Heart Failure  CO  Sympathetic activity Vasoconstriction  Cardiac filling  Renin  Angiotensin II  Aldosterone Na +, water retention Cardiac remodeling Inotropic agents  -Blockers Renin inhibitors ACE  ARBs Spironolactone Diuretics Vasodilators

Role of sympathetic activation in CHF CHF Sympathetic activation Inotropy (  contractility) Lusitropy (  Ventricular relaxation & filling) Chronotropy (  Heart rate)

 -Adrenoceptor antagonists:  agonists dobutamine as also dopamine provide relief in CHF but their long term use increases mortality Long term administration of  -antagonists reduce mortality rate in CHF Initially the systolic function decreases but over 2-4 months it recovers and improvement beyond baseline occurs Mechanism of beneficial effects in CHF not clear By preventing myocardial ischemia without significantly influencing serum electrolytes, they may decrease frequency of unstable tachyarrhythmias Betterment of left ventricular morphology by decreasing left ventricular size and increasing ejection fraction

By inhibiting sustained sympathetic discharge, they reduce catecholamine induced cardiomyote toxicity and prevent or delay myocardial contractile dysfunction Decrease cardiomyocyte apoptosis May induce positive myocardial remodeling by decreasing oxidative stress on myocardium Drugs used: metoprolol, carvedilol, bisoprolol- other  -blockers are not effective Combined  and  blocker is preferred Carvedilol has additional advantages that it reduces free radical induced lipid peroxidation and prevents cardiac and vascular smooth muscle mitogenesis independent of its  or  receptor blocking activity

 Adrenoceptor blockers have proven utility in improving symptoms, hospitalization and mortality in patients of CHF They are recommended for use in patients along with ACE inhibitors or ARBs Recommended only when the ejection fraction of heart is <35% to counter the deleterious effects of circulating catecholamines They are usually given in small doses initially, less than 1/10 th of the final dose and gradually titration of dose is done Not recommended for use in patients with severe, new onset or acutely decompensated CHF

Inotropes- for increasing ventricular contractions: Cardiac glycosides- digitalis, digoxin, oubain  Adrenergic and dopaminergic agonists- dobutamine PDE inhibitors- Inamrinone, milrinone Heart Failure

Cardiac cell Na + NCX Depolarised Ca 2+ 3 Na + Ca 2+ ATPase Ca 2+ NCX Polarised Ca 2+ Na + Na + K + ATPase 3 Na + 2 K + SERCA2 Ca 2+ Ryanodine receptor (RyR2) SR Ca 2+ (LType) Cations K+K+

Na + K + ATPase H + K + ATPase

Cardiac glycosides bind and inhibit the phosphorylated  sub unit of sarcolemal Na + K + ATPase They  Na + extrusion from cell and  its level in cell At therapeutic serum levels they: Increase vagal tone and decrease sympathetic tone Decrease automaticity Increase maximal diastolic resting membrane potential in atrial and AV nodal tissues Prolongs ERP and slows conduction in AV nodal tissues These effects result in sinus bradycardia or arrest, prolongation of AV nodal conduction and AV block

In higher concentrations it increases sympathetic activity. Simultaneously, there is Ca 2+ overload which together may cause development of cardiac arrhythmias Non-cardiac effects: Blood vessels- constriction (direct) in normal; in CHF vasodilatation due to decreased sympathetic activity Kidney- Diuresis GIT- anorexia, nausea,vomiting (CTZ) CNS- disorientation, hallucinations, visual & colour disturbances

Uses: CHF PSVT Atrial flutter/Atrial fibrillation

ADRs: Cardiac CNS- fatigue, neuralgia, blurred vision GIT- anorexia, nausea, vomiting, abdominal cramps Endocrinal- gynaecomastia in males Contraindications: Hypokalemia, children below 10 years age, elderly with renal/hepatic impairment MI, hypothyroidism, myocarditis

Dobutamine: Racemic mixture that stimulates both  1 and  2 receptors and (-) enantiomer that is agonist and (+) enatiomer that is partial agonist of  adrenoceptors  1 -positive ionotropic and increase in stroke volume Relatively little increase in heart rate Vasoconstriction by (-) enantiomer is countered by (+) enatiomer and  2 agonist activity- ultimate result is a decrease in PVR and mild decrease in systemic blood pressure Continuous infusion 2-3  g/kg/min Tolerance may occur after some time ADRs: tachycardia, arrhythmias

PDE Inhibitors: Inamirinone, milrinone Decrease cellular degradation of cAMP resulting in increased levels in cardiac and smooth muscle myocytes Produces positive inotropic effect on heart and dilatation of resistance and capacitance vessels Nett effect: positive ionotropy and decrease in pre and after load resulting in improvement in cardiac output Also called “inodilator” (inotropy + vessel dilatation) Theophylline, caffeine have low cardiac specificity and side effects, so are not used Inamirinone and milrinone are selective PDE3 inhibitors Directly stimulate myocardial contractility & relaxation

Shock

Haemorrhaegic (hypovolemic): replace with blood or plasma expanders Anaphylactic : Adrenaline  agonist-  BP  1 agonist- +ve ino & chronotropy  2 agonist- bronchial relaxation Physiological antagonist of histamine Corticosteroids Antihistamine

Cardiogenic: Dopamine hydrochloride 2-5  g/kg/min i.v. infusion till a maximal dose of  g/kg/min is achieved Dobutamine NE- rare- reserved for patients with refractory hypotension

Septicemic (warm shock): Dopamine hydrochloride Chemotherapeutic agent Recombinant activated protein- C known as drotrecogin alpha (activated)- continuous infusion 24  g/kg/hr for 96 hrs, improves rate of mortality Vasopressin (ADH)- peripheral vasoconstriction by V 1 receptors Corticosteroids Adrenaline, dobutamine