Výsledek obrázku pro ischemická choroba srdeÄ�nà Group of diseases with the presence of myocardial ischemia, which occurs on the basis of the pathological process in the coronary vessels. •Organic - atherosclerosis (95%), thrombus, arteritis.. •Functional - coronary spasm or combined • Reducing the flow in coronary arteries>>> ischemia angina-srdíčko koronární cévy 2 The commonest form of hearth disese caused by Atheroma in the coronary artheries, complcated by trombosis on ruptered atheromatous plaque Tato skupina je velmi heterogenní. Mezi další choroby patří hypertenze, chronické srdeční selhání (akutní, chronické ) – AP, IM, arytmie, …. Skupiny léčiv používané k léčbě ICHS nejsou specifické pouze pro léčbu ICHS, používají se některé z nich i k léčbě hypertenze, srdečního selhání, arytmie atd. anti-anginal drugs act indirectly by reducing cardiac work smooth muscle relaxation of coronary artery, reducing cardiac work Výsledek obrázku pro score chart cholesterol Risk factors §gender §Smoking status §Cholesterol level §Systolic blood pressure RISK STRATIFICATION of CARCIOVASCULARS DISEASE Strategy and type of pharmacotherapy STK = systolický krevní tlak SCORE = systematic coronary risk estimation Podrobněji budou mít na cvičení Inhibition of RAAS Inhibiton of sympathetic system* Increase of diuresis/natriuresis ACE inhibitors (ACEi) AT1 receptor antagonists (sartans) Renin inhibitors Natriuretic peptides Antagonization of β +/- α receptors Diuretics *Activation durig acute phase (NA, dobutamin) Vasodilatation Ca-channel blockers (CCB) Activation of pottasium-channel (A-KATP) Nitrates and NO donors Periferal vasoprotective drugs Inhibitors of phosphodiesterase-5 (PDE-5) ↑myocardial contraction Ca senzitizers Inhibitors of phosphodiesterasis-3 (PDE-3) Cardiac glycosides Coordination of cardiac rhytm Antidysrhytmics Drugs with positive effect on vascular endothelium Vazoprotectives Risk factors: •Should not be influenced - age, gender, family history •Should be influenced - hypertension, hyperlipoproteinaemia, smoking, stress, obesity, physical inactivity, dietary habits kouření obezita-muž Unstable angina Acute myocardial infarction Sudden death CLASSIFICATION Angina pectoris Silent ischaemia Syndrom X Dysrhytmias Exertional AP Mixed AP Variant AP •Most frequent clinical manifestations of IHD caused by the myocardial ischemia, in which the patient has chest pain (stenocardia). • Imbalance between myocardial oxygen supply and demand • Anti-anginal drugs act indirectly by smooth muscle relaxation of coronary artery and reducing cardiac work • Classification of severity: I. stenocardia provoked by extraordinary exertion II. stenocardia provoked more than usual exertion III. stenocardia provoked by regular exertion stenocardia IV. stenocardia provoked by minimal exertion or at rest Therapy of Ischaemic Heart Disese: §Non-pharmacological life-style, smoking, diet… §Pharmacological §Acute Intervention PTCA /PCI PTCA = Percutaneous transluminal coronary angioplasty PCI = Percutaneous coronary intervention (angioplasty with stent) DRUG_ELUTING STENTS cytostatics (tacrolimus, sirolimus, paclitaxel…) slowly releases a drug to block cell proliferation PTCA or Percutaneous Transluminal Coronary Angioplasty is the process of dilating a coronary artery stenosis using an inflatable balloon and a metallic stent introduced into the arterial circulation via the femoral, radial or the brachial artery. Percutaneous Coronary Intervention is another name given to this procedure. Therefore, there is no difference between PTCA and PCI. 1.Stopping or slowing progress of atherogenesis ð LIPID-LOWERING DRUGS Compenzation of DM ð ANTIDIABETICS 2.Provention of vascular thrombus occlusion ð ANTIPLATELET DRUGS Obesity as disease ð ANTI-OBESITY DRUGS Antiobezitika – zvláště, ty ze skupiny sym stopping or slowing progress of atherogenesis control of risk factors: - correction of BP – antihypertension th. - corrections of lipids – hypolipidemics - DM – glucose control - antidiabetics patomimetik nejsou ideální pro KVS , především ICHS, protože zvyšují práci srdce Prevention of vascular thrombus occlusion 3.Improvement of coronary blood flow Drugs that improve improve perfusion of the myocardium ð1. NITRATES and NO donors 2. CALCIUM CHANNEL BLOCKERS - dihydropyridines Pottasium-channel activation ð3. BETA-BLOCKERS 2. CCB -non-dihydropyridines 4. IVABRADIN (I f ) 4.Reducing the metabolic demand (slow the heart) VASODILATOR DRUGS Play a major role in the treatment of cardiovascular diseases (able to relax vascular smooth muscle) Teď si probereme skupinu léčiv, která jsou schopna navozovat relaxaci hladké svaloviny cév, ne všechny skupiny jsou však vhodné pro ICHS, ale jejich indikací je třeba arteriální hypertenze, o které budeme více mluvit příští hodinu VASODILATION should be achieved by: A.Plasma membrane voltage-dependent calcium channel §Calcium antagonists ð CCB §Activation of ATP-sensitive pottasium channel ð A-KATP B.Increasing cellular concentration of cAMP/cGMP §Nitric oxide increase ð nitrates and NO donors §Inhibition of phosphodiesterase-5 ð PDE-5 inhibitors C.Increase cytoplasmic cyclic nucleotides ð prostacyclines D.Blocade of endothelin system § inhibition of endothelin rcp. ETA a ETB ð antagonists of endothelin rcp. Of either cAMP or cGMP vCALCIUM Channel Blockers (CCB)/ CALCIUM Antagonists / CALCIUM Entry Blockers They block entry rather than preventing the intracellular action •Ca2+ channel blockers/ Ca2+ antagonists/ Ca2+ entry blockers/ works by blocking voltage-gated calcium channels type L in cardiac muscle and blood vessels. sinoatrial node (SA) and atriventricular node (AV) – Ca2+ initiates action potentials ð controlling cardiac rate and rhythm ↓ intracellular calcium leading to ↓ cardiac contractility In blood vessels ↓ vascular smooth muscle and therefore ↑ vasodilation. Vasodilation decreases total peripheral resistance Mechanism of Action - block cellular entry of Ca2+ through voltage-gated L-type channels Vazodilatation ð periferal resistence decreased Vascular Smooth Muscle (generalised arterial/arteriolar dilatation, coronary vasodilatation) (biliary, urinary tract, uterus – less important therapeutically ) Cardiac action (SA, AV nodes) negative inotropic, chronotropic and dromotropic effects „selectivity“ of CCB The main effects are on cardiac and smooth vessles Other type of smooth muscle aleso relaxed DIHYDROPYRIDINES NON-DIHYDROPYRIDINES §Greater effect on vascular smooth muscle and coronary vessels than on the hearth §Preferentially effects the heart (AV block and cardiac slowing by their actions on conducting tissue, but causes reflex tachycardia) Classification accoring to half life… CCB = relatively cardioselective = relatively smooth muscle selective ØShort half-life NIFEDIPIN immediatelly causes vazodilatation ð reflex tachycardia ØLong half-life AMLODIPIN, LACIDIPIN Highly vasoselective CCB ØIntermediatte half-life FELODIPIN NITRENDIPIN, LERKANIDIPIN DIHYDROPYRIDINES SR drug form INDICATION §Hypertenzion (monotherapy or combination) CONTRAINDICATION §Cardiogenic shock, acute hearth failure CCB DIHYDROPYRIDINES ADVERSE EFFECTS §Dose-dependent perimaleolar oedema flushes, gingival hyperplasia (dose-dependent). Conventional drug forms Headache, flushes, palpitation, hyponsension, rexlef tachycardia CCB NON-DIHYDROPYRIDINES DILTIAZEM, VERAPAMIL SA a AV nodes: §negative chronotropic ò action potential in SA node §negative dromotropic effect ò rate of conduction §negative batmotropic effect ò irritability §negative inotropic effect ò force of contraction (SR – slow release forms) ANTIDYSRHYTMICS IV. class (Vaughan/Williams) §Treatment and prophylaxy of supraventricular tachyarhytmias §Treatment of preeclampsia (verapamil) §SA blocade, AV-blocade type 2.a 3. §bradycardia (↓ 50 beats/min) §Non-compensated heart failure with ↓ systolic function §Gravidity (exemption for life-threatening condition – eclampsia) CCB INDICATION CONTRAINDICATION NON-DIHYDROPYRIDINES ADVERSE EFFECTS §Negative inotropia - bradykardia §obstipation (smooth muscle GI) (VERAPAMIL) CCB NON-DIHYDROPYRIDINES PHARMACOKINETICS RISK OF DRUG INTERACTION §High protein binding §Variable bioavailability (0-30%) §Variabile half-life §cytochrom P450 involved - inhibitors CYP3A4 and substrate of P-gp DILTIAZEM, VERAPAMIL ð ↑plazmatic concentration of statins Phenobarbital, fenytoin, karbamazepin ð decrese plasmatic level of verapamil and diltiazem CCB – VERAPAMIL, DILTIAZEM VERAPAMIL + digoxin ð renal excretion decreased vPOTTASIUM-CHANNEL ACTIVATORS (A-KATP) MINOXIDIL, NIKORANDIL currently not available in CZ Opening of KATP leads to ↑ sarcoplasmatic pottasium draslíku ðmembrane hyperpolarisation ð ativation of CaL decreased I: patients who remain symptomatic despite optimal management vOrganic Nitrates MECHANISM OF ACTION Metabolised to nitric oxide – stimulation of guanylyl cyclase ð incerasing formation of cGMP ð ↓ intracellular calcium ð Smooth muscle relaxation NO donors Nitrates Enzymatic step – reaction with tissue sulfhydryl (-SH) groups - S-nitrosothiol and NO release Depletion of free SH-groups ð tolerance (with longer-acting drugs) Should be administered with prolonged effect MLC kináza /LCM – kináza (používány oba pojmy) = myosin light chain kináza, která fosforyluje lehké řetězce myosinu a aktivuje tvorbu aktin-myozinových můstků, což je princip kontrakte hladkých svalů Nitrates lNitroglycerin was synthesized by the chemist Ascanio Sobrer in 1847 lNitroglycerin is converted to nitric oxide – NO - identical to the 'endothelium-derived relaxing factor' (EDRF) l lLOCAL: the direct effect on coronary artery tone - dilation of coronary arteries l lSYSTEMIC: venorelaxation – consequent reduction in central venous pressure – reduce preload l lRelaxation of larger muscular arteries – reduce afterload §GLYCERYL TRINITRATE (Nitroglycerin®) t1/2 3 minutes risk of tachyfylaxis / repeated admin. §ISOSORBID DINITRATE (ISDN) active metabolite ISMN with longer t1/2 Drugs Short-acting ADMINISTRATION SUBLINGUAL / i.v. / INHALATION Short – acting (15-30 min) Unstable angina i.v. INDICATION Treatment of stenokardias (sublingual) (i.v. infusion, higher doses lead to hypotension) Acute heart failure, HT crisis, aortal aneurysm §ISOSORBID 5-MONONITRÁT (ISMN) (t1/2 5 hod.) metabolised more slowly §Taken twice a day for prophylaxy – morning and lunch, nitrate-free period to avoid tolerance §MOLSIDOMIN DRUGS Long-acting Prophylaxy of Stable angina INDICATION ADMINISTRATION Orally swallowed, SR formulation §Concomitant administration of PDE-V inhibitors (sildenafil,…) CONTRAINDICATION §headache §Ortostatic hypotension §Tachycardia §Flush §Long-acting nitrates – tolerance, short-acting tachyphylaxis ADVERSE EFFECTS Usually well tolerated VASODILATATORS… vInhibitors of phosphodiesterase-5 (PDE-5-inhibitors) vEndothelin-1 receptor antagonists vSyntetic analogs of prostacyclins vInhibitors of phosphodiesterase-5 (PDE-5-inhibitors) MECHANISM OF ACTION Specifically inhibit isoform 5 of cGMP-dependent phosphodiesterase in in the corpus cavernosum ð increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood CONTRAINDICATION §Arterial and orthostatic hypotension §Aortal stenosis §Hypertrofic cardiomyopathy §Retinitis pigmentosa §Retinopathy cGMP je druhý posel v signální kaskádě guanylátcyklázových receptorů DRUGS Liší se rychlostí nástupu účinku a jeho délkou Onset 1 hod; effect 4-6 hours SILDENAFIL VARDENAFIL Onset 2 hod; effect 24-48 hours TADALAFIL Onset 30 min; effect 12-24 hours AVANAFIL Pulmonary hypertension Erectile dysfunction BHP Pulmonary hypertension INDICATION BHP = benigní hyperplázie prostaty ADVERSE EFFECTS §headache, flush, dyspepsia, nasal congestion §Mild or moderate transient difference in colour discrimination (blue/green) §priapism RARE: Vasodilatation and hypotension, dysrhytmia and heart failure SILDENAFIL A VARDENAFIL inhibit partly also PDE 6 involved in phototransduction cascade in retina Drug interactions ! nitrates or another drugs ↑cGMP Priapismus = (dlouhotrvající a neustupující erekce) vEndothelin-1 receptor antagonists INDICATION Pulmonary hypertension MECHANISM OF ACTION Block binding of endothelin-1 to ETA a ETB – pulmonary arthery pressure decreased DRUGS BOSENTAN - competitive non-selective antagonist of rcp ETA i ETB AMBRISENTAN -selective antagonist of receptoru ETA Teratogenic. ADVERSE EFFECTS Hepatotoxicity (FDA requires monthly monitoring of liver function tests), anaemia (hematocrit) Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes constriction of the pulmonary blood vessels. By blocking this interaction, bosentan decreases pulmonary vascular resistance. Bosentan has a slightly higher affinity for ET-A than ET-B vSyntetic analogs of prostacyclins MECHANISM OF ACTION Increase cyclic nucleotides by increasing adenylyl cyclase aktivity – directly acting vasodilatators INDICATION Pulmonary hypertension EPOPROSTENOL: only i.v. infusion, t1/2 3-5 min. ILOPROST: t1/2 20-25 min. i.v., peroral or inhalation TREPROSTINIL: s.c. nebo i.v. infusion DRUGS Prostacyclins = prostaglandines PGI2 Prostacyklin je endogenní prostaglandin, který má kromě vazodilatačního účinku také cytoprotektivní vliv, snižuje adhezi leukocytů k cévní stěně, inhibuje agregaci destiček, snižuje tvorbu a sekreci endotelinu a vede k inhibici migrace a proliferace buněk. 3.Improvement of coronary blood flow Drugs that improve improve perfusion of the myocardium ðNITRATES and NO donors CALCIUM CHANNEL BLOCKERS - dihydropyridines Pottasium-channel activation ðBETABLOKÁTORY BKK-non-dihydropyridiny BRADINY 4.Reducing the metabolic demand (slow the heart) Back to previuos slides – cíle farmakoterapie ICHS Β-adrenoceptor antagonists (beta-blockers, β sympatolytics) Reverzible antagonization of adrenergic β receptors (antagonists of endogenous katecholamins) Competitive antagonists (intrinsic activity = 0) or Partial agonists (ISA - intrinsic sympathomimetic activity) MECHANISM OF ACTION Non- selective cardioselective Competitive antagonists (intrinsic activity = 0) or partial agonists (ISA - intrinsic sympathomimetic activity) Non-selective or cardioselective (primary blocs of b[1] receptors) Cardiovascular effects of BB oAntihypertensive action reducing sympathetic activity, decreased heart rate, reduction in cardiac output, reduction of renin release oMyocardial action negative chronotropic (HR), inotropic (contractility) dromotropic (vedení vzruchu) a bathmotropic (excitability) oCardioprotective effects - antiischaemic (decreased heart rate, reduction in cardiac output ð decreased myocardial oxygen consumption) - antidysrhythmic (II. class) ð better coronary flow Antagonisation of endogenous katecholamins (through β rcp.) §bronchoconstriction §reduction of renin release §metabolic effects (↓glycogenolysis, lipolysis) §Antiglaucomatic effect § Long term use of β blockers ð hypersensitization , receptor up-regulation ð REBOUND FENOMEN oSelectivity (non-selective x cardioselective) oPartial agonistic aytivity ( with ISA x withou ISA) oCombined effect (antagonisation of α -receptor, direct vasodilatation) CLASSIFICATION ISA - β1 rcp. ð increase the heart rate at rest, but reduce during exercise Lipophylic §High resorption from GI §High first pass efect and protein-binding §Longer t1/2 §Central effects (cross HEB) §CYP2D6 metabolization PHARMACOKINETIC üGenetic polymorphism ð AUC difference 10-30x üDrug interaction with CYP2D6 inhibitors Depends on lipophylity/hydrophylity METOPROLOL Preferably SR form Bylo zjištěno, že AUC lipofilních betablokátorů se liší u rychlých a pomalých metabolizérů 10-30 násobně. Např, metoprolol má plazmatický poločas u pomalých metabolizérů víc než 10 hodin, u středních a rychlých (většinová populace) 3-5 hodin, u velmi rychlých jen 2 hodiny. Hydrophylic §Decreased resorption §Don´t cross HEB §↓ t1/2 §Renal excretion – glomerulal filtration PHARMACOKINETIC Depends on lipophylity/hydrophylity Variable half-life …2-10 min (esmolol - hydrophylic); 30-50 hod (nebivolol- lipophylic) ! Renal insuficiency Metabolised to an active metabolite that potentiates the L/NO pathway - vasodilatation sotalol hydrophilic timolol hydrophilic Antiglaucomatic drug ISA + karteolol NON_SELECTIVE β1 + β2 receptors atenolol hydrophilic betaxolol hydrophilic (less) bisoprolol hydrophilic (less) metoprolol lipophylic esmolol hydrophilic t1/2 = 2-10 min ISA + acebutolol hydrophilic celiprolol hydrophilic ISA na β2-rp ðVAZODILATATION Combined nebivolol lipophylic t1/2= 30-50 hours CARDIOSELEKTIVE β1 selective 1) „1. generation“ Drugs CARVEDILOL - lipophylic LABETALOL - hydrophylic vSelective antagonist of α1-rp ð vazodilatation vNon-selective antagonist of β-receptors vReduction of renin release - ↓ RAAS vAntioxidative effect vINDICATION: hypertension, chronic cardiac failure vSelective antagonist of α1-rp ð vazodilatation vNon-selective antagonist of β-receptors v Partial agonist (ISA) of β2-rp vINDICATION: hypertension in pregnancy, i.v. severe hypertension crisis 2) Betablockers with combined activity (alpha and beta antagonists) „2. generation“ MAIN INDICATION MAIN INDICATION 4. Hearth Failure sympato-adrenergic hyperactivation decreased, antidysrhytmic effect BISOPROLOL, METOPROLOL (SR), KARVEDILOL, NEBIVOLOL only in well-compensated patients because of negative inotropic effect ! 5. Therapy and prophylaxy of dysrhytmias (II. class) supraventricular dysrhytmias, atrial fibrilation or flutter §Thyrotoxicosis §Severe infantile haemangioma §Benign essential tremor §Anxiety to control symptoms (palpitation, treamor…) §Glaucoma e.g. Timolol eye drops !! Up to 80 % eye drops should be absorbed - systemic effect - bradycardia and bronchospasm ! OTHER USES: ADVERSE EFFECTS Non-selective BB (through β2-rcp). §BRONCONSTRICTION ð relative KI: pacients with AB/CHOPN (…cardioselective nebivolol) §COLD EXTREMITIES §ERECTILE DYSFUNCTION §HYPOGLYCAEMIA §FATIGUE, INSOMNIA §CARDIOVASCULAR ü hypotension ü bradykardia ü AV-blocades CONTRAINDICATION §Hearth failure (exception well-compenated HF, low doses) §SA a AV blocades (II. and III. grades) §Hypotension §Bradycardia (<50 beats/min) RELATIVE CONTRAINDICATION §Astma bronchiale §COPD §Diabetes mellitus §Depression §Erectile dysfunction vBradines MECHANISM OF ACTION Selective inhibition the pacemaker If in SA node ð slowing the heart rate ð allowing more time for blood to flow to the myocardium (only negative chronotropic effect) DRUG IVABRADIN INDICATION §Symptomatic treatment of myocardial ischaemia in patients with AP / chronic heart failure NYHA II-IV §in adults unable to tolerate or with a contra-indication to the use of beta-blockers or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker