating heart failure

1. Myocardial ischemia or infarct.2. Dietary sodium excess.3. Arrhythmias.4. Intercurrent illness (eg. infection).5. Conditions associated with increased metabolic demand

(eg. pregnancy, thyrotoxicosis, excessive physical activity).

6. Administration of drug with negative inotropic properties or fluid retaining properties (e. NSAIDs, corticosteroids).

7. Alcohol.

New classification of heart failure

Stage A: Asymptomatic with no heart damage but have risk factors for heart failureStage B: Asymptomatic but have signs of structural

heart damageStage C: Have symptoms and heart damageStage D: End stage disease

Compensatory changes in heart failure

I. Activation of SNS.

II. Activation of RAS.

III. Increased heart rate.

IV. Release of ADH.

V. Release of atrial natriuretic peptide.

VI. Chamber enlargement.

VII.Myocardial hyperatrophy.

Goals of treatment

•To improve symptoms and quality of life.

•To decrease likelihood of disease progression.

•To reduce the risk of death and need for hospitalization.

1. Drugs increasing the strength of the cardiac muscle contraction

• i.e., drugs with positive inotropic action

2. Diuretic agents.

• decrease extracellular fluid volume (decrease preload and congestion - oedema)

• antagonize aldosteron receptors

3. ACE inhibitors (reduce both preload and after load).

4. Other vasodilators (hydralazine)

5. -blockers(carvidolol).

6. Antiarrhythmic agents occasionally are required to normalize cardiac rate and rhythm.

Drugs Classes used in the heart failure treatment

Diuretics

ReduceReduceFluidFluid

VolumeVolume

Vasodilators

DecreaseDecreasePreloadPreload

andandAfterloadAfterload

Inotropes

AugmentAugmentContractilitContractilit

yy

Natriuretic Peptide

DecreaseDecreasePreloadPreload

andandAfter load; After load;

Reduce Reduce Fluid Fluid

VolumeVolume

DecreaseDecreasePreloadPreload

andandAfter load; After load;

Reduce Reduce Fluid Fluid

VolumeVolume

Drugs increasing the strength of cardiac contraction

Drugs with direct positive inotropic effectsIncrease in contractility ↑ CO improve perfusion of

organs

Drugs

1) Cardiac glycosides.

2) Phosphodiesterase inhibitors.

3) Sympathomimetic agents.

4) Calcium sensitizers.

Ion movements during the contraction of cardiac muscle ATPase = adenosine triphosphatase

(according to Lippincott´s Pharmacology, 2006)

Often called digitalis or digitalis glycosidesSource: medicinal plants

Digitalis purpurea and alba (purple and white foxglove) their medical use goes 3000 years ago.

o Chemically similar compounds that can increase the contractility of the heart muscle and are therefore they had been widely used in treating heart failure.

o The drugs have a low therapeutic index.Agents

Digoxin – clinically used Digitoxin Oubain

1.cardiac glycosides

DigoxinEnhances LV function, normalizes baroreceptor-mediated

reflexes and increases cardiac output at rest and during exercise.

Recommended to improve clinical status of patients with heart failure due to LV dysfunction and should be used in

conjunction with diuretics, ACE inhibitors and beta-blockers.Also recommended in patients with heart failure who have

atrial fibrillation.Digoxin initiated and maintained at a dose of 0.25 mg daily.

It cause inhibition of Na/K-ATPas &also caused vagal stimulation.

1. Mechanical effects - increase in cardiac contractility intracellular Na+ increased intracellular Ca2+ content increased release of calcium from sarcoplasmatic reticulum.

2. Direct electrophysiological effects

AP shortening (esp. the plateau phase) – potassium conductance that is caused by increased intracellular calcium.

resting membrane potential is increased - made less negative (due to the Na+, Ca2+) in ↑ doses.

delayed after depolarization (DAD) - Ca2+ from stores - may reach threshold - premature ventricular depolarization or „ectopic beat“.

3. ANS system mediated effects: central stimulation of nervous vagus

decreased SA pacemaker activity.

decreased AV conductanc→ decreased HR .

Pharmacological action

o Oral absorption: 65-80 %, parenteral administration for emergencies

o Wide distribution into the organ/tissues including CNS

o Excretion: 80% of drug – unchanged in the urine – mostly glom. filtration

dose individualisation in renal failure according GF small amount eliminated via active transport – renal tubules and bile –

interactions – importance during renal failure

DigoxinDigitoxin

Half-life36 hours164 hours

Therapeutic plasma concentration

0.5 - 2 ng/mL10 - 25 ng/mL

Toxic plasma concentration 2 ng/mL 35 ng/mL

Daily dose (slow loading or maintenance)

0.125 - 0.5 mg0.05 - 0.2 mg

Rapid digitalizing dose0.5 - 0.75 mg every 8 h for 3 doses

0.2 - 0.4 mg every 12 h for 3 doses

Pharmacokinetics

A comparison of the properties of digoxin and digitoxin

Congestive heart failure In association with atrial fibrillation/flutter (clear indication)

Digoxin reduces hospitalizations and improves symptoms, however, without improving survival (generally poor)

indicated in severe forms of HF in combination with other treatment to improve symptoms of HF and clinical status

Not to be used in diastolic HF and acute MI related HF

Antiarrhythmic indications Supraventricular arrhythmias

AV conduction will help control an excessively high ventricular rate - improving ventricular filling and increasing cardiac output

• Contraindicated in Wolf-Parkinson-White syndrome.

Indications

Cardiac effects a) bradycardia, decreased or blocked AV conduction

b) AV junctional rhythm

c) premature ventricular depolarization, bigeminia rhythm (complex of normal and premature ventricular beats) ventricular fibrillation

o GIT: anorexia, nausea, vomiting (nausea etc. can be among the first warning signs of toxicity .)

o CNS: headache, fatigue, confusion, agitation, blurred vision, alteration of colour perception, and haloes on dark objects.

o Gynecomastia in men upon prolonged use.

Adverse effects

Drugs Quinidine - reduces the renal clearance of digoxin (competition for renal

excretion) and displaces digitalis from tissue protein increases the toxicity of digoxin

Verapamil, amiodaron, spironolacton - displace digoxin from protein increase digoxin by 50-75 % (it may be necessary to reduce dose)

Potassium-depleting diuretics and corticosteroids

Diseases Hypothyroidism, hypoxia, renal failure, and myocarditis are predisposing

factors to digitalis toxicity

Factors predisposing to digitalis toxicity

o Hypokalemia K+ competes with digoxin for Na+/K+-ATPase binding site→

hypokalemia facilitate digoxin binding and Na+/K+-ATPase inhibition, while hyperkalemia has the opposite effects

hypokalemia generally makes the heart more imbalanced and sensitive to proarythmogenic stimuli

SIGNIFICANT RISK patients heavily vomiting, GIT infections with diarrhoea patients receiving diuretics (loop/thiazides), dose effect

PREVENTION co-administration of a potassium-sparing diuretic or supplementation with KCl

o Hypercalcemia – increased Ca loading of cardiomyocytes

o hypernatremia, hypomagnesemia, and alkalosis

Factors predisposing to digitalis toxicity

Drugs interacting with digoxin and other digitalis glycosides

Increased digitalis concentration may occur during

concurrent therapy

Enhanced potential for cardiotoxicity

Decreased levels of blood potassium

AmiodaroneErythromycin

QuinidineTetracyclineVerapamil

CorticosteroidsThiazide diuretics

Loop diuretics

Fab-fragments against digoxin largely increase renal excretion of digoxin (antidote).

KCl administration.

phenytoin may be used to suppress the ventricular arrythmia.

Atropine may be used to antagonize concomitant bradycardia.

Treatment of severe acute intoxication (overdose)

Amrinone and Milrinone

o Phosphodiesterase inhibitors III (heart specific subtype) increase the intracellular concentration of cAMP increase in

intracellular Ca, and therefore cardiac contractility .

o Amrinone given only i.v. mainly for short-term management of acute congestive

heart failure. is associated with reversible thrombocytopenia (milrinone does not

affect platelets).

o Milrinone showed increased mortality and no beneficial effects, amrinone did not reduced the incidence of sudden cardiac death or prolong survival in

patients with CHF.

2.PHOSPHODIESTERASE III Inhibitirs

Dopamine act on alpha , beta & dopaminergic receptors ,while Dobutamine act on B,D &less on alpha receptors

Improves cardiac performance by their positive inotropic effects and vasodilatation (minimum effects on HR by dobutamine)

Increase in intracellular cAMP results in the entry of Ca2+ into the myocardial cells increases, thus enhancing contraction

Dopamine preferred in cases of HF associated with hypotension .

Dobutamine preferred in HF with normal BP.

Diminished effects after long-time infusions and possible worsening upon withdrawal

Ibopamine (pro-drug, - beta1, beta2, D1 and D2 effects, does not increase HR)

3 .BETA1-ADRENERGIC AGONISTS

(according to Lippincott´s Pharmacology, 2006)

Sites of action by -adrenergic agonists on heart muscle

Levosimendan(simdax)

No increase intracellular Ca2+ - in contrast to previous agents.

it increase calcium sensitivity to myocyte by binding to cardiac troponine C so increase myocardial contractility.

Also it have vasodilatory effect mediated by opening of vascular ATP-sensitive K-channel.

No major proarrhythmogenic effects

Indication: i.v. for treatment acute decompositions of CHF., it give 6-12 Mg\kg(loading dose)over 10 min. followed by 0.05-0.2Mg\kg\min. as continuous infusion.

Adverse reactions: hypotension, headache

4 .CALCIUM SENSITIZERS

Angiotensin Converting Enzyme Inhibitors :

they first line in all pt. with chronic HF.They decrease PVR(after load),decrease salt &water

retention by suppress aldosteron(decrease preload),also decrease sym. activity by suppressing

NE release.Decrease remodeling effect on heart.

decrease in the progression of chronic HF.decreased hospitalization.enhanced quality of life.

renin

Angiotensinogen Angiotensin I

Other pathways Angiotensin II

Receptors

AT1 AT2

Vasoconstriction Proliferative Action

VasodilatationAntiproliferative

Action

ACE

ACE InhibitorContraindications

Renal artery stenosis (relative).Hyperkalemia. Renal insufficiency. Arterial hypotension.Cough.Angioedema.

AlternativesHydralazine + ISDN, AT-II inhibitor .

Guidelines to ACE Inhibitor TherapyAll patients with symptomatic heart failure and those in

functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless

contraindicated or not tolerated.

ACE inhibitors should be continued indefinitely.

In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac

output.

B-blocker in CHFB-blockers give protection against catecholamine

myocyte toxicity.we should start slowly& then up titrate gradually

&watching adverse effects.B-blockers add only to existing therapy include ACEI

&diuretic &(in some studies) digoxin & idealy not give for pt. with class 3 &4.

only carvidolol& metaprolol are approved in USA.carvidolol reduce mortality more than metaprolol

DiureticsIndicated in patients with symptoms of heart failure

who have evidence of fluid retention.Enhance response to other drugs in heart failure such

as beta-blockers and ACE inhibitors.Therapy initiated with low doses followed by

increments in dosage until urine output increases and weight decreases by 0.5-1 kg daily.

.decrease venous return(preload)so decrease edema, decrease cardiac size &increase pump function.

The Future of HF Pharmacotherapy Management

1) natriuretic peptides (Nesiritide, ularitide, carperitide).

2) Levosimendan (inotrope/vasodilator).

3) Vasopressin Receptor Antagonists(Tolvaptan)&IV Conivaptan (dual vasopressin blocker).

4) Endothilin-1 receptor antagonists (Tezosentan).

Nesiritide(natrecore)It recombinant DNA from human B-type natriuretic peptide.

It bind to NP-A receptor which activate guanylate cyclase that convert GTP to cGMP which act as 2nd messenger &induce it s

biological action. Advantages

Rapid symptomatic improvementTheoretical antagonism of RAAS activation

Disadvantages Minimal indirect effect in increasing cardiac output

Incompatibilities; cannot be infused through same IV catheter as heparin (no heparin-coated catheters), insulin,

bumetanide, enalaprilat, hydralazine, or furosemide.Associated with clinically significant hypotension .

Associated with increased serum creatinine concentration.

Vasopressin Antagonists Currently in DevelopmentTolvaptan—Oral selective V2-receptor antagonist

Treatment of decompensate heart failureLixivaptan—Oral selective V2-receptor antagonistConivaptan—Intravenous dual V1a/V2-receptor

antagonist

Treatment of euvolemic hyponatremia in hospitalized patients (FDA approved Dec. 30 2005 Vaprisol®)

Receptor

SubtypeSite of Action Activation Effects

V1A

Vascular smooth muscle PlateletsLymphocytes and monocytesHepatocytes

VasoconstrictionPlatelet aggregationCoagulation factor releaseGlycogenolysis

V1BAnterior pituitaryACTH and -endorphin release

V2Renal collecting duct

cellsFree water absorption

AVP-Receptor Subtypes

Arginine Vasopressin (AVP)aka Antidiuretic Hormone

VASCULAR SMOOTH MUSCLE CELL HEART DISTAL TUBULES

V1AV1A V2

• Vasoconstriction

• Coronary Vasoconstriction• Myocyte Hypertrophy

• Water Retention

• Increased after load and wall stress• LV hypertrophy• Ischemia• Increased preload, hyponatremia, edema

Conivaptan Usage in Patients With Heart Failure

Combined V1a/V2-receptor antagonismIn patients with heart failure, IV conivaptan resulted

in1.Significant reductions in PCWP and right atrial

pressure (RAP)2.No change in CI, HR, MAP, PVR, SVR

3.Dose-dependent increase in urine output

Endothilin antagonast (Tezosentan & Bosentan)

They antagonize ET-A & ET-B endothilin receptors so lead to inhibition of vasoconstricted effect caused by

endogenous endothilin. They decrease both systolic and diastolic arterial

pressure. They metabolite by cytochrome P450 system in liver.

Thank you