PharmacologicalPharmacological ttreatmentreatment ofof congestivecongestive heartheart failurefailure Milan Juhas, PharmD.,1,2,3 1Department of pharmacology, Masaryk University School of medicine 2Ist. Internal Cardioangiology clinic, St. Anne`s University Hospital Brno 3Hospital Pharmacy, St.Anne`s University Hospital Brno (CONGESTIVE) HEART FAILURE(CONGESTIVE) HEART FAILURE – Syndrome of myocard inability to supply organs with blood characterized with peripheral edemas, fluid retention and dyspnoe – ASTHMA CARDIALE – FUNCTIONAL CLASSES NNEWEW YYORKORK HHEARTEART AASSOCIATION (SSOCIATION (NYHANYHA CRITERIA)CRITERIA) 2 TreatmentTreatment goalsgoals ofof chronicchronic HFHF • Improve quality of life • decrease frequency of dyspnoe episodes and decompensationsand decompensations • Minimize patient`s invalidism • Delay the need for heart transplantation 3 Target of pharmacotherapy • Effects on RAAS hyperreactivity • β-down regulation – Central – Myocardial – Renal BasicBasic pharmacotherapeuticpharmacotherapeutic groupsgroups usedused inin treatmenttreatment ofof heartheart failurefailure •• MonoaminesMonoamines andand vasopressorsvasopressors •• ββ--blockersblockers •• ACEACE inhibitorsinhibitors,,•• ACEACE inhibitorsinhibitors,, •• ATAT--2 receptor2 receptor blockersblockers •• diureticsdiuretics •• InotropicInotropic agentsagents Basic pharmacological groups in treatment of acute heart failure • Dobutamin i.v. (Dobutrex) – Strong β1-agonist – High doses coupled with loss of selectivity– High doses coupled with loss of selectivity – Rapid onset of action(1-2 minutes), short blood halflife – Potentiation of latent ventricular arrhytmias – Therapeutic range 2,5 – 40 ug/kg/min ! Basic pharmacological groups in treatment of acute heart failure • Noradrenalin i.v. (Noradrenalin Léčiva) – α1 a β1 – combined agonist with dose-dependent selectivity – ≤ 2 ug/min - β1-selectivity + inotropy,– ≤ 2 ug/min - β1-selectivity + inotropy, + chronotropy – 4-10 ug/kg - β1-selectivity – increase +CH, +I – ≥ 10 ug/min – increase peripheral vascular resistance FactorsFactors affectingaffecting orallyorally administeredadministered drugsdrugs • Peripheral hypoperfusion • Cardiorenal syndrome • Compliance and confusion• Compliance and confusion – encephalopathy in cerebral hypoperfusion • Hepatic insufficiency RAAS AND HF PROGRESS Image reproduced: Dr. Macaulay T.:Cross-Reactivity of ACE Inhibitor–Induced Angioedema with ARBs 10 – Direct remodelation factor on LV – Myocardium endotel smooth muscle cell ANGIOTENSIN IIANGIOTENSIN II – Myocardium endotel smooth muscle cell proliferation – Vasoconstriction and progression of renal insufficiency 11 iACEiACE -- advantagesadvantages • decrease of HF mortality – Kaptopril (SAVE), enalapril (SOLVD); – Ramipril (AIRE), trandolapril (TRACE) • LV remodelation after myocardial infarction iACEiACE -- advantagesadvantages • ↓ hospitalization count due to HF • ↑ exercise tolerance and ↓ subjective difficulties • Always indicated in patients with symptomatic HF – In absence of contraindication – ↓ risk of manifestation in patients without symptoms RestrictionsRestrictions andand adverseadverse effectseffects ofof iACEiACE • Renal failure • History of angioneurotic edema • Renal artery stenosis • hypotension – titration „start low, go slow“• hypotension – titration „start low, go slow“ • Hyperkalemia with proteinuria • Dry cough – change of therapy indicated ??? • USE OF NSAID DECREASE THERAPEUTIC VALUE ! Case of intolerance and contraindications – use of rAT-2 blockers • Potential benefits resulting from rAT-2 block – remodelation – Hypertension treatment • Vasodilatation due to increase availability of AT-2• Vasodilatation due to increase availability of AT-2 to secondary receptors • Advantage – very good tolerance • Disadvantage – lesser results in comparison to iACE ( ELITE II, ValHeFT a iné) ACEi a HF (enalapril) – SOLVD-CURATIVE trial • Enalapril vs placebo on standard therapy (BB+diuretics) • Symptomatic patients with LV dysfunction• Symptomatic patients with LV dysfunction • Significant decrease of mortality risk and hospitalisation count due to HF ACEi a HF (enalapril) • SOLVD-CURATIVE studie Mortality Curves in the Placebo and Enalapril Groups. ββ--blockersblockers and HFand HF • First attempt since 1975 • Negative inotropy concerns • HF represented long-time contraindication of BB • Clinical trials • CIBIS I, II; MERIT-HF; COPERNICUS, CAPRICORN • Result - BB established as basic treatment of HF ββ--blockersblockers and HFand HF • Average mortality decrease by 34% – Risk of sudden death • Factors• Factors – Decrease of sympaticus activation – Decrease of heart rate – Diastola prolongation – Indirect β-receptor up-regulation ββ--blockersblockers - pleiotropy •• ↓↓ myocardium oxygenoxygen consupmtionconsupmtion – ACS, HF – Metabolism shift from anaerobic glycolysis to oxidative phosphorylation • β-receptor sensitisationsensitisation – Protective effect against high catecholamine plasma concentration – ↓ RAAS activation ββ--blockersblockers and HFand HF -- restrictionsrestrictions – bradycardia – Hypotension – Asthma bronchiale– Asthma bronchiale – Metabolic adverse effects – Induction of coronary arthery spasms The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) • Bisoprolol evaluation vs placebo in symptomatic patients • NYHA III-IV • Study design – ACEi + diuretika + BISOPROLOL – ACEi + diuretika + placebo • Untimely terminated due to ethical reasons ! The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial ; CIBIS-II Investigators and Committees The Lancet - 2 January 1999 ( Vol. 353, Issue 9146, Pages 9-13 ) , DOI: 10.1016/S0140-6736(98)11181-9 Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) • Evaluation of metoprolol (12,5 mg/25 mg) vs placebo in HF (standard therapy) • Pacients with HF NYHA II-IV• Pacients with HF NYHA II-IV • Slow titration up to 200 mg • Follow-up 1 year • Untimely terminated due to ethical reasons ! Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) MERIT-HF Study Group The Lancet - 12 June 1999 ( Vol. 353, Issue 9169, Pages 2001-2007 ) DOI: 10.1016/S0140-6736(99)04440-2 The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure • Evaluation of carvedilol vs placebo in patients with HF based on standard therapy – Digoxin + ACEi + diruetics– Digoxin + ACEi + diruetics – EF LV < 35 % – Significant mortality reduction • Untimely terminated due to ethical reasons ! Packer M. et al.: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Eng J Med. 1996; 334: 1349-1355 ClinicalClinical implicationsimplications • Expansion of pharmacotherapy of HF • ACEi + diuretics + β-blockers •• CardioselectiveCardioselective ββ--blockersblockers withoutwithout ISAISA • Increase LV EF and reverse remodelation• Increase LV EF and reverse remodelation • β-blockers on same level of therapeutic value in HF as iACE ! DiureticsDiuretics and HFand HF • Decrease of water retention – Antiedematous and hypotensive activity – Decrease of filling pressure in myocardium– Decrease of filling pressure in myocardium – Decrease of pulmonary congestion DiureticsDiuretics and HFand HF •• looploop diureticsdiuretics –– furosemidfurosemid,, torasemide,, •• sulfonamidessulfonamides –– HCHTZ,HCHTZ, chlorthalidonchlorthalidon,, indapamidindapamidindapamidindapamid • Aldosterone antagonists – spironolactone – Eplerenone – (finenrenone) – clinical trials DiureticsDiuretics and HFand HF –– adverseadverse effectseffects • Mineral imbalance – Hypokalaemia (digitalis glycosides) – Hyperkalemia (spironolakton) – hypomagnesemia– hypomagnesemia • Metabolic adverse effects DiureticsDiuretics andand HFHF •• FUROSEMIDEFUROSEMIDE – Dose dependent diuresis – Without estimated maximum dose– Without estimated maximum dose – Long time administration of loop diuretics leads to nephron hypertrophy and failure of excretion mechanisms in nephron loop - diuretic resistance 29 DiureticsDiuretics andand HFHF • Monitoring K++ and minerals (Na+, Cl-, Ca2+) • Acute heart failure in i.v. formulation• Acute heart failure in i.v. formulation continual infusion or i.v. bolus • Bowel edema DIURETIC RESISTANCE – Inability of kidneys to excrete 90 mmol Na+ – After administration of oral dose of furosemide – 2x 160 mg in period of 72 hrs– 2x 160 mg in period of 72 hrs [Epstein et. al., 1977] 31 DIURETIC RESISTANCE • Causes ??? – Absorption failure due to bowel edema, possible bowel mucose blood hypoperfusion – Renal hypoperfusion– Renal hypoperfusion – Long-time administration of high dose diuretic therapy (loop hypertrophy) DIURETIC RESISTANCE • SOLUTION ? – Low dose of sulfonamide diuretics – Hydrochlorothiazide 12,5 mg – 25 mg in combination with loop diuretics SpironolactoneSpironolactone – Aldosterone antagonist – Absent diuretic activity – Prevents loss of potassium and protone – Sodium and cloride secretion in distal tubulus– Sodium and cloride secretion in distal tubulus – Inhibition of LV remodelation – 10 % male patients - gynecomastia 35 EPLERENON (INSPRA, PFIZER)EPLERENON (INSPRA, PFIZER) • Selective aldosterone antagonist • Advantageous properties of spironolactone • Without hypertrophy effects of spironolactone DigoxinDigoxin and HFand HF –– mechanismmechanism ofof effecteffect and toxicityand toxicity DigoxinDigoxin and HFand HF • Block Na+/K+-ATPase • DIG trial • 0,125 – 0,250 mg p.o. • 0,500 mg i.v. -• 0,500 mg i.v. • Requires TDM (0,5-1,5 ng/mL) • Risk of toxicity increases in corelation to diuretic dose and patient age DigoxinDigoxin and HFand HF • Binding to albumin (25 %) and tissue distribution (skeletal muscles) • p-glycoprotein substrate • Enterohepatal circulation DigoxinDigoxin –– CVS mortalityCVS mortality datadata The Digitalis Investigation group.: The Effect of digoxin on mortality and morbidity in patients with heart failure. N Eng J Med.1997;336: 525-533 DigoxinDigoxin –– HF mortalityHF mortality datadata The Digitalis Investigation group.: The Effect of digoxin on mortality and morbidity in patients with heart failure. N Eng J Med.1997;336: 525-533 NovelNovel moleculesmolecules inin developementdevelopement forfor HFHF treatmenttreatment –– clinicalclinical trialstrials inin progressprogress • OMECAMTIV MECARBIL • SERELAXINE• SERELAXINE • ULARITIDE OMECAMTIV MECARBILOMECAMTIV MECARBIL • Myosine activator • Cardiotonic activity • 2.phase of clinical trials finished – HF decompensation • Good p.o. bioavailability OMECAMTIV MECARBIL (AMGEN)OMECAMTIV MECARBIL (AMGEN) • 2nd phase clinical trial – Tested parenteral administration • 75 mg/L i.v. infusion • 4 hrs loading dose • 44 hrs maintenance dose • Dose dependent limiting factor – Myocardium ischemia Thank you milan.juhas@fnusa.cz