TreatmentTreatment ofof ischemicischemic heartheart diseasedisease –– coronarycoronary arteryartery diseasedisease (CAD)(CAD) Regina DemlovaRegina Demlova IschemicIschemic heartheart diseasedisease Group of diseases with the presence of myocardial ischemia, which occurs on the basis of the pathological process in the coronary vessels. Reducing the flow in coronary arteries>>> ischemia IschemicIschemic heartheart diseasedisease The cause • Organic - atherosclerosis (95%), thrombus, embolism, arteritis, etc. • Functional - coronary spasm • Combined Atherosclerotic plaque>> reduce the flow>> ischemiaAtherosclerotic plaque>> reduce the flow>> ischemia IschemicIschemic heartheart diseasedisease unstable AP nonQIM QIM (cTnI < 0,4 ug/l) (cTnI >0,4 ug/l) (cTnI > 0,4ug ) Risk factors: • Should not be influenced - age, gender, family history • Should be influenced - hypertension, hyperlipoproteinaemia, smoking, stress, obesity, physical inactivity, dietary habits IschemicIschemic hearthhearth diseasedisease Classification: • acute (unstable) - acute myocardial infarction, unstable angina, sudden death IschemicIschemic hearthhearth diseasedisease unstable angina, sudden death • chronic (stable) - angina pectoris (exertional, mixed, variant), silent ischaemia, arrhythmic forms • Angina pectoris: • Most frequent clinical manifestations of IHD caused by the myocardial ischemia, in which the patient has chest pain (stenocardia). IschemicIschemic hearthhearth diseasedisease patient has chest pain (stenocardia). • Imbalance between myocardial oxygen supply and demand Angina pectoris Main cause: • atherosclerotic plaque in coronary artery lumen stenosis lower than 50% - insignificantlumen stenosis lower than 50% - insignificant lumen stenosis above 50% - a significant lumen stenosis above 95% - critical Angina pectoris Classification of severity: I. stenocardia provoked by extraordinary exertion II. stenocardia provoked more than usual exertion III. stenocardia provoked by regular exertionIII. stenocardia provoked by regular exertion stenocardia IV. stenocardia provoked by minimal exertion or at rest Angina pectoris Clinical picture: constringent pain with / without feeling a lack of breath, pain with the propagation to the back, neck, shoulders, upper extremities. Usually it is a link to the previous load (walking, stress, food, ....) Typically takes a few minutes and gradually subsides after removal causing torque. • Angina pectoris Diagnosis: History - family, personal, pharmacological, social.. Problems - duration, time from first occurrence of pain, frequency, repetition, connection to the load,pain, frequency, repetition, connection to the load, etc. Complete clinical examination, exclusion of noncardiac etiology problems (nerve, muscle, gastrointestinal, pulmonary, other ... ..) Laboratory signs - Troponin-I, CK-MB Angina pectoris Diagnostic procedures: ECG – at rest and during exercise, 24-hour ambulatory monitoring, during of angina found in a typical case of ECG changes (depression /case of ECG changes (depression / ST segment elevation), between angina symptoms ECG is negative. Ergometer stress test Angina pectoris Diagnostic procedures: • Echocardiography: at rest and during the exercise • Coronary angiography – used to directly view the coronary field using a contrast agent injected into coronary arteries, allowing accurate identification of narrowing or occlusion vessel, its significance, may be determined by the residual flow of the affected artery TreatmentTreatment ofof CADCAD Objective: • to improve the quality of life • to improve patient prognosis Methods:Methods: 1st: stopping or slowing progress of atherogenesis 2nd: improve the flow of ischemic myocardium 3rd: prevention of vascular thrombus occlusion TreatmentTreatment ofof CADCAD • nonpharmacologic - lifestyle changes • pharmacological - drug therapy• pharmacological - drug therapy • intervention - PTCA with / without stent surgical revascularization TreatmentTreatment ofof CADCAD Non-pharmacological: Motion mode - aerobic (running, swimming, cycling, ....) Dietary measures - change in eating habits (limit saturated fats, increase the proportion of unsaturated fats, fish, vegetables, fruits) Abstinence of smoking, alcohol in moderation Mental relaxation - sports, culture, yoga, psychotherapyMental relaxation - sports, culture, yoga, psychotherapy Control of diabetes and hypertension TreatmentTreatment ofof CADCAD Interventions: • Percutaneous transluminal coronary angioplastic (PTCA) The principle consists from delivery of a catheter (thin tube - at the end of the cylindrical balloon) into the narrowed or closed coronary artery and the balloon expands narrow blood vessels. The next step may be followed by stent (metallic reinforcement) in place of the previous narrowing. • Critical stenosis of the left coronary artery solved successfully by PTCA with stent implantation. a peripheral or coronary stents (a scaffold) placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. Drug-eluting stents – DES The stent is usually placed within the peripheral or coronary artery by an Interventional cardiologist or Interventional Radiologist during an angioplasty procedure. CypherCypher sirolimussirolimus TaxusTaxus paclitaxelpaclitaxel BiomatrixBiomatrix,, NoboriNobori biolimusbiolimus XienceXience everolimuseverolimus Drug-eluting stents – DES XienceXience everolimuseverolimus EndevourEndevour tacrolimustacrolimus TreatmentTreatment ofof CADCAD Methods of interventional treatment: • Surgical revascularization Coronary artery bypass is the process of restoring theCoronary artery bypass is the process of restoring the flow of blood to the heart. The surgical procedure places new blood vessels around existing blockages to restore necessary blood flow to the heart muscle. Critical stenosis of the left coronary artery bypass solved successfully by surgery. TreatmentTreatment ofof CADCAD Methods of pharmacological treatment: 1st: stopping or slowing progress of atherogenesis1st: stopping or slowing progress of atherogenesis 2nd: improve the flow of ischemic myocardium 3rd: prevention of vascular thrombus occlusion MethodsMethods ofof pharmacologicalpharmacological treatmenttreatment:: 1st: stopping or slowing progress of atherogenesis control of risk factors: - correction of BP – antihypertension th.- correction of BP – antihypertension th. - corrections of lipids – hypolipidemics - DM – glucose control - antidiabetics MethodsMethods ofof pharmacologicalpharmacological treatmenttreatment:: 2nd: improve the flow of ischemic myocardium smooth muscle relaxation of coronary artery stenosis slowing the heart rate - a reduction of metabolic demandsslowing the heart rate - a reduction of metabolic demands reduction of myocardial contractility - improving coronary perfusion nitrates, beta-blockers, Ca-channel blockers, If-channel blockers MethodsMethods ofof pharmacologicalpharmacological treatmenttreatment:: 3rd: Prevention of vascular thrombus occlusion Antiplatelet/anticoagulants, such as aspirin or warfarin TreatmentTreatment ofof CADCAD Methods of pharmacological treatment: 1st: stopping or slowing progress of atherogenesis1st: stopping or slowing progress of atherogenesis 2nd: improve the flow of ischemic myocardium 3rd: prevention of vascular thrombus occlusion Hypolipidemics Statins: inhibition of HMGCoA (3-OH-3 CH3 glutaryl coenzyme A) reductase. Fibrates: activate lipoprotein lipase, reduces VLDL and increase HDL Ezetimibe: blocks absorption of Cholesterol in the intestine Niacin: blocking the breakdown of adipose tissue (inhibition of lipolysis) Resin: inhibiting resorption of bile acids TreatmentTreatment ofof CADCAD Methods of pharmacological treatment: 1st: stopping or slowing progress of atherogenesis1st: stopping or slowing progress of atherogenesis 2nd: improve the flow of ischemic myocardium 3rd: prevention of vascular thrombus occlusion MethodsMethods ofof pharmacologicalpharmacological treatmenttreatment:: 2nd: I . improve the flow and perusion of ischemic myocardium - smooth muscle relaxation of coronary artery stenosis II . Reduce its metabolic demand slowing the heart rate reduction of myocardial contractility • I+II : nitrates, Ca-channel blockers • II : beta-blockers + If-channel blockers Nitrates Nitroglycerin was synthesized by the chemist Ascanio Sobrero in 1847 Nitroglycerin is converted to nitric oxide in the body by mitochondrial aldehyde dehydrogenase NO - nitric oxide - identical to the 'endothelium-derived relaxing factor' (EDRF) is a natural vasodilator ( stimulation of guanylate cyclase of smooth muscle - relaxation-vasodilatation) NO Endothelial cell Nitrates = nitric oxid Enzymatic step – reaction with tissue sulfhydryl (-SH) groups guanylate cyclase → ↑cGMP ↑ ↓ relaxation - vasodilitation Smooth muscle NitratesNitrates • Effects: local x systemic LOCAL: the direct effect on coronary artery tone dilation of coronary arteries SYSTEMIC: venorelaxation – consequent reduction in central venous pressure – reduce preload Relaxation of lareger muscular arteries – reduce afterload NitratesNitrates • Adverse reactions: • headache, orthostatic hypotension, • onset of tolerance (possibly partly because of depletion of free –SH groups), mainly longeracting drugs NitratesNitrates • Representatives: Nitroglycerin (glyceryl trinitrate) - rapidly inactivated by hepatic metabolism - well absorbed from the mouth – is taken as a tbl.- well absorbed from the mouth – is taken as a tbl. under the tongue or sublingual spray – effects within few minutes - Effectiveduration of action app. 30 minutes - Well absorbed through the skin – transdermal patch NitratesNitrates • Representatives: Isosorbite 2-mononitrate (ISMN) longer acting – half-life app. 4 hours , the same farmacological action I: prophylaxy twice daily (morning, lunch time – toI: prophylaxy twice daily (morning, lunch time – to avoid tolerance) Isosorbit 2,5-dinitrate (ISDN) - iv Molsidomin (does not produce tolerance, use of overnight) ProphylaxisProphylaxis ofof anginaangina TreatingTreating thethe patientspatients withwith unstableunstable Beta - blockers TreatingTreating thethe patientspatients withwith unstableunstable anginaangina slowing the heart rateslowing the heart rate andand reductionreduction ofof myocardial contractilitymyocardial contractility CompetitiveCompetitive antagonistsantagonists ((intrinsicintrinsic activityactivity = 0)= 0) oror partialpartial agonistsagonists (ISA(ISA -- intrinsicintrinsic sympathomimeticsympathomimetic activityactivity)) Beta - blockers NonNon--selectiveselective oror cardioselectivecardioselective ((primaryprimary blocsblocs ofof bb11 receptorsreceptors)) Non-selective (ββββ1 + ββββ2) propranolol (Cardio)selective (ββββ1) metoprolol classification Non-selective with ISA (ββββ1 + ββββ2) S ISA pindolol (Cardio)selective (ββββ1) with ISA acebutolol Combining αααα + ββββ blocade = ββββ-blockers of II.generation labetalol BetaBeta blockersblockers IndicationIndication:: anginaangina pectoris,pectoris, hearthhearth failurefailure withwith titrationtitration tacharrhytmiatacharrhytmia, glaukom, glaukom ContraindicationContraindication::ContraindicationContraindication:: absoluteabsolute:: AVAV blockblock (grade 2(grade 2 oror 3),3), asthmaasthma,, AdverseAdverse eventsevents - Bronchoconstriction - Bradycardia - Hypoglycaemia - Fatique IIff blockersblockers ––SA nodeSA node Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node controlled by the If current (f is for "funny", so called because itf had unusual properties compared with other current systems known at the time of its discovery) IIff blockersblockers ––SA nodeSA node Ivabradine acts on the If ion current, which is highly expressed in the sinoatrial node. If is a mixed Na+–K If is one of the most important ionic currents forIf is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. IvabradineIvabradine (PROCORALAN)(PROCORALAN) • selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing thereduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium. IvabradineIvabradine –– indicationindication :: I: Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm. - in adults unable to tolerate or with a contraindication to the use of beta-blockers - or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose and whose heart rate is > 60 bpm. CalciumCalcium--channelchannel blockersblockers (CCB)(CCB) • works by blocking voltage-gated calcium channels in cardiac muscle and blood vessels. • ↓ intracellular calcium leading to ↓ cardiac contractility • In blood vessels ↓ vascular smooth muscle and therefore ↑ vasodilation. Vasodilation decreases total peripheral resistance. CalciumCalcium--channelchannel blockersblockers (CCB)(CCB) • 3 chemically distinct classes: - Phenylalkylamines - Benzothiazepines - Dihydropyrimidines - PhenylalkylaminePhenylalkylamine:: verapamilverapamil Preferentially affects Ca-channel in hearth Indications: antiarrhytmics Contraindications: Non DHP CCB Contraindications: absolute: AV block (grade 2 or 3), heart failure relative: bradycardia below 50/min, concomitant with BB BenzithiazepinyBenzithiazepiny :: diltiazemdiltiazem Affects both Ca-channel in hearth and in vessels Indications: angina pectoris Contraindications: Non DHP CCB Contraindications: absolute: AV block (grade 2 or 3), heart failure relative: bradycardia below 50/min, concomitant with BB DHP CCB DihydropyridineDihydropyridine CCBCCB Indications: elderly - angina pectoris, coronary disease of lower extremities, atherosclerotic carotid disabilitycarotid disability Contraindications: relative: tachyarrhythmias, heart failure Calcium-channel blockers (CCB) Class 1st generation 2nd generation Fenylalkylamines Benzothiazepines Dihydropyridines Verapamil Diltiazem Nifedipin Verapamil SR Diltiazem SR Nifedipin GITS Isradipin SRO FelodipinFelodipin Nitrendipin Nilvadipin Nisoldipin Nimodipin Amlodipin Lacidipin CalciumCalcium--channelchannel blockersblockers (CCB)(CCB) ADRs: results from vasodilation and the effect on the conduction system • headache, orthostatic hypotension, palpitations,• headache, orthostatic hypotension, palpitations, swollen ankles, • AV block non-DHP in combination with betablockers, significant bradycardia CombinationCombination ofof antianginousantianginous drugsdrugs • Nitrates + beta-blockers – a suitable combination • Nitrates + CCB – need BP corrections• Nitrates + CCB – need BP corrections • Beta-blockers+ CCB – a suitable, but ! AV block non-DHP in combination with beta-blockers, significant bradycardia