Adobe Systems Výsledek obrázku pro léÄ�ba srdeÄ�nÃho selhánà Adobe Systems §Ischaemic Heart Disease §Cardiomyopathy §Arterial hypertension §Severe dysrrhytmias §myocarditis Acute Coronary Syndroma (AIM…) ü pulmonary oedema ü cardiogennic shock Hypertension crisis Acute arrhytmia….. right, left ventricles CHRONIC üde novo üdecompensation of CHF Systolic failure Diastolic failure (decreased contractility) (more often in older patients) Vital organs chronically suffer from inadequate blood perfusion (caused by dysfunction of the myocard of ventricles due to various diseases)… ACUTE Adobe Systems Cardiac output CO = Stroke volume SV x Heart rate HR Decreased CO…. ↓ SV or ↓ HR Primary compensation by ↑ HR… leads to ↑ metabolic demand…vicious circle Factors influencing SV… Preload Contractility Afterload = fiber length-dependent activation…tension of the heart muscle before contraction (EDV) = Resistance to which the heart must pump blood = cardiac contractility (inotropy) Adobe Systems Compensatory mechanisms of HF… Adobe Systems ñPreload ñ Afterload Ventricle volume overloading Ventricle pressure overloading ↑ Contractility and Stroke volume ð activation of sympathetic activity ↑ Enddiastolic volume ðmuscle contraction less efficient ð RAAS activation Hypertrophy of left vetricle §Fluid and Na+ retention §Peripheral vasocontriction §Metabolic decompensation inotropics diuretics spironolakton ACEi/sartans Adobe Systems CHRONIC HEART FAILURE Adobe Systems §Shortness of breath (at rest or exertion) §Fatigue §Oedema §tachycardia §tachypnoe §peripheral oedema §hepatomegaly Clinical symptoms… Adobe Systems ACEi /sartans THE DRUG OF FIRST CHOICE FOR HEART FAILURE ARNI Valsartan + sakubitril (inhibitor of neprilisin) Nesiritide je rekombinant human natriuretic peptid type B . RAAS inhibition ð affect heart remodelation ð↓ vascular resistance (↓ volume + vasodilatation) ↓ afterload ↓ preload Adobe Systems Beta-blockers or Bradins ò SF Decreased sympathetic activity (indicated only in patients with compensated HF) The pacient have to be haemodynamically stabilised before BB teratment. Start with low dose, that incease if tolerated ( 1-2 weeks interval) ò dromotropic effect ò chronotropic effect Adobe Systems Aldosteron – antagonists §Antagonists of AR §Inhibit fibroblast proliferation Second line tretament (ACEi a BB as firt choice) – some RCT show decreased mortality (low dose add-on therapy ) spironolakton Not combine with other potassium- sparing diuretics Adobe Systems Drugs with positive inotropic effect ↑ contractility (inotropy) Cardiotonics Katecholamins PDE-3 inhibitors 1.↑ Ca2+ v sarcoplasma ð ↑ Ca2+ influx ´ ð beta-receptor stimulation ð signaling pathway interference Calcium sensitizers 2. ↑ binding of troponin C to the action of Ca2+ Adobe Systems ACUTE HEART FAILURE Adobe Systems Acute Coronary Syndroma ü pulmonary oedema ü cardiogenic shock Hypertensive crisis Acute arrhytmia Acute myocarditis cardiomyopathy Aortic dissection Acute valvular regurgitation… ACUTE HEART FAILURE Strong diuretics – furosemid i.v. Bolus, continual infusion Nitrates (nitroglycerin i.v. ) – BP monitoring !! Inotropics levosimendan dopamin ð vasocontrction - incease BP + renovascular vasodilatation dobutamin Acute oedema Hypertensive crisis ↑ contractility Antiarrhytmics beta blockers amiodaron digoxin Severe systemic hypotension norepinephrin i.v. Cardial Intervention PTCA, PCI (angioplasty, stents) DIURETICS and aldosteron antagonists DIURETICS Mechanism of antihypertensive action: - decrease in plasma volume - decrease in peripheral resistance - vasodilatation - act via several mechanisms directly in kidney on different parts of nephron: proximal tubules ascending limb of Henle loop distal tubules collecting ducts Adobe Systems CLASSIFICATION oTHIAZIDES (distal tubules) oLOOP DIURETICS oPOTTASIUM-SPARING DIURETICS ALDOSTERON RCP: ANTAGONISTS oCARBOANHYDRASE INHIBITORS (proximal tubulus) oOSMOTIC DIURETICS Cl-/Na+ symport inhibition in distal tubules. Inhibition of Na+ resorbtion ð inhibition of H2O reabsorbtion ð ↑ diurhesis Na+ transport capacity in distal tubulus (5-8%) ð lower diuretic effect Thiazides (distal tubules) MECHANIS OF ACTION §if ↓ GFR 0,5ml/s…loop diuretics indicated slow onset af antihypertensive effect Adobe Systems Thiazides PK - well absorbed, excreted in proximal tubules - diuretic effect lasts up to 12 hours, hypotensive effects with 3-4 days delay - latency occurs also in withdrawal INDICATION §Hypertension (essential), manly in combination §Heart Failure (prevention of cardial oedema) AE hypokalaemia, metabolic alkalosis, hyperuricemia, hypovolemia Adobe Systems vhydrochlorothiazid vchlortalidon longer half-life than hydrochlorothiazid vindapamid vmetipamid indapamid in combination with ACEi in DM patients (prospective RCT) DRUGS Thiazides Adobe Systems Inhibition of 4 ions contransport (Na, K, 2xCl) Loop diuretics MECHANIS OF ACTION -very strong, short effects (significant loss of ions) - -RAA system activation – long-term treatment is not recommended . Adobe Systems Loop diuretics furosemid Strong effect Also in patients with ↓ GF DRUG INDICATION •lung oedema •congestive heart failure •hypercalcemia (furosemid) •chronic renal failure •forced diuresis (intoxications) •post-operative anuria Adobe Systems AE DRUG INTERACTIONS §Ion imbalance (loss of Na+, Cl-, K+, Ca2+, Mg2+) §Osteoporosis §Hypovolemia ð risk of trombosis Furosemid bounds to albumin ð ↑ plasmatic level of metformin, amiodaron, digoxin,… ↑ Nephrotoxicity of cefalosporins Loop diuretics Adobe Systems Na+/K+ antiport inhibition through direct channel affecting, or as aldosterone receptor inhibitors Potassium sparing diuretics aldosteron. rcp. antagonists MECHANISM OF ACTION Potassium sparing diuretics Antagonists of aldosteron receptors aldosteron receptor antagonisation Directly ion channel Adobe Systems § inhibition of resorbtion Na+ ionts + H2O § inhibition of excretion K+ ionts → potassium sparing Antagonists of aldosteron receptors: üExtrarenal effect - inhibition of fibroblast proliferation in myocard and vessels üMg2+ sparing § Indicated for pts. with HF Adobe Systems DRUG Potassium sparing amilorid Weaker effect, used in combinations with other potassium-loss causing diuretics Hypertension in combination Prevention of cardial oedema INDICATION Adobe Systems DRUG Antagonist of aldosteron spironolakton (often combined with furosemide) positive effects on remodelation → in heart failure also in monotherapy Antiandrogenic effect üInhibition of bounding of testosteron to rcp. üInhibition of P-glp efflux pump AE - gynecomastia, menstruation problems Adobe Systems eplerenon MoA: Selective antagonist of mineralokortikoid receptors §Hypertension (in combination with furosemid, e.g. resistent HT form) §Primary hyperaldosteronism §Heart failure INDICATION Advantages: −useful combinations with others AHT −increase effect of other AHT effects −no influence on CNS −cheap Disadvantages: −metabolic effects (thiazides) −low tolerance (elderly) Diuretics in general AE: −potassium depletion (except K+ sparing) −hyperuricemia (thiazides, loop diuretics) −weakness, nausea −imbalance in glycid and lipid metabolism (thiazides) −hypovolemia, hypotension (furosemid) −hyperkalaemiaa (amiloride, spironolactone) −Chronic therapy – disruption of kidneys functioning − CI: −gout (thiazides) −renal failure, hyperkalaemia (K+ sparing) −relative: pregnancy, metabolic syndrome Diuretics Adobe Systems INDICATION of diuretics (general) Loop diuretics §HT older pts. §Systolic isolated HT §Chronic heart failure in combination §HT in renal insufficiency §Chronic heart failure Hyperkalcemia §Pulmonary oedema K-sparing Aldosteron antagonists §Resistent form of hypertension (spironolakton) §HT and primary hyperaldosteronism (spironolakton) §Chronic heart failure Thiazides + ACEi /sartans Previous lecture DRUGS with POSITIVE INOTROPIC EFFECTS Cardiac glycosides (cardiotonics) Katecholamines PDE-3 inhibitors Ca2+ sensitizers Adobe Systems Cardiac glycosides (cardiotonics) MECHANISM OF ACTION: §Inhibition of Na+/K+ ATPasa pump ð increase intracellular sodium concentration (Na+/Ca+ exchange transporter ð secondary rise of Ca2+ - ð increased contractility ð ↑inotropic effect efekt §Activation of parasympatics (n. vagus) and ACH release ð SA node, AV conduction slow ð ↓ chronotropy ð ↓ dromotropy ð antiarrhytmic effect DRUG digoxin Adobe Systems Cardiac glycosides (cardiotonics) Adobe Systems PHARMACOKINETICS §t1/2 = 36 hours §TDM (plasma level 0,5–1,5 ng/ml) §Variable bioavailability (50-70 %) §P-glp pump substrate (drug interaction ! ) §Binding to the albumin 20-40% §Renal elimination, GFR depending §Liver metabolization app. 20 % Adobe Systems ADVERSE EFFECTS Cardial, CNS and GI – clinically significant DIGITALIS INTOXICATION Cardial signs §↓ intracelullar K+ leds to ↑ excitability (tachyarrhytmia) §Parasympatic activation (sinus bradycardia, AV blocades) Others : CNS: Visual disturbance (yelow colors, disorientation, confusion GI: Anorexia, nausea, vomiting Adobe Systems DRUG INTERACTIONS Strong or moderate Pglp pump inhibitors …should increase plasmatic level of digoxin verapamil, amiodaron, propafenon, telmisartan, cyklosporin, antimycotics (ketokonazol), macrolides ATB (clarithromycin) DIGITALIS INTOXICATION Hypocalemia should leads to digoxin intoxication Adobe Systems INDICATION CONTRAINDICATION §AV blockades §Cardial insufficiency with bradycardia §Digoxin intoxication RELATIVE: aIM §Chronic HF §Sinoatrial tachyfibrilation Adobe Systems Catecholamines norepinephrin α1 rcp. agonist increase BP Dose-dependent D rcp. ð renovascular dilatation β1 rcp. ð inotropic effect ↑ dose α1 rcp. Agonist ð increase BP dopamin INDICATION Severe hypotension (NA) Vasodilatation of renal vessels (dopamin) Adobe Systems Catecholamines adrenalin, dobutamin INDICATION Acute HF, cardiopulmonal resuscitation PK: §Low bioavailability ð i.v. administration §Short half-life (2 minutes) AE: Arrhytmogenic effect cAMP-dependent phosphodiesterase- myocardial isophorm3 - inhibitor ðarterial dilatation (reduction of afterload) ð cardiostimulation (+ chrono-, ino- a dromotropic effects) PDE-3 inhibitors DRUGS milrinon AE: §Decreased BP, headache §Proarrhytmogenic effect – less used MECHANISM OF ACTION INDICATION Treatment of acute and refractory HF §↑ the force of contraction of the heart by binding troponin C and sensitising it to the action of Ca2+ ð §Binds to the KATP channel – membrane hyperpolarization ð ↓ opening of the CaL channel ð vasodilatation (systemic, lung) Calcium sensitizers agent DRUG: levosimendan MECHANISM OF ACTION INDICATION Acute HF PK: i.v. infusion Metabolised to active metabolite with long half-life (80hrs) ANTIARRHYTMICS Antiarrhythmic agents Vaughan-Williams classification (based on electrophysiological effects, 1970) Active agents Clinical use MoA Class I a Prajmalin Limited use Interfere with Na+ channel / effects on cardiac potentials Class I b Lidocain Ventricular tachycardia Class I c Propafenon Atrial fibrilation, reccurent tachyarrhythmias Class II B –blockers (metoprolol, atenolol Tachyarrhythmias decrease conduction through the AV node Class III Amiodaron, Sotalol Dronedaron Ibutilid Vetnricular tachycardia Atrial fibrilation - the most effective AA K+ channel blocker, prolong repolarisation ( QT int.) Class IV Ca channel blockers Atrial fibrilation - rate reduction Paroxysmal supraventricular tachycardia prevention Ca++ channel blocker Drug class Mechanism of action Drug Cardiac glycosides Parasympathetic activation digoxin Bradins ↓ depolarization of SA pacemaker ivabradin Agonists of β1 rcp positive chronotropic, dromotropic, bathmotropic effects catecholamines ↓ depolarization of SA and decreased AV conduction adenosin Others… Adobe Systems THE PHASE OF ACTION POTENCIAL Phase 0: rapid depolarition Phase 1: partial repolarization Phase 2: plateau Phase 3: final repolarization Phase 4: resting stage Adobe Systems Výsledek obrázku pro kÅ™ivka AKÄŒnÃho potenciálu IV. class Ca2+ III. class K+ I. class Na+ II. class Four classes of antiarrhytmics Adobe Systems ANTIARRHYTMICS class I Subgroups: IA prajmalin Risk of torsade de pointes IB lidokain IC propafenon Prophylaxy and treatment of supraventricular arrhytmias Class I drug block sodium channel §Inhibit action potential propagation in excitable cells §Membrane-stabilising activity ð reduce the maximum rate of depolarisation Now seldom used Adobe Systems ANTIARRHYTMICS class II Antiarrhytmic effect caused by lowering of proarrhytmogenic effect of sympathetic activity (negative chrono-,dromo- a bathmo-tropic effects) Leads to: §Increase the refractory period of the AV node §Prevent reccurent attacks of SVT § ð prolongation of repolaritazion INDICATION: §Prophylaxy of supraventrikular and ventricular tachyarrhytmias §Sinoatrial fibrillation Adobe Systems ANTIARRHYTMICS class III Class III inhibit potassium channel involved in cardiac repolarization, mainly Ikr ð prolong the cardiac action potential ð prolong repolarization The most often used DRUGS amiodaron, sotalol INDICATION §Pharmacological cardioversion (fibrillation or flutter) §Prophylaxy of fibrillation or flutter superior in reducing the recurrence of ventricular arrhythmias and atrial fibrillation – but many Aes ! Adobe Systems Amiodaron pharmacokinetic: §Active metabolite (desmetylamiodaron) highly lipophilic ð accumulates in the liver, skin and fat Bioavailability of amiodarone is quite variable (ranges 22 to 95%, with better absorption when it is given with food) Loaded dose (3-6x higher for weeks, orally) Extensively bound in tissues Long elimination half-life (40-50 days) §Biotransformation - izoenzymes CYP (mainly CYP2C9, CYP2D6, CYP3A4) §P glp inhibitor §Liver elimination Drug interaction Adobe Systems amiodaron x digoxin DRUG INTERACTIONS ↑ digoxin plasma level Dose changes P-glp. pump amiodaron x statins (simvastatin) amiodaron x CCB amiodaron x BB (lipophylic) ↑ plasma level – clinically significant P-glp. pump + CYP3A4 Adobe Systems Adverse effects dose-dependent 1.MoA §dysrrhytmia § decreased heart contractility 2. Specific AEs § reverzible corneal deposits §blue´discoloration of the skin is (10%) § irriversible severe lung fibrosis 3. Thyreoid toxicity § Hypothyreosis (10%) § Typerthyreosis (less common) All antiarrhytmics to avoid sun exposure due to photosensitivity Adobe Systems ANTIARRHYTMICS class IV Blocking voltage-sensitive calcium-channel §Slow conduction in the SA and AV nodes §Shorten the plateau of the action potential §Reduce the force of contraction Antiarrhytmic effect of verapamil is better than diltiazem Not indicated for patients with left vetricle dysfunction of heart failure Adobe Systems Other antiarrhytmics adenosin MÚ: activation of adenosin rcp. A1 in SA a AV nodes slow conduction Activation of rcp. A2 – vasodilatation I: re-entry arrhytmias PK: i.v. bolus centrally atropin (parasympatolytic effect) MoA: competitive inhibition of M2 rcp in SA a AV nodes I: treatment of sinus bradycardia PK: i.v. administration Adobe Systems Thank you for your attention