Heart failure treatment

1. Heart failure treatment Martin Štěrba, PharmD., PhD. Department of Pharmacology Faculty of Medicine HK, Charles University

2. HEART FAILURE • Inability of the heart as a „ pump“ to maintain adequate tissue perfusion • Compensatory responses – sympathetic and RAAS • HF classification • Acute & chronic • Left & right sided • Systolic & diastolic • Severity according symptom scoring NYHA I-IV • Aim: to affect both symptoms and prognosis • Different endpoints – acute vs. chronic HF • Acute HF & acute decompensation of chronic HF • To support and maintain adequate organ perfusion - an imperative • Chronic HF treatment • Antagonize chronic overstimulation of the sympathetic NS and RAAS which became contraproductive • To decrease: preload, afterload, heart remodelling

3. DRUG CLASSESS USED IN THE HEART FAILURE TREATMENT • Drugs increasing the strength of the cardiac muscle contraction • i.e., drugs with positive inotropic action • Diuretic agents • decrease extracellular fluid volume (decrease preload and congestion - oedema) • antagonize aldosterone receptors • ACE inhibitors (reduce both preload and afterload) • Other vasodilators • -blockers • Antiarrhythmic agents occasionally are required to normalize cardiac rate and rhythm

4. DRUGS INCREASING THE STRENGHT OF CARDIAC CONTRACTION • Drugs with direct positive inotropic effects • Increase in contractility  ↑ CO  improve perfusion of organs • Drugs • Cardioglycosides • Phosphodiesterase inhibitors • Sympathomimetic agents • Calcium sensitizers

5. 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 • Oleander, Lilly of the Valley (Convalaria majalis), Sea Squill (Scilla maritima) • Chemically similar compounds that can increase the contractility of the heart muscle and are therefore they had been widely used in treating heart failure • Pharmacodynamics:Na+/K+ ATPaseinhibition • The drugs have a low therapeutic index • Agents • Digoxin(di JOX in) – clinically used • Digitoxin(di ji TOX in) • Oubain

6. DIGITALIS AND W. WITHERING Digilis purpurea Purple foxglove William Withering (1741 - 1799)

7. CARDIOGLYCOSIDESChemical structure sugar aglycone lactone ring steroid

8. Ion movements during the contraction of cardiac muscle ATPase = adenosine triphosphatase (according to Lippincott´s Pharmacology, 2006)

9. CARDIOGLYCOSIDESEffects on the heart • 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 afterdepolarization (DAD) - Ca2+ from stores - may reach threshold - premature ventricular depolarization or „ectopic beat“

10. CARDIOGLYCOSIDESEffects on the heart • ANS system mediated effects • significant parasympathomimetic effects = central stimulation of nervus vagus • decreased SA pacemaker activity • decreased AV conductance → decreased HR !!! • during intoxications - increased sympathetic outflow may be present (sensitizing for other cardiac tox.)

12. DIGOXINPharmacokinetics • 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

13. CARDIOGLYCOSIDESPharmacokinetic properties

14. A comparison of the properties of digoxin and digitoxin (according to Lippincott´sPharmacology, 2006)

16. CARDIOGLYCOSIDESIndications • 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 IM 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 sy (AVRT)

17. CARDIOGLYCOSIDESAdverse effects • Target organs:heart, CNS, GIT • Mechanisms:Na+/K+-ATPase inhibition, vagal mediated effects • Cardiac effects • bradycardia, decreased or blocked AV conduction • AV junctional rhythm • premature ventricular depolarization, bigeminia rhythm (complex of normal and premature ventricular beats) ventricular fibrillation • GIT:anorexia, nausea, vomiting (nausea etc. can be among the first warning signs of toxicity !!!) • CNS:headache, fatigue, confusion, agitation, blurred vision, alteration of colour perception, and haloes on dark objects • Gynecomastia in men upon prolonged use

18. CARDIOGLYCOSIDESFactors predisposing to digitalis toxicity • Electrolytic disturbances • 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 • Hypercalcemia !!!– increased Ca loading of cardiomyocytes • hypernatremia, hypermagnesemia, and alkalosis

19. CARDIOGLYCOSIDESFactors predisposing to digitalis toxicity Drugs • Quinidine- reduces the renal clearance of digoxin (competition for renal excretion) and displaces digitalis fromtissue protein increases the toxicity of digoxin • Verapamil, amiodaron, spironolakton- displace digoxin from protein  increase digoxin by 50-75 % (it may be necessary to reduce dose) • Potassium-depleting diuretics, corticosteroids and • other drugs Diseases • Hypothyroidism, hypoxia, renal failure, and myocarditis are predisposingfactors to digitalis toxicity TDMto well individualize the therapy and avoid toxicity

20. CARDIOGLYCOSIDESTreatment of severe acute intoxication (overdose) • Fab-fragments against digoxin largely increase renal excretion of digoxin (antidote) • KCl administration • Fenytoin may be used to suppress the ventricular exrasystoles • Atropine may be used to antagonize concomitant bradycardia

21. Drugs interacting with digoxin and other digitalis glycosides Amiodarone Erythromycin Quinidine Tetracycline Verapamil Increased digitalis concentration may occur during concurrent therapy Enhanced potential for cardiotoxicity Corticosteroids Thiazide diuretics Loop diuretics Decreased levels of blood potassium (according to Lippincott´sPharmacology, 2006)

22. OTHER POSITIVE INOTROPIC AGENTS • Due to the mechanisms and risks, they are used only in: • acute HF arising from the surgery or shocks (cardiogenic, septic) • severe acute decompensation of chronic HF with signs of organ hypoperfusion • BETA1-ADRENERGIC AGONISTS • PHOSPHODIESTERASE III INHIBITORS • CALCIUM SENSITIZERS

23. A. BETA1-ADRENERGIC AGONISTS • DobutamineandDopamine • 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 • Could be used for bridging the severe hemodynamic complications • Diminished effects after long-time infusions and possible worsening upon withdrawal • Ibopamine(pro-drug, - beta1, beta2, D1 and D2 effects, does not increase HR)

24. Sites of action by b-adrenergic agonists on heart muscle Sites of action by b-adrenergic agonists on heart muscle (according to Lippincott´s Pharmacology, 2006)

25. B. PHOSPHODIESTERASE III INHIBITORS • Amrinoneandmilrinone • 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 !!!!!!

26. C. CALCIUM SENSITIZERS Levosimendan • No increase intracellular Ca2+ - in contrast to previous agents • Major effects – sensitizing troponin C to calcium and vasodilatation (also some antiischemic effects) • Increased contractility without worsening Ca2+ metabolism a increased O2 demands • No major proarrhythmogenic effects • Indication: i.v. for treatment acute decompensations of CHF • Adverse reactions: hypotension, headache • ↑ costs !!!