Congestive heart failure Congestive heart failure CHF It

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. beri hyperthyroidism anemia arteriovenus shunts • Respond poorly to +ve ionotrophic drugs • Cause should be treated

↓↓ FC Heart failure ↓↓ CO ↓↓ renal perfusion ↓↓ carotid sinus firing ↑↑ sympathetic discharge ↑↑ renin release ventricular dilatation vasoconstriction ß 1 activation ↑ preload ↑ afterload ↑ FC ↑ HR ↓↓ GFR AT-1 ↑ AT-2 ↑ preload ↑ afterload ↑ aldosterone CARDIAC REMODELLING BACK PRESSURE pulmonary congestion dyspnea & cyanosis EDEMA HEPATIC CONGESTION ENLARGED LIVER ANOREXIA peripheral congestion Na & H 2 O retention

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

Drugs used in heart failure 1) 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 nonsugar 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 Ca 2+ • Any drug that increases free cytosolic Ca 2+ levels ↑↑ force of contraction sensitivity of contractile mechanisms to Ca 2+

• Ca 2+ initially enter through voltage sensitive L-type of Ca 2+ • • • channels It triggers the release of larger quantity of Ca 2+ from the sarcoplasmic reticulum (SR) by activating SR- Ca 2+ release – ryanodine receptor The ↑↑ Ca 2+ concentration initiates the contractile process During restorative process of periodic contractions Ca 2+ ions are removed by re-uptake into SR by SR- Ca 2+ ATPase It is also extruded by a Na+/ Ca 2+ 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+/ Ca 2+ exchange mechanisms • This exchanger normally extrudes Ca 2+ in exchange for Na+ • In the presence of ↑↑ intracellular Na+ concentration it extrudes Na+ in exchange for extracellular Ca 2+ • There is also an ↑↑ in Ca 2+ permeability through voltage sensitive L channels during plateau phase • Digitalis also inhibits SR- Ca 2+ ATPase & reduces reuptake of Ca 2+ by SR

• Ultimately ↑↑↑ cytosolic Ca 2+ 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 ↓↓ ↓↓ O 2 consumption for work output i. e ↑↑ work done for ↓↓ O 2 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 & H 2 O 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 Ca 2+ Mg 2+ & 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 N H A N C E D D I G I T A L I S T O X I C I T Y

• • Digitalis effects ↓↓ by Antacids Sucralfate ↓↓ absorption Neomycin Enzyme inducers Phenobarbitone ↑↑ metabolism Phenytoin ↓↓ entero-hepatic Cholestyramine 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 c. AMP ↑↑ contractility (heart) ↑↑ vasodilatation (blood vessels)

• They also have direct vasodilating effect • They also ↑↑ inward Ca 2+ 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

ß 1 adrenergic agonists • ß 1 adrenergic stimulation improves cardiac performance by +ve ionotropic effects • They cause an ↑↑ in intracellular c. AMP activation of protein kinases phosphorylation of slow Ca channels ↑↑ Ca inflow into myocardial cells ↑↑ force of contraction

ß 1 agonists Ca++ ß 1 agonist Ca++ Adenyl cyclase ATP Active protein kinases Inactive protein kinases myofibrils c. AMP PDE ↑↑ force of contraction Θ phosphodiesterase AMP inhibitors

• • Dobutamine It is a derivative of dopamine with selective ionotrophic effect, negligible chronotropic effect & peripheral vascular effects It is a selective ß 1 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 & ß 1 receptors • Given as intravenous infusion 2 -5 μ gm/kg/minute

Diuretics • They are most commonly used in CHF • Mechanism of action They ↓↓ salt & H 2 O 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+ & H 2 O resultant ↑↑ in urinary excretion of H+ & K+ arrhythmias digitalis toxicity • Mg 2+ & Ca 2+ 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+ & H 2 O Sphironolactone being aldosterone antagonist enhances diuresis by promoting Na+ & H 2 O 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 1 st choice of drugs in CHF Angiotensin I Θ ACE (angiotensin converting enzyme) Angiotensin II Θ ACE Aldosterone secretion ↓↓ salt & H 2 O 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 ß 1 receptors - up regulation of ß 2 receptors cardiac hypertrophy apoptosis

• This rationale favors the use of a combined nonselective ß & α blocker – carvedilol • It has ß 1, ß 2 & 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 NO 3 ↓↓ pulmonary congestion ii) with ↓↓ ventricular output - arteriolar dilator – hydrallazine ↑↑ cardiac output iii) in severe CHF where both are present - ACE inhibitors - hydrallazine + long acting NO 3 (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 1 st 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 NO 3 s 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 + 3 rd 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