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HEART FAILURE Abnormality of cardiac contraction &/or relaxation result in common symptoms of shortness of breath and tiredness, so the heart became unable to meet body requirement. HF classification Acute & chronic Left & right sided Systolic & diastolic Main causes I. Coronary artery disease II. Hypertension III. Valvular heart disease IV.Cardiomyopathy V. Corpulmonale Factors aggravating heart failure 1. 2. 3. 4. 5. Myocardial ischemia or infarct. Dietary sodium excess. Arrhythmias. Intercurrent illness (eg. infection). Conditions associated with increased metabolic demand (eg. pregnancy, thyrotoxicosis, excessive physical activity). 6. Administration of drug with negative inotropic properties or fluid retaining properties (e. NSAIDs, corticosteroids). 7. Alcohol. New classification of heart failure Stage A: Asymptomatic with no heart damage but have risk factors for heart failure Stage B: Asymptomatic but have signs of structural heart damage Stage C: Have symptoms and heart damage Stage D: End stage disease Compensatory changes in heart failure I. Activation of SNS. II. Activation of RAS. III. Increased heart rate. IV. Release of ADH. V. Release of atrial natriuretic peptide. VI. Chamber enlargement. VII.Myocardial hyperatrophy. Goals of treatment •To improve symptoms and quality of life. •To decrease likelihood of disease progression. •To reduce the risk of death and need for hospitalization. Drugs Classes used in the heart failure treatment 1. Drugs increasing the strength of the cardiac muscle contraction • i.e., drugs with positive inotropic action 2. Diuretic agents. • decrease extracellular fluid volume (decrease preload and congestion - oedema) • antagonize aldosteron receptors 3. ACE inhibitors (reduce both preload and after load). 4. Other vasodilators (hydralazine) 5. -blockers(carvidolol). 6. Antiarrhythmic agents occasionally are required to normalize cardiac rate and rhythm. Treatments for HF Diuretics Reduce Fluid Volume Vasodilators Decrease Preload and Afterload Inotropes Augment Contractility Natriuretic Peptide Decrease Preload and After load; Reduce Fluid Volume Drugs increasing the strength of cardiac contraction Drugs with direct positive inotropic effects Increase in contractility ↑ CO improve perfusion of organs Drugs 1) Cardiac glycosides. 2) Phosphodiesterase inhibitors. 3) Sympathomimetic agents. 4) Calcium sensitizers. Ion movements during the contraction of cardiac muscle ATPase = adenosine triphosphatase (according to Lippincott´s Pharmacology, 2006) 1.cardiac glycosides Often called digitalis or digitalis glycosides Source: medicinal plants Digitalis purpurea and alba (purple and white foxglove) their medical use goes 3000 years ago. o Chemically similar compounds that can increase the contractility of the heart muscle and are therefore they had been widely used in treating heart failure. o The drugs have a low therapeutic index. Agents Digoxin – clinically used Digitoxin Oubain Digoxin Enhances LV function, normalizes baroreceptor-mediated reflexes and increases cardiac output at rest and during exercise. Recommended to improve clinical status of patients with heart failure due to LV dysfunction and should be used in conjunction with diuretics, ACE inhibitors and beta-blockers. Also recommended in patients with heart failure who have atrial fibrillation. Digoxin initiated and maintained at a dose of 0.25 mg daily. It cause inhibition of Na/K-ATPas &also caused vagal stimulation. Pharmacological action 1. 2. 3. Mechanical effects - increase in cardiac contractility intracellular Na+ increased intracellular Ca2+ content increased release of calcium from sarcoplasmatic reticulum. Direct electrophysiological effects AP shortening (esp. the plateau phase) – potassium conductance that is caused by increased intracellular calcium. resting membrane potential is increased - made less negative (due to the Na+, Ca2+) in ↑ doses. delayed after depolarization (DAD) - Ca2+ from stores - may reach threshold - premature ventricular depolarization or „ectopic beat“. ANS system mediated effects: central stimulation of nervous vagus decreased SA pacemaker activity. decreased AV conductanc→ decreased HR . Pharmacokinetics o o o Oral absorption: 65-80 %, parenteral administration for emergencies Wide distribution into the organ/tissues including CNS Excretion: 80% of drug – unchanged in the urine – mostly glom. filtration dose individualisation in renal failure according GF small amount eliminated via active transport – renal tubules and bile – interactions – importance during renal failure Digoxin Digitoxin Half-life 36 hours 164 hours Therapeutic plasma concentration 0.5 - 2 ng/mL 10 - 25 ng/mL Toxic plasma concentration 2 ng/mL 35 ng/mL Daily dose (slow loading or maintenance) 0.125 - 0.5 mg 0.05 - 0.2 mg Rapid digitalizing dose 0.5 - 0.75 mg every 8 h for 3 doses 0.2 - 0.4 mg every 12 h for 3 doses A comparison of the properties of digoxin and digitoxin Indications Congestive heart failure In association with atrial fibrillation/flutter (clear indication) Digoxin reduces hospitalizations and improves symptoms, however, without improving survival (generally poor) indicated in severe forms of HF in combination with other treatment to improve symptoms of HF and clinical status Not to be used in diastolic HF and acute MI related HF Antiarrhythmic indications Supraventricular arrhythmias AV conduction will help control an excessively high ventricular rate - improving ventricular filling and increasing cardiac output • Contraindicated in Wolf-Parkinson-White syndrome. Adverse effects Cardiac effects a) bradycardia, decreased or blocked AV conduction b) AV junctional rhythm c) premature ventricular depolarization, bigeminia rhythm (complex of normal and premature ventricular beats) ventricular fibrillation o GIT: anorexia, nausea, vomiting (nausea etc. can be among the first warning signs of toxicity .) o CNS: headache, fatigue, confusion, agitation, blurred vision, alteration of o colour perception, and haloes on dark objects. Gynecomastia in men upon prolonged use. Factors predisposing to digitalis toxicity Drugs Quinidine - reduces the renal clearance of digoxin (competition for renal excretion) and displaces digitalis from tissue protein increases the toxicity of digoxin Verapamil, amiodaron, spironolacton - displace digoxin from protein increase digoxin by 50-75 % (it may be necessary to reduce dose) Potassium-depleting diuretics and corticosteroids Diseases Hypothyroidism, hypoxia, renal failure, and myocarditis are predisposing factors to digitalis toxicity Factors predisposing to digitalis toxicity o Hypokalemia K+ competes with digoxin for Na+/K+-ATPase binding site→ hypokalemia facilitate digoxin binding and Na+/K+-ATPase inhibition, while hyperkalemia has the opposite effects hypokalemia generally makes the heart more imbalanced and sensitive to proarythmogenic stimuli SIGNIFICANT RISK patients heavily vomiting, GIT infections with diarrhoea patients receiving diuretics (loop/thiazides), dose effect PREVENTION co-administration of a potassium-sparing diuretic or supplementation with KCl o Hypercalcemia – increased Ca loading of cardiomyocytes o hypernatremia, hypomagnesemia, and alkalosis Drugs interacting with digoxin and other digitalis glycosides Increased digitalis concentration may occur during concurrent therapy Amiodarone Erythromycin Quinidine Tetracycline Verapamil Enhanced potential for cardiotoxicity Decreased levels of blood potassium Corticosteroids Thiazide diuretics Loop diuretics Treatment of severe acute intoxication (overdose) Fab-fragments against digoxin largely increase renal excretion of digoxin (antidote). KCl administration. phenytoin may be used to suppress the ventricular arrythmia. Atropine may be used to antagonize concomitant bradycardia. 2.PHOSPHODIESTERASE III Inhibitirs Amrinone o o o and Milrinone Phosphodiesterase inhibitors III (heart specific subtype) increase the intracellular concentration of cAMP increase in intracellular Ca, and therefore cardiac contractility . Amrinone given only i.v. mainly for short-term management of acute congestive heart failure. is associated with reversible thrombocytopenia (milrinone does not affect platelets). Milrinone showed increased mortality and no beneficial effects, amrinone did not reduced the incidence of sudden cardiac death or prolong survival in patients with CHF. 3. BETA1-ADRENERGIC AGONISTS Dopamine act on alpha , beta & dopaminergic receptors ,while Dobutamine act on B,D &less on alpha receptors Improves cardiac performance by their positive inotropic effects and vasodilatation (minimum effects on HR by dobutamine) Increase in intracellular cAMP results in the entry of Ca2+ into the myocardial cells increases, thus enhancing contraction Dopamine preferred in cases of HF associated with hypotension . Dobutamine preferred in HF with normal BP. Diminished effects after long-time infusions and possible worsening upon withdrawal Ibopamine (pro-drug, - beta1, beta2, D1 and D2 effects, does not increase HR) Sites of action by -adrenergic agonists on heart muscle (according to Lippincott´s Pharmacology, 2006) 4. CALCIUM SENSITIZERS Levosimendan(simdax) No increase intracellular Ca2+ - in contrast to previous agents. it increase calcium sensitivity to myocyte by binding to cardiac troponine C so increase myocardial contractility. Also it have vasodilatory effect mediated by opening of vascular ATP- sensitive K-channel. No major proarrhythmogenic effects Indication: i.v. for treatment acute decompositions of CHF., it give 6- 12 Mg\kg(loading dose)over 10 min. followed by 0.05-0.2Mg\kg\min. as continuous infusion. Adverse reactions: hypotension, headache Angiotensin Converting Enzyme Inhibitors: they first line in all pt. with chronic HF. They decrease PVR(after load),decrease salt &water retention by suppress aldosteron(decrease preload),also decrease sym. activity by suppressing NE release. Decrease remodeling effect on heart. decrease in the progression of chronic HF. decreased hospitalization. enhanced quality of life. renin Angiotensinogen Angiotensin I ACE Other pathways Angiotensin II Receptors AT1 Vasoconstriction Proliferative Action AT2 Vasodilatation Antiproliferative Action ACE Inhibitor Contraindications Renal artery stenosis (relative). Hyperkalemia. Renal insufficiency. Arterial hypotension. Cough. Angioedema. Alternatives Hydralazine + ISDN, AT-II inhibitor . Guidelines to ACE Inhibitor Therapy All patients with symptomatic heart failure and those in functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless contraindicated or not tolerated. ACE inhibitors should be continued indefinitely. In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac output. B-blocker in CHF B-blockers give protection against catecholamine myocyte toxicity. we should start slowly& then up titrate gradually &watching adverse effects. B-blockers add only to existing therapy include ACEI &diuretic &(in some studies) digoxin & idealy not give for pt. with class 3 &4. only carvidolol& metaprolol are approved in USA. carvidolol reduce mortality more than metaprolol Diuretics Indicated in patients with symptoms of heart failure who have evidence of fluid retention. Enhance response to other drugs in heart failure such as beta-blockers and ACE inhibitors. Therapy initiated with low doses followed by increments in dosage until urine output increases and weight decreases by 0.5-1 kg daily. .decrease venous return(preload)so decrease edema, decrease cardiac size &increase pump function. The Future of HF Pharmacotherapy Management 1) natriuretic peptides (Nesiritide, carperitide). 2) Levosimendan (inotrope/vasodilator). ularitide, 3) Vasopressin Receptor Antagonists(Tolvaptan)&IV Conivaptan (dual vasopressin blocker). 4) Endothilin-1 receptor antagonists (Tezosentan). Nesiritide(natrecore) It recombinant DNA from human B-type natriuretic peptide. It bind to NP-A receptor which activate guanylate cyclase that convert GTP to cGMP which act as 2nd messenger &induce it s biological action. Advantages Rapid symptomatic improvement Theoretical antagonism of RAAS activation Disadvantages Minimal indirect effect in increasing cardiac output Incompatibilities; cannot be infused through same IV catheter as heparin (no heparin-coated catheters), insulin, bumetanide, enalaprilat, hydralazine, or furosemide. Associated with clinically significant hypotension . Associated with increased serum creatinine concentration. Vasopressin Antagonists Currently in Development Tolvaptan—Oral selective V2-receptor antagonist Treatment of decompensate heart failure Lixivaptan—Oral selective V2-receptor antagonist Conivaptan—Intravenous dual V1a/V2-receptor antagonist Treatment of euvolemic hyponatremia in hospitalized patients (FDA approved Dec. 30 2005 Vaprisol®) AVP-Receptor Subtypes Receptor Subtype Site of Action Activation Effects V1A Vascular smooth muscle Platelets Lymphocytes and monocytes Hepatocytes Vasoconstriction Platelet aggregation Coagulation factor release Glycogenolysis V1B Anterior pituitary ACTH and -endorphin release V2 Renal collecting duct cells Free water absorption Arginine Vasopressin (AVP) aka Antidiuretic Hormone V1A VASCULAR SMOOTH MUSCLE CELL V1A HEART V2 DISTAL TUBULES • Vasoconstriction • Coronary Vasoconstriction • Myocyte Hypertrophy • Water Retention • Increased after load and wall stress • LV hypertrophy • Ischemia • Increased preload, hyponatremia, edema Conivaptan Usage in Patients With Heart Failure Combined V1a/V2-receptor antagonism In patients with heart failure, IV conivaptan resulted in 1. Significant reductions in PCWP and right atrial pressure (RAP) 2. No change in CI, HR, MAP, PVR, SVR 3. Dose-dependent increase in urine output Endothilin antagonast (Tezosentan & Bosentan) They antagonize ET-A & ET-B endothilin receptors so lead to inhibition of vasoconstricted effect caused by endogenous endothilin. They decrease both systolic and diastolic arterial pressure. They metabolite by cytochrome P450 system in liver. Thank you