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 1/10th 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

Ca2+

3 Na+ Ca2+

ATPase

Ca2+

NCX Polarised

Ca2+

Na+

Na+K+

ATPase

3 Na+

2 K+

SERCA2

Ca2+

Ryanodine receptor (RyR2)

SR

Ca2+

(LType)

Cations

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 Ca2+ 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 relaxationPhysiological antagonist of histamine

Corticosteroids

Antihistamine

•Cardiogenic:

Dopamine hydrochloride 2-5 g/kg/min i.v. infusion till a maximal dose of 20-50 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 V1 receptors

Corticosteroids

Adrenaline, dobutamine