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Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD Jerzy Jankowski, MD.

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Presentation on theme: "Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD Jerzy Jankowski, MD."— Presentation transcript:

1 Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD Jerzy Jankowski, MD

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4 FORMS OF ANGINA PECTORIS (AP) ATHEROSCLEROTIC (CLASSIC) ANGINA ATHEROSCLEROTIC (CLASSIC) ANGINA VARIANT (VASOSPASTIC ANGINA) VARIANT (VASOSPASTIC ANGINA)

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7 Anginal conditions other than CAD causing chest discomfort Non-CAD causes of chest discomfort Syndrome X: Chest pain syndrome with objective evidence of ischemia and normal coronary arteries on angiography Prinzmetals angina: Vasospastic angina with normal or near- normal coronary arteries; can have Prinzmetals angina with significant CAD Aortic stenosis: Myocardial ischemia can be caused by an imbalance between the increased myocardial oxygen demand related to left ventricular hypertrophy and increased wall stress and the available coronary blood supply in the absence of coronary atherosclerosis Esophageal disease: Esophagitis, reflux, motility disorders

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9 ANTIANGINAL DRUGS ORGANIC NITRATES ORGANIC NITRATES ΒETA- ADRENORECEPTOR- BLOCKING DRUGS ΒETA- ADRENORECEPTOR- BLOCKING DRUGS CALCIUM CHANNEL- BLOCKING DRUGS CALCIUM CHANNEL- BLOCKING DRUGS METABOLIC AGENTS METABOLIC AGENTS HEART – RATE LIMITING AGENTS HEART – RATE LIMITING AGENTS

10 DRUG ACTION IN ANGINA DECREASE MYOCARDIAL O 2 REQUIREMENT BY: DECREASE MYOCARDIAL O 2 REQUIREMENT BY: decreasing peripheral vascular resitance decreasing peripheral vascular resitance decreasing cardiac output decreasing cardiac output both ways both ways INCREASE MYOCARDIAL O 2 DELIVERY INCREASE MYOCARDIAL O 2 DELIVERY nitrates nitrates calcium channel antagonists calcium channel antagonists

11 ORGANIC NITRATES

12 NTG, ISDN, IS-5-MN NTG, ISDN, IS-5-MN Donors of NO in vascular smooth muscle cells Donors of NO in vascular smooth muscle cells Induce cross-tolerance when given in large doses Induce cross-tolerance when given in large doses All are highly lipophylic All are highly lipophylic The lipophility (depending on the stereochemical configuration and the number of ONO2-groups) affects the degree of activation of guanylate cyclase, of the NO- release and of a rapid onset of efficacy (NTG > ISDN > IS-5-MN) The lipophility (depending on the stereochemical configuration and the number of ONO2-groups) affects the degree of activation of guanylate cyclase, of the NO- release and of a rapid onset of efficacy (NTG > ISDN > IS-5-MN) Due to a slow denitration IS-5-MN maintaines the effects for hours Due to a slow denitration IS-5-MN maintaines the effects for hours

13 ORGANIC NITRATES The higher the lipophylity of a nitrate, the higher the velocity of its uptake in different tissues The higher the lipophylity of a nitrate, the higher the velocity of its uptake in different tissues ( NTG > ISDN > IS-5-MN ), particularly in the smooth muscle cells of blood vessels ( NTG > ISDN > IS-5-MN ), particularly in the smooth muscle cells of blood vessels Nitrates are acting via the release of NO – they need intracellular SH-groups to form NO Nitrates are acting via the release of NO – they need intracellular SH-groups to form NO

14 PHARMACOKINETICS CHARACTERISTICS AFTER ORAL ADMINISTRATION AFTER ORAL ADMINISTRATION EXTENSIVE FIRST-PASS EFFECT (90%) EXTENSIVE FIRST-PASS EFFECT (90%) LOW BIOAVAILABILITY (10%) LOW BIOAVAILABILITY (10%) AFTER SUBLINGUAL ADMINISTRATION AFTER SUBLINGUAL ADMINISTRATION RAPID ONSET OF ACTION (1-3 min) RAPID ONSET OF ACTION (1-3 min) BRIEF DURATION OF ACTION (up to 30 min) BRIEF DURATION OF ACTION (up to 30 min)

15 MECHANISM OF ANTIANGINAL ACTION OF NITRATES DECREASED MYOCARDIAL O2 CONSUMPTION DECREASED MYOCARDIAL O2 CONSUMPTION - decreased LV dimension - decreased LV dimension - decreased LV filling pressure - decreased LV filling pressure - decreased LV systolic pressure - decreased LV systolic pressure - decreased vascular impedence - decreased vascular impedence INCREASED CORONARY BLOOD SUPPLAY INCREASED CORONARY BLOOD SUPPLAY - epicardial coronary artery dilation - epicardial coronary artery dilation - coronary stenosis enlargement - coronary stenosis enlargement - dilation of coronary collaterals - dilation of coronary collaterals ANTIPLATELET ANTITHROMBOTIC ACTION ANTIPLATELET ANTITHROMBOTIC ACTION

16 UNDESIRABLE EFFECTS OF NITRATES INCREASED MYOCARDIAL O2 DEMAND INCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia - reflex tachycardia - reflex increase in contractility - reflex increase in contractility DECREASED MYOCARDIAL PERFUSION DECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion time - decreased diastolic perfusion time due to tachycardia due to tachycardia

17 Adverse effects of nitrates EFFECTOCCURRENCE HeadacheCommon Nausea and vomiting Occasional Dizziness or overt syncope Occasional Palpitations and tachycardia Uncommon Tolerance and attenuation Common

18 MECHANISMS OF NITRATE TOLERANCE BIOCHEMICAL TOLERANCE = CELLULAR BIOCHEMICAL TOLERANCE = CELLULAR - exhaustion of the cysteine (SH) store - exhaustion of the cysteine (SH) store - decreased sensivity of guanylate cyclase - decreased sensivity of guanylate cyclase PSEUDO-TOLERANCE = ACTIVATION OF NEUROHUMORAL MECHANISMS PSEUDO-TOLERANCE = ACTIVATION OF NEUROHUMORAL MECHANISMS - increased sympathetic activity - increased sympathetic activity - increased ACE activity - increased ACE activity

19 Avoidance of nitrate tolerance Use smallest effective dose Administer the fewest possible doses per day Avoid continuous or sustained exposure to nitrates Provide a nitrate-free interval of ≥10 h every day

20 EXCRETION OF NITRATES Primarily in the form of glucuronide derivatives of the denitrated metabolites Primarily in the form of glucuronide derivatives of the denitrated metabolites Largely by way of the kidney Largely by way of the kidney

21 BETA-ADRENORECEPTOR BLOCKING DRUGS

22 MAJOR DIFFERENCES AMONG BBs ISA ISA Beta-receptor selectivity Beta-receptor selectivity Cardioselective Cardioselective Nonselective Nonselective Local anesthetic action Local anesthetic action Pharmacokinetic characteristics Pharmacokinetic characteristics

23 Beta-blockers with ISA Acebutolol Acebutolol Cartreolol Cartreolol Celiprolol Celiprolol Oxprenolol Oxprenolol Penbutolol Penbutolol pindolol pindolol

24 Cardioselective beta-blokckers Acebutolol Acebutolol Atenolol Atenolol Betaxolol Betaxolol Bisoprolol Bisoprolol Celiprolol Celiprolol Metoprolol Metoprolol

25 Non-selective beta-blockers Labetalol Labetalol Nadolol Nadolol Penbutolol Penbutolol Pindolol Pindolol Propranolol Propranolol Sotalol Sotalol Timolol Timolol

26 Generations of beta-blockers I generation: non-selective BBs I generation: non-selective BBs II generation: cardioselective BBs II generation: cardioselective BBs III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol

27 Local anesthetic action Acebutolol Acebutolol Betaxolol (slight) Betaxolol (slight) Labetalol Labetalol Metoprolol Metoprolol Pindolol Pindolol Propranolol Propranolol

28 Pharmacokinetic differences Lipid solubility: penbutolol, propranolol, labetalol, metoprolol, pindolol, timolol Lipid solubility: penbutolol, propranolol, labetalol, metoprolol, pindolol, timolol Low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol Low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol

29 A. Solubility characteristics of -blocking agents Hydrophilicity Lack of hepatic first-pass effect lowers the chance of drug interactions and food interference Lack of hepatic first-pass effect lowers the chance of drug interactions and food interference Often results in longer half-life Often results in longer half-life Low penetrability into CNS, resulting in fewer side effects Low penetrability into CNS, resulting in fewer side effects Lipophilicity Requires hepatic metabolism Requires hepatic metabolism Greater chance of significant first-pass effect Greater chance of significant first-pass effect Often results in shorter half-life Often results in shorter half-life Higher penetrability into the CNS Higher penetrability into the CNS

30 Mechanism of action in angina and cardiovascular effects of -blocking agents Decreased myocardial oxygen consumption Decreased myocardial oxygen consumption Decreased heart rate Decreased heart rate Decreased blood pressure Decreased blood pressure Decreased myocardial contractility Decreased myocardial contractility Increased coronary blood supply Increased coronary blood supply Preserved coronary blood flow because of prolonged diastole Preserved coronary blood flow because of prolonged diastole

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32 Adverse effects of -blocking agents Cardiac Increased ventricular volume resulting in congestive heart failure Increased ventricular volume resulting in congestive heart failure Excessive heart rate slowing or heart block Excessive heart rate slowing or heart block Withdrawal syndrome Withdrawal syndrome Noncardiac Fatigue Mental depression Mental depression Insomnia Nightmare Nightmare Raynauds phenomenon Raynauds phenomenon Worsened claudication symptoms Worsened claudication symptoms Bronchoconstriction Bronchoconstriction Metabolic Increased LDL cholesterol and triglycerides; lowered HDL cholesterol Increased LDL cholesterol and triglycerides; lowered HDL cholesterol Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms Increased blood sugar in insulin-resistant diabetics Increased blood sugar in insulin-resistant diabetics

33 CALCIUM CHANNEL- BLOCKING DRUGS

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35 PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS VER DIL DHPS VER DIL DHPS HR ↓ ↓ ↑↔ A-V CONDUCTION ↓↓↓ ↓ ↔ CONTRACTILITY ↓↓ ↓ ↓ ↔ PERIPHERAL VASODILATION ↑ ↑ ↑↑ CO v v v CBF ↑ ↑ ↑ MO 2 DEMAND ↓ ↓ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE;

36 A. Adverse cardiovascular effects of calcium channel antagonists SYMPTOMCAUSE IMPLICATED CALCIUM CHANNEL ANTAGONIST Dizziness, light-headedness, syncope, palpitation Excessive hypotension All Bradycardia Verapamil, diltiazem Reflex tachycardia Dihydropyridines Exacerbation or precipitation of congestive heart failure Negative inotropic action Most; amlodipine, felodipine are the safest to use, even in heart failure Severe bradycardia or heart block Negative chronotropic action, especially sick sinus node disease Verapamil, diltiazem Precipitation of angina Hypotension, coronary steal Nifedipine and possibly other dihydropyridines

37 B. Noncardiac Side Effects Associated with Calcium Channel Blockers SYMPTOMVERAPAMILDILTIAZEMNIFEDIPINE HeadacheRareRareOccasional Postural dizziness RareRareCommon FlushingRareRareCommon Peripheral edema RareRareCommon ConstipationCommonRareRare Other gastrointestinal disorders RareRareRare ParesthesiasRareRareOccasional

38 METABOLIC DRUGS METABOLIC INHIBITORS WITH CARDIO- CYTOPROTECTIVE EFFECT RANOLAZINE (RANEXA 375mg, 500mg, 750mg) TRIMETAZIDINE (PREDUCTAL MR 35mg)

39 TRIMETAZIDINE 3 - ketoacylo – CoA thiolase inhibitor 3 - ketoacylo – CoA thiolase inhibitor In cells exposed to ischaemia, the drug: - prevents a decrease in intracellular ATP levels In cells exposed to ischaemia, the drug: - prevents a decrease in intracellular ATP levels - reduces intracellular acidosis - reduces intracellular acidosis - alterations in transmembrane ion flow - alterations in transmembrane ion flow - decreases the migration and infiltration of PNN - decreases the migration and infiltration of PNN

40 TRIMETAZIDINE In man the drug: In man the drug: - increases coronary flow reserve - increases coronary flow reserve - limits rapid swings in blood pressure - limits rapid swings in blood pressure - decreases the frequency of angina attacks - decreases the frequency of angina attacks - decreases the use of NTG - decreases the use of NTG

41 PK OF TRIMETAZIDINE Well absorbed with Cmax, on average, 5 hours after taking the tablet Well absorbed with Cmax, on average, 5 hours after taking the tablet Protein binding is low Protein binding is low Eliminated primarily in the urine, mainly in the unchanged form; T 1/2 7 hours Eliminated primarily in the urine, mainly in the unchanged form; T 1/2 7 hours

42 TRIMETAZIDINE Side effects: Side effects: - gastrointestinal (dyspepsia, diarrhoea, nausea, - gastrointestinal (dyspepsia, diarrhoea, nausea, vomiting, constipation) vomiting, constipation) - nervous system (headaches, vertigo, sleep disorders) - nervous system (headaches, vertigo, sleep disorders) aggravation of Parkinsonian symptoms aggravation of Parkinsonian symptoms - cardiovascular (orthostatic hypotension) - cardiovascular (orthostatic hypotension) - skin disorders - skin disorders Special warnings: pregnancy and breastfeedindg Special warnings: pregnancy and breastfeedindg

43 RANOLAZINE ( R ) Inhibitor of the late Na + current (late I Na ) Inhibitor of the late Na + current (late I Na ) Inhibitor of the fast rectifying K + current (I Kr ) Inhibitor of the fast rectifying K + current (I Kr ) Reduces Ca ++ overload in the ischemic myocyte Reduces Ca ++ overload in the ischemic myocyte Does not affect Na + - H + and Na + - Ca ++ exchangers Does not affect Na + - H + and Na + - Ca ++ exchangers Antianginal effect related to decreased LV diastolic tension and improved myocardial perfusion Antianginal effect related to decreased LV diastolic tension and improved myocardial perfusion

44 PHARMACOKINETICS OF R Sustained – release form Sustained – release form Prolonged absorption with C max 4 – 6 h after oral administration Prolonged absorption with C max 4 – 6 h after oral administration Bioavailability 30% - 55% Bioavailability 30% - 55% Plasma protein binding ~ 62% Plasma protein binding ~ 62% T 1/2 ~ 7h T 1/2 ~ 7h Steady state within 3 days Steady state within 3 days

45 RANOLAZINE METABOLISM CYP 3A4 – the major pathway CYP 3A4 – the major pathway Additional pathways include: Additional pathways include: - CYP 2D6 (10% - 15%) - CYP 2D6 (10% - 15%) - glucuronidation (< 5%) - glucuronidation (< 5%) ~ 5% excreted unchanged ~ 5% excreted unchanged Weak inhibitor of CYP 3A4 and CYP 2D6 Weak inhibitor of CYP 3A4 and CYP 2D6 Inhibitors of CYPs 3A4 and 2D6 increase plasma R concentration 2 – 4 fold Inhibitors of CYPs 3A4 and 2D6 increase plasma R concentration 2 – 4 fold Clearance of R is reduced by renal insufficiency and moderate hepatic impairment Clearance of R is reduced by renal insufficiency and moderate hepatic impairment

46 DRUG – DRUG INTERACTION Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juice Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juice Inhibitors of CYP 2D6 (paroxetine) Inhibitors of CYP 2D6 (paroxetine) Inhibitors of P-gp (cyclosporin, verapamil) Inhibitors of P-gp (cyclosporin, verapamil) INCREASED EXPOSURE TO RANOZALINE INCREASED EXPOSURE TO RANOZALINE

47 DRUG-DRUG INTERACTION CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) DECREASED EXPOSURE TO RANOZALINE

48 ADVERSE DRUG REACTIONS Mild to moderate in severity Mild to moderate in severity Common ADRs: dizziness, headache, constipatin, vomiting, nausea, Common ADRs: dizziness, headache, constipatin, vomiting, nausea, ECG effects: ↑QTc, ↓T wave amplitude, T wave notching ECG effects: ↑QTc, ↓T wave amplitude, T wave notching

49 CONTRAINDICATIONS Hypersensitivity to the drug Hypersensitivity to the drug Severe renal impairment (CrC < 30ml/min) Severe renal impairment (CrC < 30ml/min) Moderate or severe hepatic impairment Moderate or severe hepatic impairment Co-administration of potent CYP 3A4 inhibitors Co-administration of potent CYP 3A4 inhibitors LQTS LQTS Co-administration QT-prolonging drugs (quinidine, dofetilide, sotalol) Co-administration QT-prolonging drugs (quinidine, dofetilide, sotalol)

50 HEART-RATE LOWERING DRUGS Ivabradin (Procoralan 5 mg, 7,5 mg tablets) Ivabradin (Procoralan 5 mg, 7,5 mg tablets) Selective and specific inhibitor of I f current that controls the spontaneous diastolic depolarisation in the sinus node Selective and specific inhibitor of I f current that controls the spontaneous diastolic depolarisation in the sinus node Dose-dependent reduction in heart rate and MO 2 Dose-dependent reduction in heart rate and MO 2

51 INDICATIONS Symptomatic treatment of chronic stable angina pectoris with normal sinus rhythm: Symptomatic treatment of chronic stable angina pectoris with normal sinus rhythm: - in adults unable to tolerate or with a contra- - in adults unable to tolerate or with a contra- indication to the use of beta-blockers indication to the use of beta-blockers - or in combination with beta-blockers in pts - or in combination with beta-blockers in pts inadequately controlled with an optimal beta- inadequately controlled with an optimal beta- blocker dose and whose rate is > 60 bpm blocker dose and whose rate is > 60 bpm Treatment of chronic heart failure Treatment of chronic heart failure

52 PHARMACOKINETICS S-enantiomer, highly water-soluble S-enantiomer, highly water-soluble Rapidly and completely absorbed from the gut Rapidly and completely absorbed from the gut C max after 1 hour under fasting condition C max after 1 hour under fasting condition Food delays absorption by 1 h and increases plasma contrentation by 20 to 30% Food delays absorption by 1 h and increases plasma contrentation by 20 to 30% Plasma protein bounding 70% Plasma protein bounding 70% Half-life 11 hours Half-life 11 hours

53 BIOTRANSFORMATION Metabolised by CYP 3A4 only Metabolised by CYP 3A4 only Active metabolite – N-desmethlated derivative Active metabolite – N-desmethlated derivative Very low affinity for CYP 3A4 Very low affinity for CYP 3A4 CYP 3A4 inhibitors and inducers influence its metabolism and pharmacokinetics CYP 3A4 inhibitors and inducers influence its metabolism and pharmacokinetics Treatment including potent CYP 3A4 inhibitors as azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone is contraindicated Treatment including potent CYP 3A4 inhibitors as azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone is contraindicated

54 BIOTRANSFORMATION the combination of ivabradine with moderate CYP 3A4 inhibitors (diltiazem, verapamil) is not recommended the combination of ivabradine with moderate CYP 3A4 inhibitors (diltiazem, verapamil) is not recommended CYP 3A4 inducers (rifampicin, barbiturates, phenytoin, St John, s Wort) may decrease ivabradine exposure and activity CYP 3A4 inducers (rifampicin, barbiturates, phenytoin, St John, s Wort) may decrease ivabradine exposure and activity

55 CONTRAINDICATIONS Hypersensitivity to the active substance Hypersensitivity to the active substance Resting heart rate below 60 bpm prior to treatment Resting heart rate below 60 bpm prior to treatment Acs, cardiogenic shock, severe hypotension Acs, cardiogenic shock, severe hypotension Severe hepatic insufficiency Severe hepatic insufficiency Sick sinus syndrom, sino-atrial block Sick sinus syndrom, sino-atrial block A-V block of 3rd degree A-V block of 3rd degree Combination with strong CYP 3A4 inhibitors Combination with strong CYP 3A4 inhibitors Pregnancy, lactation Pregnancy, lactation

56 UNDESIRABLE EFFECTS Headache Headache Dizziness Dizziness Bradycardia – 3,3% Bradycardia – 3,3% Luminous phenomena (phosphenes) – 14,5% Luminous phenomena (phosphenes) – 14,5% Uncontrolled blood pressure Uncontrolled blood pressure

57 Combinations of antianginal drugs COMBINATIONBENEFICIAL SHOULD BE AVOIDED OR IS RELATIVELY CONTRAINDICATED Nitrates + b-blocker X Nitrates + diltiazem, verapamil X Nitrates + dihydropyridine X b-blockers + dihydropyridine X b-blockers + diltiazem, verapamil X

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60 Thienopyridines Ticlopidine (2 x 250 mg) Ticlopidine (2 x 250 mg) Clopidogrel (1 x 75 mg) Clopidogrel (1 x 75 mg) P2Y12 adenosine diphosphate receptor blocker P2Y12 adenosine diphosphate receptor blocker For 1 year after NSTEMI, STEMI, PCI + DES For 1 year after NSTEMI, STEMI, PCI + DES

61 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY ASA causes topical injury to the mucosa and systemic effects induced by prostaglandin depletion ASA causes topical injury to the mucosa and systemic effects induced by prostaglandin depletion Tissue PGs are produced via 2 pathways: COX-1 and COX-2 pathway Tissue PGs are produced via 2 pathways: COX-1 and COX-2 pathway Clopidogrel – impairs the healing of gastric ulcers by inhibiting platelet release of pro-angiogenic growth factors ( VEGF ) which promotes endothelial proliferation and accelerates the healing of ulcers Clopidogrel – impairs the healing of gastric ulcers by inhibiting platelet release of pro-angiogenic growth factors ( VEGF ) which promotes endothelial proliferation and accelerates the healing of ulcers

62 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY Recommendation: the use of low-dose ASA for cardioprophylaxis is associated with a 2-4 – fold increase in UGIE. Enteric-coated preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with dose of ASA; thus, doses greater than 81mg should not be prescribed Recommendation: the use of low-dose ASA for cardioprophylaxis is associated with a 2-4 – fold increase in UGIE. Enteric-coated preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with dose of ASA; thus, doses greater than 81mg should not be prescribed

63 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY Recommendation: substitution of clopidogrel for ASA is not recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk patients and is inferior to the combination of ASA plus PPI Recommendation: substitution of clopidogrel for ASA is not recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk patients and is inferior to the combination of ASA plus PPI Recommendation: when warfarin is added to ASA plus clopidogrel an INR of 2,0 to 2,5 is recommended Recommendation: when warfarin is added to ASA plus clopidogrel an INR of 2,0 to 2,5 is recommended Recommendation: PPIs are the preferred agents for the therapy and prophylaxis of ASA-associated UGIE Recommendation: PPIs are the preferred agents for the therapy and prophylaxis of ASA-associated UGIE

64 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY Esomeprazol and pantoprazol are preferred PPIs in patients treated with clopidogrel Esomeprazol and pantoprazol are preferred PPIs in patients treated with clopidogrel Omeprazol is not recommended due to a risk of significant interaction with clopidogrel Omeprazol is not recommended due to a risk of significant interaction with clopidogrel

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66 EUROPA TRIAL EU ropean trial on R eduction O f cardiac evens with P erindopril in stable coronary A rtery disease Randomized, placebo controled, duble blind study Randomized, placebo controled, duble blind study 4 years follow-up 4 years follow-up patients at low risk; perindopril 8 mg vs placebo patients at low risk; perindopril 8 mg vs placebo

67 EUROPA TRIAL - RESULTS The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% Risk of MI ( fatal + nonfatal ) ↓ 24% Risk of MI ( fatal + nonfatal ) ↓ 24% Hospitalisation for HF ↓ 39% Hospitalisation for HF ↓ 39%

68 PERTINENT TRIAL PERindopril, Thrombosis, INflammation, Endothelial dysfunction and Neurohormonal activaTion Rate of apoptosis of ECRate of apoptosis of EC Activity and expression of NOSActivity and expression of NOS Proapoptotic protein BaxProapoptotic protein Bax Antiapoptotic protein Bcl-2Antiapoptotic protein Bcl-2 Von Willebrand factorVon Willebrand factor Levels of AT II, bradykinin, TNFLevels of AT II, bradykinin, TNF Assesment at baseline and after 1 year of treatmentAssesment at baseline and after 1 year of treatment

69 PERTINENT TRIAL - RESULTS One year of treatment with perindopril was able significantly reduce the rate of apoptosis and increase the activity and expression of NOS One year of treatment with perindopril was able significantly reduce the rate of apoptosis and increase the activity and expression of NOS

70 LIPID-LOWERING THERAPY Statins – HMG-CoA reductase inhibitors Statins – HMG-CoA reductase inhibitors Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin Significant LDL reduction, relatively small reduction in TG, minor increas in HDL Significant LDL reduction, relatively small reduction in TG, minor increas in HDL Lower is better ( LDL < 70 mg%) Lower is better ( LDL < 70 mg%) Fibrates – fenofibrate (↑ HDL) Fibrates – fenofibrate (↑ HDL) Ezetimib (Ezetrol 10mg) Ezetimib (Ezetrol 10mg)

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72 S T A T I N S Natural (fungal fermentation): lovastatin, simvastatin, pravastatin Natural (fungal fermentation): lovastatin, simvastatin, pravastatin Synthetic: fluvastatin, atorvastatin, rosuvastatin Synthetic: fluvastatin, atorvastatin, rosuvastatin Metabolized by CYP 3A4: lovastatin, simvastatin, atorvastatin Metabolized by CYP 3A4: lovastatin, simvastatin, atorvastatin CYP 2C9 for fluvastatin CYP 2C9 for fluvastatin Pravastatin does not use CYP P450 Pravastatin does not use CYP P450 Hydrophilic statins: pravastatin, fluvastatin Hydrophilic statins: pravastatin, fluvastatin

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74 ADVERSE EFFECTS OF STATINS All statins are well tolerated All statins are well tolerated Most common ADRs are mild, transient, reversible – dyspepsia, abdominal pain, flatulence Most common ADRs are mild, transient, reversible – dyspepsia, abdominal pain, flatulence The most important ADRs are liver toxicity (↑ ATs) and myopathy ( pain, weakness, ↑CK ≥ 10 X) The most important ADRs are liver toxicity (↑ ATs) and myopathy ( pain, weakness, ↑CK ≥ 10 X) Rhabdomyolysis and acute renal failure – very rare Rhabdomyolysis and acute renal failure – very rare Risk of muscle toxicity increases during therapy with cyclosporine, erythromycin, clarithromycin, azole antifungals, protease inhibitors – CYP 3A4 inhibitors Risk of muscle toxicity increases during therapy with cyclosporine, erythromycin, clarithromycin, azole antifungals, protease inhibitors – CYP 3A4 inhibitors

75 Major purposes of the treatment To improve short and long term prognosis by preventing MI and death and thereby increase the length of life To improve short and long term prognosis by preventing MI and death and thereby increase the length of life To improve quality of life by reducing symptoms of angina and occurrence of ischemia To improve quality of life by reducing symptoms of angina and occurrence of ischemia

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78 Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: The following agents should be used in patients with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: Aspirin (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated (level of evidence: B) Aspirin (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated (level of evidence: B) ß-Blockers in patients with previous MI (level of evidence: A) or without previous MI (level of evidence: B) ß-Blockers in patients with previous MI (level of evidence: A) or without previous MI (level of evidence: B) Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) ACE inhibitor (level of evidence: A) ACE inhibitor (level of evidence: A)

79 Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to reduce symptoms only: The following agents should be used in patients with symptomatic chronic stable angina to reduce symptoms only: Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina (level of evidence: B) Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates when ß-blockers are clearly contraindicated (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates when ß-blockers are clearly contraindicated (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B). Calcium antagonists (long-acting) or long-acting nitrates in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B).

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81 TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS I correction of risk factors, nitroglycerin sl aspirin 75 mg aspirin 75 mg CLASS II as above+ chronic therapy with LA nitrates or LA nitrates or ß 1 -blockers or ß 1 -blockers or LA Calcium antagonists or LA Calcium antagonists or Trimetazidine or Trimetazidine or combination of these drugs combination of these drugs

82 TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS III and IV As above and establish indications for invasive treatment establish indications for invasive treatment

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