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 H 2 O ↑ afterload ↑ HR ↑ aldosterone retention BACK PRESSURE pulmonary EDEMA peripheral congestion congestion dyspnea & cyanosis HEPATIC CONGESTION ENLARGED LIVER ANOREXIA CARDIAC REMODELLING

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 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 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 – 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 D T N I O H G X A I I N T C C A I E L T D 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 c AMP ↑↑ 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 ++ 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 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 non- selective 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 – 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