pathophysiology of congestive heart failure

PATHOPHYSIOLOGY OF CONGESTIVE HEART FAILURE Decreased force of contraction Positive Inotropic Drugs. Low Cardiac Output Renal blood flow Decreased Carotid Sinus firing Decreased Activate Renin-Angiotensin Activate sympathetic system Aldosterone system Increase sympathetic discharge. ACEIs ARB Aldosterone AT-II Salt & Water Vasoconstriction Increased Heart rate Retention. Volume expansion Venous Arterial Vasoconstriction Vasoconstriction Increased Preload Increased Preload Increased Afterload Diuretics Venodilators Arterial vasodilators Classification of C.H.F according to Symtomatology

Class I: - Symptoms (fatigue and palpitaton) occur with greater than ordinary exercise.

Class II: - Symptoms occur on ordinary exercise. Class III: - Symptoms occur at minimal activity. Class IV: - Symptoms occur even at rest.

Management of Ambulatory (non-hospitalized) Heart failure

Class I: - Diuretics. Class II: - Angiotensin-converting enzyme inhibitors (ACEIs) or Angiotensin

receptor blockers (ARBs). Class III: - Diuretics + ACEIs or ARBs. Class IV: - Diuretics + ACEIs or ARBs + Digoxin.

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v In Patients intolerable to ACEIs, use Hydralazine or Nitrates.

Management of Hospitalized patients (Acute Heart failure or refractory H.F) Parenteral drugs:

1. Diuretics: - Loop diuretics. 2. Vasodilators: - Sodium nitroprusside. 3. Sympathomimetics: - Dobutamine, Dopamine. 4. Phosphodiesterase inhibitors: - Inamrinone, Amrinone.

Diuretic drugs in Heart failure Reduce extracellular fluid volume and ventricular filling pressure (Preload).

Therefore, they are effective in controlling congestive symptoms (dyspnea, edema) and improving exercise capacity.

Patients should be advised to limit dietary intake of Na+ to 2-3 grams/day.

1- Thiazide diuretics: Useful for therapy of mild Heart failure. 2- Loop diuretics: Useful for therapy of moderate and severe Heart failure. Dose: - 40mg Frusemide given once daily. 3- Potassium sparing diuretics (Aldosterone antagonists): Not effective as diuretics when used alone. Combined with Potassium loosing diuretics. Beneficial effects: 1) Useful in limiting renal K+ and Mg++ loss induced by other diuretics. 2) Augment the response to other classes. 3) Low dose of Spironolactone improves survival in advanced Heart failure.

Causes of Diuretic resistance in Heart failure:

Non-compliance and excess dietary Na+ intake. Decreased renal perfusion and G.F.R due to:

i) Volume depletion by diuretics. ii) Decline in cardiac output due to worsening of heart failure. iii) High dose of ACEI causes decrease in glomerular perfusion pressure.

NSAIDs lead to decreased vasodilator renal prostaglandins. Impaired diuretic absorption due to gut wall edema and reduced splanchnic blood

flow in C.H.F.


Vasodilator drugs used in C.H.F

I- Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor blockers (ARBs).

II- Organic nitrates (Isosorbide dinitrate, Nitroglycerine). III- Hydralazine.

I- ACEIs in C.H.F

1- Arteriolar dilatation leading to decreased afterload and improve Cardiac output

resulting in decreased fatigue. 2- Decreased renovascular resistance (decreases renal vasoconstriction of AT-II)

resulting in increased renal blood flow. 3- Decreases Aldosterone secretion.

Increased Renal blood flow & Decreased Aldosterone secretion Natriuresis

4- Venodilatation resulting in decreased preload. Natriuresis & Preload filling pressures improve pulmonary & venous congestion

5- Reversal of ventricular remodeling through:

- Decreased preload and afterload. - Preventing the trophic effects of AT-II on myocytes. - Attenuating Aldosterone induced cardiac fibrosis.

II- Organic Nitrates

Venodilators that produce decreased preload resulting in decreased venous and

pulmonary congestion thereby relieving edema and dyspnea.

III- Hydralazine

Arterial vasodilator leading to decreased afterload and increased cardiac output thereby decreasing fatigue.

Effective in increasing renal blood flow. Most effective when combined with organic nitrates therefore useful in patients

who can not tolerate ACEIs.


CARDIAC GLYCOSIDES (Digitalis)

All cardiac glycosides contain a steroid nucleus combined with unsaturated lactone ring and a series of sugars (glycosidic residues).

Digoxin and Digitoxin are active orally. Molecular mechanism of action of Digitalis:

1. Digitalis inhibits membrane Na+/K+ ATPase responsible for the Na+ pump. 2. Inhibition of this enzyme increases intracellular Na+ and consequently increases

free intracellular Ca++ through increasing Na+/Ca++ exchange mechanism. Digitalis also facilitates Ca++ entry through the voltage gated Ca++ channels.

3. Increased intracellular Ca++ triggers Ca++ release from the sarcoplasmic reticulum.

4. Increased intracellular Ca++ facilitates excitation-contraction coupling. Ca++ Ca++ Na+ Na+ K+ 1) Digitalis inhibits Na+/K+ ATPase Ca++ Ca++ Na+ Na+ K+ Ca++ stores in 2) Increased intracellular Na+ Sarcoplasmic Reticulum 3) Increased Na+ leads to increased Ca++ influx resulting in increased Increased free Ca++ Ca++ release from S.R producing Contraction. 4) Excitation-contraction of Myofibrils Pharmacological actions of Cardiac glycosides: Digitalis induces mechanical and electrical effects that occur simultaneously: I- Mechanical effects: - Positive inotropic effect:

The main action of Digitalis is to increase the force of contraction of the heart in patients with heart failure.

Increased force of contraction increases Cardiac output increasing blood flow to various organs and inhibiting the compensatory sympathetic and renin-angiotensin system activation, all of which result in: i) Decreased heart rate.


ii) Decreased preload (venous pressure) leading to decreased heart size and improvement of cardiac performance and relief of pulmonary congestion. iii) Decreased afterload increasing tissue perfusion. iv) Decreased salt and water retention relieving edema.

II- Electrophysiological effects:

A- At Therapeutic doses: - Digitalis increases vagal tone and decreases sympathetic activity resulting in:

1- Decreased heart rate. 2- Decreased conduction in AV node. 3- Decreased refractory period in atrial and ventricular tissues.

B- At Higher doses: 1- Increases automaticity by direct effect and sympathetic activation. 2- Decreases intracellular K+. v These effects predispose to arrhythmia.

C- At Toxic doses: - Overloading of intracellular Ca++ leads to extra-systoles leading to pulsus bigeminy then trigeminy and produces ventricular tachycardia resulting in ventricular fibrillation.

v The simultaneous increase in automaticity and blockade of AV node conduction and Ca++ overload produces All forms of arrhythmias.

Pharmacokinetics of Digoxin:

Moderately lipophilic, well absorbed from GIT. Bioavailability 70%, plasma protein binding is 30%. Widely distributed in all tissues including CNS and crosses placenta. t1/2 is 36-48 hours. Excreted unchanged by kidneys: Renal impairment prolongs its t1/2.

Therapeutic uses of Cardiac glycosides

1- Congestive heart failure: - Reserved for patients with heart failure who are in atrial fibrillation or remain symptomatic despite therapy with ACEI. v For initiating Digoxin therapy, begin with 0.125 0.25mg/day.

2- Atrial fibrillation with rapid ventricular response: Blocks AV node thereby protects ventricle from rapid atrial rate. Loading dose 1mg over 24 hours i.e. 0.25mg/6hrs I.V. Maintenance dose 0.125mg daily. 3- Atrial flutter: - It may convert Atrial flutter to Atrial fibrillation (shorten

Effective Refractory Period), which may return to normal rhythm on withdrawal of Digoxin.

Contraindications of Digitalis:

1- Partial heart block. 2- Hypertrophic obstructive cardiomyopathy. 3- Acute myocardial infarction. 4- Rheumatic fever.


Drug Interactions of Digoxin

A- Pharmacokinetic interactions: Drugs which decrease plasma level of Digoxin include: I- Cholestyramine, Neomycin, Antacids; these produce decreased absorption. II- Thyroxin; produces increased renal clearance and increased volume of

distribution. Drugs which increase plasma level of Digoxin: I- Erythromycin, Tetracycline, Omeperazole; these increase absorption. II- Quinidine, Amiodarone, Verapamil, Diltiazem and Captopril; these decrease

renal clearance and decrease volume of distribution.

B- Pharmacodynamic interactions: Potassium loosing diuretics decrease serum K+ resulting in increased automaticity

and inhibition of Na+/K+ ATPase leading to toxicity. Sympathomimetics: - Increases automaticity. Beta-adrenoceptor blockers and calcium channel blockers:

1- Decrease SA node and AV node conduction leading to bradycardia and heart block.

2- Decrease force of myocardial conduction; thereby antagonize the positive inotropic effect of cardiac glycosides.

Digitalis Toxicity Digitalis has a low safety margin. Its cardiac toxicity is potentiated by hypokalemia and hypercalcemia.

A- Cardiac toxicity (most frequent side effect): - Digitalis can cause every variety of Arrhythmia:

1- Marked sinus bradycardia. 2- Second and third degree heart block. 3- Atrial tachycardia and Atrial flutter and fibrillation. 4- Ventricular premature beats, ventricular tachycardia and fibrillation.

B- Extra-cardiac toxicity: Psychiatric: - Fatigue, Malaise, Confusion, Dizziness, Abnormal dreams. Visual: - Blurred or Yellow vision. GIT: - Anorexia, Nausea, Vomiting, Abdominal pain.

Treatment of Digitalis toxicity:

1- Stop the drug and the Potassium loosing diuretic. 2- Treatment of Digitalis-induced arrhythmias:

i) Atropine for: - Bradycardia and Second or Third degree heart block. ii) Lidocaine for ventricular arrhythmia. iii) Potassium administration in tachy-arrhythmia (K+ competes with

Digitalis for Na+/K+ ATPase preventing inhibition of the enzyme by Digitalis).

iv) K+ administration is contraindicated in AV block.


Parenteral drugs for hospitalized patients with heart failure

I- Diuretics: I.V administration of a Loop diuretic provides more rapid diuresis. Initial bolus injection of 40mg Frusemide followed by 10mg/hour

infusion. II- Parenteral Vasodilators:

i) Sodium nitroprusside (I.V): Venous vasodilator producing decreased preload leading to decreased

pulmonary and venous congestion resulting in decreased dyspnea and edema.

Arterial vasodilator producing decreased Arterial resistance resulting in increased Cardiac output.

Potent with rapid onset of action 2-4 minutes. ii) Nitroglycerine (I.V):

Rapid and potent venular vasodilator that decreases preload producing decreased pulmonary and venous congestion thereby decreases dyspnea and edema.

High infusion rates producing Arterial vasodilatation leading to decreased afterload and increased Cardiac output.

iii) Parenteral positive inotropic drugs: 1- Dobutamine and Dopamine: Stimulate myocardial contractility. Dopamine has renal vasodilator effect resulting in diuresis. Not active orally. Reserved for management of acute Heart failure or refractoriness to

oral agents. 2- Phosphodiesterase inhibitors (Inamrinone and Milrinone): Selective inhibitors of Phosphodiesterase enzyme resulting in

increased cAMP. Stimulate myocardial contractility. Induce arterial and venous dilatation. Used I.V. for short term support in advanced heart failure. Toxicity: - Nausea, Vomiting, Thrombocytopenia, Liver toxicity. Milrinone is preferred because it reduces risk of thrombocytopenia and

liver toxicity.


pathophysiology of congestive heart failure

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