Congestive heart failure

Congestive heart failure (CHF)

• It is a condition in which the heart is unable to pump sufficient amount of blood to meet the metabolic demands of the body

• It is a syndrome with multiple causes that may involve the

- right ventricle - left ventricle - both ventricles

The ventricular dysfunction may be primarily• Systolic - inadequate force generation to eject blood

normally - ↓ CO EF ↓45% - typical of acute failure especially resulting from

myocardial infarction (MI)• Diastolic - inadequate relaxation to permit normal filling - CO, EF may be normal - result of hypertrophy & stiffening of myocardium - does not respond to +ve ionotrophic drugs

High output failure:• Demands of the body are so great that even ↑↑

CO is insufficient eg. beriberi hyperthyroidism anemia arteriovenus shunts• Respond poorly to +ve ionotrophic drugs• Cause should be treated

↓↓ FC Heart failure ↓↓ CO

↓↓ carotid sinus firing ↓↓ renal perfusion

↑↑ sympathetic ↑↑ renin release ↓↓ GFR discharge ventricular dilatation

AT-1 vasoconstriction ß1 activation ↑ AT-2 ↑ preload Na & ↑ preload ↑ FC ↑ afterload H2O ↑ afterload ↑ HR ↑ aldosterone retention

BACK PRESSURE

pulmonary EDEMA peripheral congestion congestion dyspnea & cyanosis HEPATIC CONGESTION ENLARGED LIVER ANOREXIA

CARDIACREMODELLING

• The therapeutic goal in the management of heart failure is to ↑↑ the cardiac output

Drugs used in heart failure1) Drugs with positive ionotrophic effects a) Cardiac glycosides – digoxin, digitoxin, oubain b) Phosphodiesterase inhibitors –

inamrinone, milrinone c) ß adrenergic agonists – dopamine, dobutamine

2) Drugs without positive ionotrophic effects a) Diuretics – furosemide, hydrochlorthiazide b) ACE inhibitors – enalapril c) ß blockers – carvedilol, bisoprolol, metoprolol d) Vasodilators – hydrallazine, Na nitroprusside

Cardiac glycosides(cardenolides)

Cardiac glycosides • If a sugar molecule is joined together with a non-

sugar molecule by an ether linkage it is called a glycoside

sugar ether non-sugar glycoside link

Digitoxose X steroidal cardiac lactone glycoside

• Pharmacological activity – non-sugar moiety• Pharmacokinetic properties – sugar part

• Digitalis lanata (leaves) – 2 active principles digoxin, digitoxin• Digitalis purpurea (foxglove) - digitoxin

Mechanism of action

• The force of contraction of the cardiac muscle is directly related to the concentration of free cytosolic Ca2+

• Any drug that increases free cytosolic Ca2+ levels

↑↑ force of contraction sensitivity of contractile mechanisms to Ca2+

• Ca2+ initially enter through voltage sensitive L-type of Ca2+ channels

• It triggers the release of larger quantity of Ca2+ from the sarcoplasmic reticulum (SR) by activating SR- Ca2+ release – ryanodine receptor

• The ↑↑ Ca2+ concentration initiates the contractile process

• During restorative process of periodic contractions Ca2+ ions are removed by re-uptake into SR by SR- Ca2+ ATPase

• It is also extruded by a Na+/ Ca2+ pump exchange pump• Intracellular Na+ balance is then restored by

Na+/K+/ATPase pump

• Mechanism of action:

• Digitalis binds to & reversibly inhibits cardiac cell membrane associated Na+/K+/ATPase

• Progressive accumulation of intracellular Na+ and loss of intracellular K+

• ↑↑ intracellular Na+ concentration prompts diversion Na+ ions to the Na+/ Ca2+ exchange mechanisms

• This exchanger normally extrudes Ca2+ in exchange for Na+

• In the presence of ↑↑ intracellular Na+ concentration it extrudes Na+ in exchange for extracellular Ca2+

• There is also an ↑↑ in Ca2+ permeability through voltage sensitive L channels during plateau phase

• Digitalis also inhibits SR- Ca2+ ATPase & reduces reuptake of Ca2+ by SR

• Ultimately ↑↑↑ cytosolic Ca2+

triggers contractile mechanisms of failing heart

↑↑ cardiac output• Higher serum K+ concentration inhibits digitalis

binding to Na+/K+/ATPase - hyperkalemia can ↓ digitalis toxicity - hypokalemia ↑↑ risk of digitalis toxicity Hypercalcemia ↑↑ risk of digitalis Hypomagnesemia induced arrhythmias

Pharmacological actions Cardiovascular system (CVS)

• In normal individuals no significant variation - ↑↑ force of contraction - ↑↑ cardiac output Also ↑↑ peripheral resistance affect ↑↑ venous pressure nullified• Heart rate unchanged

• Contractility In heart failure - ↑↑ force of contraction

↑↑ stroke volume

complete emptying of heart Diastolic size of heart ↓↓

↓↓ O2 consumption for work output i.e ↑↑ work done for ↓↓ O2 consumption & ↓↓ energy Hence, known as cardiotonic drug

Heart rate• It decreases heart rate by - direct Na+/K+/ATPase inhibition - ↓ sympathetic activity - indirect vagal stimulation Conduction velocity• Irrespective of the dose it - ↓↓ conduction velocity - ↑↑ ERP of the AV node & purkinje fibres by - vagal action - extravagal action (Na+/K+/ATPase)• This protects the ventricles from - atrial flutter - atrial fibrillation

• In relatively smaller doses it ↑↑ conduction velocity ↓↓ ERP of atrial muscles• High doses – ↑↑ automaticity contractility ↓↓ ERP of atria & ventricles causing - extrasystoles - pulsus bigeminus - ventricular fibrillation• As the cholinergic innervation is only upto the AV node – vagal

effects of digitalis are more pronounced at - the AV node & atria - than on purkinje system or ventricles

Blood vessels • In normal people it has direct vasoconstrictor effect• In heart failure compensatory sympathetic over activity removed

– ↓↓ in heart rate ↓↓ in peripheral resistance ↓↓ in preload Blood pressure • No prominent effect Coronary circulation• Improvement secondary to ↑↑ in CO & ↓↓ in heart rate Venous system• ↓↓ in venous pressure secondary to improvement in circulation• In CHF ↓↓ venous tone ↑↑ peripheral blood flow

• Extra cardiac effects Kidney• Diuresis occurs due to improvement in renal perfusion

which brings edematous fluid into circulation• It occurs due to – - ↓↓ sympathetic activity - ↓↓ renin angiotensin aldosterone system - ↓↓ aldosterone - ↓↓ Na & H2O retention GIT • Anorexia, nausea, vomiting CNS • Disorientation, hallucinations, visual disturbances

Kinetics • The safety margin of cardiac glycosides is very

narrow• Minor variations in bioavailability

therapeutic failure toxicity

Digoxin • Fairly well absorbed orally (40-60%)• Half life – 38-40 days• Eliminated largely by the kidney Digitoxin • Absorbed rapidly & completely• Half life 6-7 days• Metabolized in the liver• Excreted via bile into the gut• Entero-hepatic circulation is present• Can be used in renal failure

ADRs Cardiac side effects • Bradycardia• Partial or complete heart block• Atrial & ventricular extrasystoles• Pulsus bigeminy (coupled beats)• Ventricular fibrillation• Fatal cardiac arrhythmias• If cardiac arrhythmias develop Ca2+ Mg2+ & K+

states should be corrected

Treatment of digitalis toxicity• Brief cases of bigeminy – - oral K+ supplementation - withdrawal of digoxin• Serious arrhythmias - parenteral K+ - lignocaine• Ventricular fibrillation - (digitalis induced) cardioversion• Ventricular & supraventricular tachycardia - propranolol (if AV block not ++)

• Severe digitalis intoxication (with depressed automaticity) - anti-arrhythmatic drugs fatal - Digiband Fab fragments - digitalis antibodies• Such patients can be saved by administration of

these antibodies• They are extremely useful in reversing severe

intoxication

Extra cardiac ADRs • GIT

- anorexia, nausea, vomiting, diarrhea, abdominal cramps

• CNS

- headache, fatigue, neuralgias, blurred vision, loss of color perception

• Endocrinal - gynaecomastia

Drug interactions:• Loop diuretics• Thiazides ↓↓ K+ levels• Corticosteroids• Ca salts synergistic action• Catecholamines cause• Succinylcholine arrhythmias• Amiodarone• Quinidine displace• Verapamil digitalis from• Tetracyclines protein binding• Erythromycin

E D TN I OH G XA I IN T CC A IE L TD I Y S

Digitalis effects ↓↓ by• Antacids• Sucralfate ↓↓ absorption• Neomycin Enzyme inducers• Phenobarbitone ↑↑ metabolism• Phenytoin • Cholestyramine entero-hepatic circulation• Hyperthyroidism ↑↑ renal clearance

↓↓

Uses • Congestive heart failure• Paroxysmal supra-ventricular tachycardia• Atrial flutter & atrial fibrillation

Phosphodiesterase inhibitors • Amrinone• Milrinone• Levosimendon

Mechanism of action• These drugs inhibit the enzyme

phosphodiesterase isoenzyme III which is specially located in cardiac myocytes & vascular smooth muscle

• They prevent degradation of cAMP

↑↑ cAMP ↑↑ contractility (heart) ↑↑ vasodilatation (blood vessels)

• They also have direct vasodilating effect• They also ↑↑ inward Ca2+ influx during action

potential• In patients of CHF they - ↑↑ CO

- ↓↓ pulmonary wedge pressure - ↓↓ PR

Kinetics • They are administered in loading dose by

intravenous (IV) infusion• Followed by slow maintenance infusions in saline• They are unstable in dextrose• Fluid balance potential problem & drawback

in CHF patients• Toxicities also limit their use

Amrinone • Toxicity - nausea, vomiting• Dose dependent thrombocytopenia• Arrhythmias – ventricular rate ↑↑ in patients of

atrial flutter & atrial fibrillation Milrinone • Safer than amrinone• Arrhythmias ↑↑ incidence• Renal impairment - ↑↑ plasma half life

ß1 adrenergic agonists• ß1 adrenergic stimulation improves cardiac

performance by +ve ionotropic effects• They cause an ↑↑ in intracellular cAMP

activation of protein kinases

phosphorylation of slow Ca channels

↑↑ Ca inflow into myocardial cells

↑↑ force of contraction

ß1 agonists Ca++ ß1 agonist

Ca++

Active protein kinases ATP Inactive protein kinases

myofibrils cAMP PDE Θ

↑↑ force of contraction phosphodiesterase AMP inhibitors

Adenyl cyclase

Dobutamine • It is a derivative of dopamine with selective ionotrophic

effect, negligible chronotropic effect & peripheral vascular effects

• It is a selective ß1 agonist • Given as an infusion, half life is 2 minutes• Dose 5-15 μ mg/kg/minute• It ↑↑ cardiac output ↑↑ urinary output• ↑↑ stroke volume without affecting heart rate, total

peripheral resistance (TPR) or blood pressure (BP) Uses • Acute heart failure with MI• Cardiac surgery

Dopamine • Acts on dopamine & ß1 receptors• Given as intravenous infusion 2-5 μ gm/kg/minute

Diuretics • They are most commonly used in CHF• Mechanism of action They ↓↓ salt & H2O retention

↓↓ ventricular preload ↓↓ in venous pressure

↓↓ edema

↓↓ of cardiac size

Improved efficiency of pump function

Loop diuretics: Bumetanide, Furosemide• They promptly ↓↓ pulmonary edema by rapid diuresis• Though widely used they do not influence the primary

disease process in CHF• Enhanced urinary loss of Na+ & H2O

resultant ↑↑ in urinary excretion of H+ & K+

arrhythmias digitalis toxicity• Mg2+ & Ca2+ loss by loop diuretics further exacerbates

arrhythmias• These drawbacks overcome by using loop diuretics with

aldosterone antagonists

Thiazide diuretics Hydrochlorthiazide Metolazone• Used ↓↓ frequently• In advanced CHF – chronic use of loop

diuretics

resistance Hydrochlorthiazide or sphironolactone Metolazone added to loop diuretics• Mild heart failure- hydrochlorthiazide +

sphironolactone

Sphironolactone • The kidneys perceive ↓↓ CO from the failing

heart & activate the renin angiotensin aldosterone system to

retain Na+ & H2O Sphironolactone being aldosterone antagonist

enhances diuresis by promoting Na+ & H2O excretion & retaining K+

• It prevents myocardial & vascular fibrosis which is responsible for pathological re-modelling of the heart

• Evidence has shown aldosterone receptors on cardiac myocytes

• Studies have shown that low-moderate doses of sphironolactone in patients with severe CHF

↓↓ morbidity & mortality in patients who were also receiving standard therapy (diuretics, ACE inhibitors)

• This shows that aldosterone plays a pathological role in the progression of CHF – other than that of Na+ retention i.e prevents re-modelling

• Low dose sphironolactone – beneficial in CHF

ACE inhibitors:• Presently they are the 1st choice of drugs in CHF

Angiotensin I Θ ACE (angiotensin converting enzyme)

Angiotensin II Θ ACE

Aldosterone secretion ↓↓ salt & H2O retention

• They also prevent breakdown of bradykinin

promotes dilatation ↓↓ in venous return vasodilatation

↓↓ preload ↓↓ afterload

improve cardiac output

• They prolong survival by ↓↓ re-modelling of heart & blood vessels

• They also ↓↓ death rate due to - arrhythmias - myocardial infarction (MI)

- stroke• They also ↓↓ damaging effects of left ventricular

dysfunction in patients of CHF with EF ↓↓ 35%• ACE inhibitors + more beneficial effects + Sphironolactone ↓↓ mortality

ß blockers • Generally ß blockers are contraindicated in CHF as these

patients have a ↓↓ CO

CO = stroke volume (SV) x heart rate (HR)

• An ↑↑ HR would be necessary to maintain an adequate CO in the presence of ↓↓ SV as in CHF

ß blockers

↓↓ heart rate ↓↓ contractility

Acute de-compensation in CHF

• Nevertheless certain ß blockers - carvedelol - bisoprolol - metoprolol - improve ventricular function - prolong survival in these patients• In CHF due to stress circulating levels of nor-adrenaline ↑↑

- peripheral vasoconstriction - down regulation ß1 receptors - up regulation of ß2 receptors

cardiac hypertrophy apoptosis

• This rationale favors the use of a combined non-selective ß & α blocker – carvedilol

• It has ß1, ß2 & α blocking properties (↑↑↑) (↑)• It also - inhibits free radical induced lipid peroxidation - prevents cardiac & vascular smooth muscle

mitogenesis• These actions are independent of α & ß blocking

effects

• Therefore ß blockers (not all) are beneficial in CHF (carvedilol, bisoprolol, metoprolol)

• Mechanisms – - ↓↓ in cardiac remodelling (by ↓↓ mitogenesis) - blunting the adverse effects of higher

circulating levels of catecholamines

Vasodilators • They can be - arteriolar (hydrallazine) - venous (nitroglycerine, nitrates) - mixed (ACE inhibitors)• These drugs ↑↑ cardiac output ↓↓ pulmonary congestion

by ↓↓ preload and/or ↓↓ afterload• They are useful in CHF

as they ↓↓ preload, afterload & also prevent re-modelling of the heart

Choice of vasodilator depends on the S/S of the patient• In CHF patients i) with dyspnoea - venodilators - nitroglycerine (NTG)

- long acting NO3

↓↓ pulmonary congestion ii) with ↓↓ ventricular output - arteriolar dilator – hydrallazine ↑↑ cardiac output iii) in severe CHF where both are present - ACE inhibitors - hydrallazine + long acting NO3 (if ACE contraindicated

or not tolerated)

Nesiritide • It is a recombinant form of HUMAN B TYPE NATRIURETIC PEPTIDE

naturally occurring hormone secreted by the ventricles• Recently introduced for use in acute heart failure• It ↑↑ c GMP in vascular smooth muscle & ↓↓ venous

& arteriolar tone• It also causes natriuresis• It has a short ½ life (18 minutes)• Administered in a bolus dose of 2 mgm/kg followed by a

continuous IV infusion – 0.01-0.03 μg/kg/mt• It is used in patients with acutely de-compensated heart

failure associated with dyspnea at rest as it - ↓↓ pulmonary wedge pressure - systemic vascular resistance

Management of chronic heart failure

• Major steps in the treatment of chronic heart failure

1) Reduce workload of the heart - limit activity level - reduce weight - control HTN 2) Restrict Na 3) Diuretics 4) ACE inhibitors or Angiotensin receptor(AR) blockers 5) Digitalis 6) ß blockers 7) Vasodilators

Sodium removal• It is an important step in the management

salt restriction diuretic if edema + mild - thiazide severe - stronger agents• Na loss causes secondary K+ loss Hazardous if patient is to be given digitalis• Hypokalemia treatment – K+ supplementation or K+ sparing diuretic

ACE inhibitors & angiotensin receptor (AR) blockers• ACEI should be used in patients with LV dysfunction

without edema• Studies have shown that ACEI + diuretics considered as

1st line therapy• In patients who are asymptomatic with LV dysfunction

– ACEI are valuable• They ↓↓ preload and ↓↓ afterload slow the rate of ventricular dilatation

delay onset of clinical heart failure• ACEIs are beneficial in all subsets of patients - asymptomatic - severe chronic failure

• AR blockers should be used only in patients who are intolerant to ACEIs

Vasodilators• Choice of agent is based in - patients signs & symptoms - hemodynamic measurements• In patients with high filling pressures – dyspnea

principal symptom - venodilators - long acting NO3s helpful

↓↓ filling pressures & symptoms of pulmonary congestion

• In patients with ↓↓ ventricular output – fatigue - primary symptom Arteiolar dilator – hydrallazine given• In patients where both ++ - high filling pressures - low ventricular output

- hydrallazine - nitrates combined therapy given

Digoxin• It is indicated in patients with heart failure + atrial fibrillation• Also helpful in patients with a dilated heart + 3rd heart sound• In patients with normal sinus rhythm – 50% of

patients relieved of symptoms

ß blockers• Rationale is based on the hypothesis that - high catecholamine levels

excessive tachycardia

downward course of heart failure patients• Therapy should be initiated cautiously at low

doses – as acutely blocking the supportive effects of catecholamines can worsen heart failure