Lec.8 PHARMACOLOGY College of DentistryDr. Zainab Ghalib Al-Jassim Baghdad University

Management of Heart Failure

Heart failure   (HF), often referred to as congestive heart failure (CHF),

occurs when the heart is unable to pump sufficiently to maintain blood

flow to meet the body's needs.  

Signs and symptoms commonly include shortness of breath, excessive

tiredness, and leg swelling. The shortness of breath is usually worse

with exercise, while lying down, and may wake the person at night. A

limited ability to exercise is also a common feature.

Common causes of heart failure include coronary artery

disease including a previous myocardial infarction (heart attack), high

blood pressure, atrial fibrillation, valvular heart disease, excess alcohol

use, infection, and cardiomyopathy of an unknown cause. These cause

heart failure by changing either the structure or the functioning of the

heart.

Classification: there are two types of classifications either to Systolic

and Diastolic heart failure or to Left-sided and right-sided heart failure.

First classification→

I) Systolic (or squeezing) heart failure

• It means decreased pumping function of the heart.

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• Systolic heart failure typically affects the left side of the heart. This

is the side that pumps blood to the body.

II) Diastolic (or relaxation) heart failure

• Is a decline in performance of one (usually the left) or both

ventricles during diastole. Diastole is the cardiac cycle phase

during which the heart is relaxing and filling with incoming blood.

• Involves a thickened and stiff heart muscle.

• As a result, the heart does not fill with blood properly.

Second classification→

• Left-sided heart failure: fluid built up in the lung.

• Right-sided heart failure: fluid built up in the body (feet, leg,

abdomen…)

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Compensatory Mechanisms of heart failure

Renin-angiotensin-aldosterone system

Sympathetic nervous system

Enlargement of the muscular walls of the ventricles (ventricular

hypertrophy).

Diagnosis

A Key Indicator for Diagnosing Heart Failure is Ejection Fraction

(EF)

Ejection Fraction (EF) is the percentage of blood that is pumped out of

your heart during each beat.

• Medical history

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• Physical examination

• Tests

– Chest X-ray

– Blood tests

– Electrical tracing of heart (Electrocardiogram or “ECG”)

– Ultrasound of heart (Echocardiogram or “Echo”)

– X-ray of the inside of blood vessels (Angiogram)

Treatment goal

The goals of treatment for people with heart failure are the prolongation

of life, the prevention of acute decompensation and the reduction of

symptoms, allowing for greater activity.

TREATMENT

1- Angiotensin-converting enzyme inhibitors (ACE-I) or Angiotensin

receptor blockers (ARBS)

2-Beta-blocker (BB)

3-Vasodilators

4-Digitalis (digoxin)

5-Diuretics

1-   Angiotensin-converting enzyme inhibitors   (ACE-I) or   angiotensin

receptor blockers   (ARBs) : First-line therapy for people with heart

failure due to relaxation of blood vessels that reduces both preload and

afterload on the heart.

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2-Beta-blocker: also form part of the first line of treatment. They reduces

the action of catecholamines and slows the heart rate. Bisoprolol,

carvedilol, and metoprolol have been shown to reduce mortality rate.

3-Vasodilators: In people who are intolerant of ACE-I and ARBs or who

have significant kidney dysfunction, the use of combined hydralazine and

a long-acting nitrate, such as isosorbide dinitrate, are an effective

alternative. This regimen has been shown to reduce mortality in people

with moderate heart failure.

4-Digitalis (digoxin): Second-line drug, It is used to increase cardiac

contractility (it is a positive inotrope).

5-Diuretics have been a mainstay of therapy for treatment of fluid

accumulation, and include diuretics classes such as loop

diuretics, thiazide-like diuretic, and potassium-sparing diuretic. They

filter sodium and excess fluid from the blood to reduce the heart’s

workload.

Digitalis

Digitalis is the genus name for the family of plants that provide most of

the medically useful cardiac glycosides, eg, digoxin.  It is used to increase

cardiac contractility (it is a positive inotrope) and as an antiarrhythmic

agent to control the heart rate, particularly in the irregular (and often

fast) atrial fibrillation. Digitalis is hence often prescribed for patients in

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atrial fibrillation, especially if they have been diagnosed with congestive

heart failure.

Mechanism of action

Digitalis works by inhibiting sodium-potassium ATPase. This results in

an increased intracellular concentration of sodium ions and thus a

decreased concentration gradient across the cell membrane. This increase

in intracellular sodium causes the Na/Ca exchanger to reverse potential,

i.e., transition from pumping sodium into the cell in exchange for

pumping calcium out of the cell, to pumping sodium out of the cell in

exchange for pumping calcium into the cell. This leads to an increase in

cytoplasmic calcium concentration, which improves cardiac contractility.

Uses

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Its narrow therapeutic window, high degree of toxicity, and the failure of

multiple trials to show a mortality benefit have reduced its role in clinical

practice. It is now used in only a small number of people with refractory

symptoms, who are in atrial fibrillation and/or who have chronic low

blood pressure.

Toxicity

Digitalis toxicity (Digitalis intoxication) results from an overdose of

digitalis and causes nausea, vomiting and diarrhea, as well as sometimes

resulting in xanthopsia (jaundiced or yellow vision) and the appearance of

blurred outlines (halos), drooling, abnormal heart rate, cardiac

arrhythmias, weakness, collapse, dilated pupils, tremors, seizures, and

even death.

NOTE: the calcium-blocking drugs appear to have no role in the

treatment of patients with heart failure. Their depressant effects on the

heart may worsen heart failure.

MANAGEMENT OF ARRHYTHMIASCardiac arrhythmia, or irregular heartbeat, is a group of conditions in

which the heartbeat is irregular, too fast, or too slow. A heartbeat that is

too fast - above 100 beats per minute in adults - is called tachycardia and

a heartbeat that is too slow - below 60 beats per minute - is

called bradycardia.

Arrhythmias are due to problems with the electrical conduction system of

the heart. 

Symptoms

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Many arrhythmias have no symptoms. When symptoms are present these

may include palpitations or feeling a pause between heartbeats,

lightheadedness, passing out, shortness of breath, or chest pain. While

most arrhythmias are not serious some predispose a person to

complications such as stroke or heart failure. Others may result in cardiac

arrest.

Types

There are four main types of arrhythmias: 

1. Extra beats (include premature atrial contractions and 

premature ventricular contractions). 

2. Supraventricular tachycardias (SVT) (include atrial

fibrillation, atrial flutter, and paroxysmal supraventricular

tachycardia). 

3. Ventricular arrhythmias (include ventricular fibrillation and

ventricular tachycardia)  

4. Bradyarrhythmias .

Diagnosis

• ECG

• 24h Holter monitor

• Echocardiogram

• Stress test

ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM

The electrical impulse that triggers a normal cardiac contraction

originates at regular intervals in the Sinoatrial (SA) node, usually at a

frequency of 60-100 beats per minute. This impulse spreads rapidly

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through the atria and enters the Atrioventricular (AV) node, which is

normally the only conduction pathway between the atria and ventricles.

The impulse then propagates over the His-Purkinje system and invades all

parts of the ventricles.

Arrhythmias consist of cardiac depolarizations that deviate from the

above description in one or more aspects.ie, there is an abnormality in

the site of origin of the impulse, its rate or regularity, or its conduction.

ECG Waveforms

Each portion of a heartbeat produces a different deflection on the ECG.

On a normal ECG, there are typically up to five visible waveforms:

The P Wave → indicates atrial depolarisation.

The Q Wave → represents septal depolarisation.

The R Wave → represents early ventricular depolarisation.

The S Wave → represents the late ventricular depolarisation.

The T Wave → represents repolarisation of the ventricles.

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Ionic Basis of Membrane Electrical Activity

The transmembrane potential of cardiac cells is determined by the

concentrations of several ions chiefly sodium (Na+), potassium (K+),

calcium (Ca2+), and chloride (Cl-) on either side of the membrane and

the permeability of the membrane to each ion. Ions move across cell

membranes in response to their gradients only at specific times during the

cardiac cycle when these ion channels are open. The movements of the

ions produce currents that form the basis of the cardiac action potential.

Action potential

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An individual cardiomyocyte contracts when calcium ions enter the cell.

Each heartbeat ions enter and exit the cell through ion channels in the cell

membrane.

This   action potential   entails a number of phases;

• Phase 4 , (resting phase) the membrane potential is at -90mV

• Phase 0 sodium channels open and sodium influx (depolarizing).

• Phase 1 , potassium flows from the cell (efflux) which increases the

membrane potential restores to 0 mV

• Phase 2 , (plateau phase) potassium efflux and calcium influx.

• Phase 3 , the potassium efflux exceeds the calcium influx. The

membrane potential decreases to -90mV (repolarization).

As adjacent cardiomyocytes depolarize, a domino effect is set in motion:

the depolarization wave. This depolarization wave is registered on the

ECG.

SPECIFIC ANTIARRHYTHMIC AGENTS

The most widely used scheme for the classification of antiarrhythmic

drug actions recognizes four classes:

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1. Class 1 action is sodium channel blockade. Subclasses of this action

reflect effects on the action potential duration (APD) and the kinetics of

sodium channel blockade. Class1 drugs divided in to subclass 1A,

subclass 1B and subclass 1C.

2.Class 2 action is sympatholytic. Drugs with this action reduce β-

adrenergic activity in the heart.

3. Class 3 action is manifest by prolongation of the APD. Most drugs

with this action block the rapid component of the delayed rectifier

potassium current.

4. Class 4 action is blockade of the cardiac calcium current. This

action slows conduction in regions where the action potential is calcium

dependent, eg, the sinoatrial and atrioventricular nodes.

***A given drug may have multiple classes of action as indicated by its

membrane and electrocardiographic (ECG) effects. For example,

amiodarone shares all four classes of action. Drugs are usually

discussed according to the predominant class of action. Certain

antiarrhythmic agents, eg, adenosine and magnesium, do not fit readily

into this scheme and are described separately.

Class 1 : SODIUM CHANNEL-BLOCKING DRUGS

Subclass 1A Procainamide, Quinidine, Disopyramide.

Mechanism of action

Moderate Na+ channel blockade, also blocks K+ channels

Quinidine has moderate anticholinergic effects, which can cause

increase AV conduction velocity, and α-adrenergic blocking

effects, which can cause hypotention.

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Disopyramide also has marked anticholinergic effects.

Therapeutic uses Tachycardia

Quinidine rarely used because of its side effects

Side effects: QT interval prolongation and induction of torsade de pointes

arrhythmia, and Hypotention.

Procainamide also can cause lupus like syndrome (arthritis, pleuritis,

and pericarditis).

Quinidine can also cause tinnitus, hemolytic anemia, thrombocytopenia,

and atropine-like effects: urinary retention, dry mouth, blurred vision,

constipation, and worsening of preexisting glaucoma.

Disopyramide can cause atropine-like effects: urinary retention, dry

mouth, blurred vision, constipation, and worsening of preexisting

glaucoma.

Subclass 1B Lidocaine, Mexiletine

Mechanism of action: Mild Na+ channel blockade

Therapeutic uses Acute ventricular arrhythmia, Local anesthetic.

Side effects

-CNS: paresthesias, tremor, nausea, lightheadedness, hearing

disturbances, slurred speech, and convulsions

-In large doses, lidocaine may cause hypotension partly by depressing

myocardial contractility.

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Subclass 1C Flecainide, Propafenone, Moricizine

Mechanism of action: Marked Na+ channel blockade

Therapeutic uses: Supraventricular arrhythmias.

Side effects: Proarrhythmic effects

CLASS 2: BETA-ADRENOCEPTOR-BLOCKING DRUGS

-The antiarrhythmic effect of beta-blockers is a result of their direct

cardiac electrophysiological action such as reduced heart rate, decreased

spontaneous firing of ectopic pacemakers, and slowed conduction.

-Esmolol is a short-acting β blocker used primarily as antiarrhythmic

drug for acute arrhythmias.

-Sotalol is a nonselective β-blocking drug that prolongs the action

potential (class 3 action).

CLASS 3: DRUGS THAT PROLONG ACTION POTENTIAL

Amiodarone, Sotalol, Dofetilide, Ibutilide

Mechanism of action: K+ channel blockers prolonging repolarization.

AMIODARONE Also exerts actions that fall into each of the other three

classes : Na+ channel blocker (class I), β-blocker (class II), Ca+ channel

blocker (class IV). Also a vasodilator (secondary to α-blockade and Ca+

channel blockade) and a negative inotropic agent (secondary to β-

blockade and Ca+ channel blockade).

SOTALOL also has a non-selective β-blockade >>>> (class II+III).

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Therapeutic uses: Ventricular arrhythmias and Atrial fibrillation or

flutter.

Side effects: QT interval prolongation, and induction of torsade de

pointes arrhythmia.

AMIODARONE can result in hypothyroidism or hyperthyroidism (due

to its iodine moiety) and it can accumulates in many tissues, including the

heart, lung, liver, and skin, and is concentrated in tears, causing

pulmonary toxicity, fatal pulmonary fibrosis, abnormal liver function

tests, hepatitis, photodermatitis , gray-blue skin discoloration and rarely,

an optic neuritis may progress to blindness.

CLASS 4: CALCIUM CHANNEL-BLOCKING DRUGS

Verapamil and Diltiazem have antiarrhythmic effects.

Therapeutic Use Supraventricular tachycardia is the major arrhythmia

indication for verapamil and Diltiazem.

MISCELLANEOUS ANTIARRHYTHMIC AGENTS

Certain agents used for the treatment of arrhythmias do not fit the

conventional class 1-4 organization. These include digitalis, adenosine,

magnesium, and potassium.

ADENOSINE

Adenosine is a nucleoside that occurs naturally throughout the body. It

stimulates purinergic receptors, which result in ↓ cAMP and ↑outward K+

current → membrane hyperpolarization

Uses: supraventricular tachyarrhythmias.

MAGNESIUM

Magnesium infusion has been found to have antiarrhythmic effects.

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Magnesium therapy appears to be indicated in patients with digitalis-

induced arrhythmias, if hypomagnesemia is present.

POTASSIUM

The effects of increasing serum K+ can be depolarizing action and

Membrane stabilizing action.

**Hypokalemia results in an increased risk of depolarizations, and

ectopic pacemaker activity, especially in the presence of digitalis;

**Hyperkalemia depresses ectopic pacemakers and slows conduction.

Because both insufficient and excess potassium are potentially

arrhythmogenic, potassium therapy is directed toward normalizing

potassium gradients and pools in the body.

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