2. Heart failure Congestive heart failure (CHF)= chronic heart failure Occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs There are two main types of heart failure:  heart failure due to left ventricular dysfunction  heart failure with normal ejection fraction Heart failure is a common, costly, and potentially fatal condition In the year after diagnosis the risk of death is about 35% after which it decreases to below 10% each year

3. Terminology The term "acute" is used to mean rapid onset, and "chronic" refers to long duration. Chronic heart failure is a long term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure is a worsening of chronic heart failure symptoms

6. Management of heart failure Treatment focuses on improving the symptoms and preventing the progression of the disease. Treatments include lifestyle and pharmacological modalities. Acute decompensated heart failure In acute decompensated heart failure, the immediate goal is to re-establish adequate perfusion and oxygen delivery to end organs. This entails ensuring that airway, breathing, and circulation are adequate. Chronic management The goals of treatment for people with chronic heart failure are the prolongation of life, the prevention of acute decompensation and the reduction of symptoms, allowing for greater activity. Treatment strategies provide significant improvement in the relief of symptoms, exercise tolerance, and a decrease in the likelihood of hospitalization or death.

7. Two distinct goals of drug therapy (a) Relief of congestive/low output symptoms: ACE inhibitors Vasodilators— nitrate, nitroprusside,hydralazine β blocker—Nebivolol, Carvedilol, Metoprolol, bisoprolol Diuretics—Furosemide, thiazides Inotropic drugs—Digoxin, dobutamine (b) Arrest/reversal of disease progression and prolongation of survival: ACE inhibitors, β blockers Aldosterone antagonist—Spironolactone, eplerenone

8. The vicious cycle in CHF: compensatory mechanisms evoked in response to reduced cardiac output themselves perpetuate failure and contribute to remodeling responsible for disease progression. The parameter which is improved by different therapeutic measures is indicated

10. First-line therapy ACE inhibitors Vasodilators β blocker Second-line therapy Diuretics Inotropic drugs

11. ACE inhibitors First-line therapy for people with heart failure should include:  angiotensin-converting enzyme (ACE) inhibitors  angiotensin receptor blockers (ARBs) if the person develops a long term cough as a side effect of the ACE- inhibitors !They are recommended for all grades of CHF! Use of medicines from this class are associated with improved survival and quality of life in people with heart failure by causing:  vasodilatation,  retarding/preventing ventricular hypertrophy, fibrosis and remodeling.

12. Beta-adrenergic blocking agents A large number of trials have demonstrated subjective, objective, prognostic and mortality benefits of the β1 blockers and the αβ-blocker (carvedilol) in mild to moderate CHF treated. There is no place for β blockers in decompensated patients. β blockers should be stopped during an episode of acute heart failure.

13. Vasodilators Preload reduction: Nitrates cause pooling of blood in systemic capacitance vessels to reduce ventricular end-diastolic pressure and volume. It is indicated when the central venous pressure is raised and in dilated cardiomyopathy. Afterload reduction Hydralazine dilates resistance arteries so that even weaker ventricular contraction is able to pump more blood Calcium channel blockers (DHP)- arteriolar dilators (nifedipine, felodipine, amlodipine)

14. Pre- and after load reduction Sod. Nitroprusside is a high efficacy i.v. dilator with equal action on the two types of vessels. The action is very fast and brief. For symptomatic treatment of acute heart failure

15. Diuretics High ceiling diuretics (furosemide, bumetanide) are the diuretics of choice for mobilizing edema fluid Thiazides are used in CHF. Diuretics:  Decrease preload and improve ventricular efficiency by reducing circulating volume.  Remove peripheral edema and pulmonary congestion. Furosemide –rapid symptomatic relief in acute left ventricular failure.

16. Inotropic drugs Drugs with β adrenergic agonistic actions have positive inotropic and (at low doses) vasodilator properties which may be utilized to combat emergency pump failure. Dobutamine a selective β1 agonist with prominent inotropic action i.v. in acute heart failure or advanced decompensated CHF. Due to development of tolerance and cardiotoxic potential when used regularly- no use in the long- term management of CHF.

17. CARDIAC GLYCOSIDES They increase myocardial contractility and output in a hypodynamic heart without a proportionate increase in O2 consumption. Thus, efficiency of failing heart is increased. In contrast, ‘cardiac stimulants’ (Adr, theophylline) increase O2 consumption rather disproportionately and tend to decrease myocardial efficiency.

18. Digitalis Cardiac glycosides are found in several plants. Digitalis lanata is the source of Digoxin, the only glycoside that is currently in use. Others like Digitoxin and strophanthin, etc. are no longer clinically used. By convention the term, ‘Digitalis’ has come to mean ‘a cardiac glycoside’.

19. PHARMACOLOGICAL ACTIONS 1. Heart Digitalis has direct effects on myocardial contractility and electrophysiological properties. Force of contraction  Increase in force of contraction  Systole is shortened, diastole is prolonged Heart rate Is decreased by:  Vagal action - Vagal tone is increased reflexly by sensitization of baroreceptors, as well as by stimulation of vagal centre.  Extravagal action- A direct depressant action on SA and A-V nodes. This component of bradycardia is not reversed by atropine. Conduction  A-V conduction is demonstrably depressed Mechanism of positive inotropic action of cardiac glycosides.

20. 2. Blood vessels  Digitalis has mild direct vasoconstrictor  Digitalis has no prominent effect on BP: systolic BP may increase and diastolic may fall in CHF patients—pulse pressure increases. Hypertension is no contraindication to the use of digitalis. 3. Kidney  Diuresis occurs promptly in CHF patients, secondary to improvement in circulation and renal perfusion.  No diuresis occurs in normal Individuals 4. CNS  High doses produce central sympathetic stimulation, mental confusion, disorientation and visual disturbances. PHARMACOLOGICAL ACTIONS

21. PHARMACOKINETICS Route of administration- Oral, i.v. Bioavailability of digoxin - 60–80% It is concentrated in the heart (~20 times than plasma) Plasma t½ - 40 hrs ( Its t½ is prolonged in elderly patients and in those with renal insufficiency: dose has to be reduced). Digoxin is a cumulative drug!!!

23. Medical use Heart failure Digoxin is no longer the first choice for CHF Only for :  Acute heart failure  Decompensated CHF Cardiac arrhythmias  Atrial fibrillation  Atrial flutter The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling.  blockers or calcium channel blockers are a better first choice

24. ADVERSE EFFECTS Toxicity of digitalis is high (2/3 patients) !!!! Cardiac ADR Almost every type of arrhythmia can be produced by digitalis: atrial and ventricular extrasystoles, ventricular tachycardia, terminally ventricular fibrillation. A-V block Severe bradycardia Extracardiac ADR GIT: Anorexia, nausea, vomiting and abdominal pain are usually reported first Mesenteric vasoconstriction CNS: mental confusion, restlessness, disorientation, acute psychosis, drowsiness, dizziness, insomnia, nightmares, agitation, depression, amnesia, convulsions Visual disturbances (yellow- green visual perception) - xanthopsia

25. Treatment of ADR Further doses of digoxins must be stopped at the earliest sign of toxicity Attempts to enhance the elimination of digoxin by diuretics or haemodialysis are not very effective. For tachyarrhythmias KCl - K+ tends to antagonize digitalis induced enhanced automaticity. K+ is contraindicated if higher degree of A-V block is present, because complete A-V block and ventricular asystole may be precipitated. For ventricular arrhythmias Lidocaine i.v. repeated as required is the drug of choice. For supraventricular arrhythmias  -blokers may be given i.v. or orally depending on the urgency. For A-V block and bradycardia Atropine may help; otherwise cardiac pacing is recommended. Digoxin antibody Digoxin specific antibody is effective in treating toxicity - DIGIBIND Given by i.v. infusion it has markedly improved the survival of seriously digitalis intoxicated patients.

26. INTERACTIONS 1. Diuretics: cause hypokalemia which increases the risk of digitalis arrhythmias; potassium supplements should be given prophylactically. 2. Calcium: synergises with digitalis → precipitates toxicity. 3. Verapamil, diltiazem, captopril, propafenone and amiodarone increase plasma concentration of digoxin → plasma concentration of digoxin is doubled → toxicity can occur. 4. Adrenergic drugs: can induce arrhythmias (both increase ectopic automaticity). 5. Digoxin absorption is increased by atropinic drugs. 6. Propranolol, verapamil, diltiazem and disopyramide: may additively depress A-V conduction and oppose positive inotropic action. 7. Succinylcholine: can induce arrhythmias in digitalized patients.