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Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD www.zfk.ump.edu.pl www.ump.edu.pl/eng FORMS OF ANGINA PECTORIS (AP) • ATHEROSCLEROTIC (CLASSIC) ANGINA • VARIANT (VASOSPASTIC ANGINA) 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 nearnormal 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 ANTIANGINAL DRUGS • ORGANIC NITRATES • ΒETA- ADRENORECEPTOR- BLOCKING DRUGS • CALCIUM CHANNEL- BLOCKING DRUGS • METABOLIC AGENTS • HEART – RATE LIMITING AGENTS DRUG ACTION IN ANGINA • DECREASE MYOCARDIAL O2 REQUIREMENT BY: decreasing peripheral vascular resitance decreasing cardiac output both ways • INCREASE MYOCARDIAL O2 DELIVERY nitrates calcium channel antagonists ORGANIC NITRATES ORGANIC NITRATES NTG, ISDN, IS-5-MN Donors of NO in vascular smooth muscle cells Induce cross-tolerance when given in large doses 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 NOrelease 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 ORGANIC NITRATES 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 Nitrates are acting via the release of NO – they need intracellular SH-groups to form NO PHARMACOKINETICS CHARACTERISTICS • • • • • • AFTER ORAL ADMINISTRATION EXTENSIVE FIRST-PASS EFFECT (90%) LOW BIOAVAILABILITY (10%) AFTER SUBLINGUAL ADMINISTRATION RAPID ONSET OF ACTION (1-3 min) BRIEF DURATION OF ACTION (up to 30 min) MECHANISM OF ANTIANGINAL ACTION OF NITRATES DECREASED MYOCARDIAL O2 CONSUMPTION - decreased LV dimension - decreased LV filling pressure - decreased LV systolic pressure - decreased vascular impedence INCREASED CORONARY BLOOD SUPPLAY - epicardial coronary artery dilation - coronary stenosis enlargement - dilation of coronary collaterals ANTIPLATELET ANTITHROMBOTIC ACTION UNDESIRABLE EFFECTS OF NITRATES INCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia - reflex increase in contractility DECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion time due to tachycardia Adverse effects of nitrates EFFECT OCCURRENCE Headache Common Nausea and vomiting Occasional Dizziness or overt syncope Occasional Palpitations and tachycardia Uncommon Tolerance and attenuation Common MECHANISMS OF NITRATE TOLERANCE BIOCHEMICAL TOLERANCE = CELLULAR - exhaustion of the cysteine (SH) store - decreased sensivity of guanylate cyclase PSEUDO-TOLERANCE = ACTIVATION OF NEUROHUMORAL MECHANISMS - increased sympathetic activity - increased ACE activity 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 EXCRETION OF NITRATES Primarily in the form of glucuronide derivatives of the denitrated metabolites Largely by way of the kidney BETA-ADRENORECEPTOR BLOCKING DRUGS MAJOR DIFFERENCES AMONG BBs • ISA • Beta-receptor selectivity Cardioselective Nonselective • Local anesthetic action • Pharmacokinetic characteristics Beta-blockers with ISA Acebutolol Cartreolol Celiprolol Oxprenolol Penbutolol pindolol Cardioselective beta-blokckers Acebutolol Atenolol Betaxolol Bisoprolol Celiprolol Metoprolol Non-selective beta-blockers Labetalol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol Generations of beta-blockers I generation: non-selective BBs II generation: cardioselective BBs III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol Local anesthetic action Acebutolol Betaxolol (slight) Labetalol Metoprolol Pindolol Propranolol Pharmacokinetic differences Lipid solubility: penbutolol, propranolol, labetalol, metoprolol, pindolol, timolol Low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol A. Solubility characteristics of -blocking agents Hydrophilicity Lack of hepatic first-pass effect lowers the chance of drug interactions and food interference Often results in longer half-life Low penetrability into CNS, resulting in fewer side effects Lipophilicity Requires hepatic metabolism Greater chance of significant first-pass effect Often results in shorter half-life Higher penetrability into the CNS Mechanism of action in angina and cardiovascular effects of -blocking agents Decreased myocardial oxygen consumption Decreased heart rate Decreased blood pressure Decreased myocardial contractility Increased coronary blood supply Preserved coronary blood flow because of prolonged diastole Adverse effects of -blocking agents Cardiac Increased ventricular volume resulting in congestive heart failure Excessive heart rate slowing or heart block Withdrawal syndrome Noncardiac Fatigue Mental depression Insomnia Nightmare Raynauds phenomenon Worsened claudication symptoms Bronchoconstriction Metabolic Increased LDL cholesterol and triglycerides; lowered HDL cholesterol Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms Increased blood sugar in insulin-resistant diabetics CALCIUM CHANNELBLOCKING DRUGS PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS HR A-V CONDUCTION CONTRACTILITY PERIPHERAL VASODILATION CO CBF MO2 DEMAND VER ↓ ↓↓↓ ↓↓ ↑ v ↑ ↓ DIL DHPS ↓ ↑↔ ↓ ↔ ↓ ↓↔ ↑ v ↑ ↓ ↑↑ v ↑ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE; A. Adverse cardiovascular effects of calcium channel antagonists SYMPTOM CAUSE Dizziness, light-headedness, syncope, Excessive hypotension palpitation IMPLICATED CALCIUM CHANNEL ANTAGONIST 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 B. Noncardiac Side Effects Associated with Calcium Channel Blockers SYMPTOM VERAPAMIL DILTIAZEM NIFEDIPINE Headache Rare Rare Occasional Postural dizziness Rare Rare Common Flushing Rare Rare Common Peripheral edema Rare Rare Common Common Rare Rare Other gastrointestinal disorders Rare Rare Rare Paresthesias Rare Rare Occasional Constipation METABOLIC DRUGS METABOLIC INHIBITORS WITH CARDIOCYTOPROTECTIVE EFFECT RANOLAZINE (RANEXA 375mg, 500mg, 750mg) TRIMETAZIDINE (PREDUCTAL MR 35mg) TRIMETAZIDINE • 3 - ketoacylo – CoA thiolase inhibitor • In cells exposed to ischaemia, the drug: - prevents a decrease in intracellular ATP levels - reduces intracellular acidosis - alterations in transmembrane ion flow - decreases the migration and infiltration of PNN TRIMETAZIDINE In man the drug: - increases coronary flow reserve - limits rapid swings in blood pressure - decreases the frequency of angina attacks - decreases the use of NTG PK OF TRIMETAZIDINE Well absorbed with Cmax, on average, 5 hours after taking the tablet Protein binding is low Eliminated primarily in the urine, mainly in the unchanged form; T1/2 7 hours TRIMETAZIDINE Side effects: - gastrointestinal (dyspepsia, diarrhoea, nausea, vomiting, constipation) - nervous system (headaches, vertigo, sleep disorders) aggravation of Parkinsonian symptoms - cardiovascular (orthostatic hypotension) - skin disorders Special warnings: pregnancy and breastfeedindg RANOLAZINE ( R ) Inhibitor of the late Na+ current (late INa) Inhibitor of the fast rectifying K+ current (IKr) Reduces Ca++ overload in the ischemic myocyte Does not affect Na+- H+ and Na+- Ca++exchangers Antianginal effect related to decreased LV diastolic tension and improved myocardial perfusion PHARMACOKINETICS OF R Sustained – release form Prolonged absorption with Cmax 4 – 6 h after oral administration Bioavailability 30% - 55% Plasma protein binding ~ 62% T1/2 ~ 7h Steady state within 3 days RANOLAZINE METABOLISM CYP 3A4 – the major pathway Additional pathways include: - CYP 2D6 (10% - 15%) - glucuronidation (< 5%) ~ 5% excreted unchanged Weak inhibitor of CYP 3A4 and CYP 2D6 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 DRUG – DRUG INTERACTION Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juice Inhibitors of CYP 2D6 (paroxetine) Inhibitors of P-gp (cyclosporin, verapamil) INCREASED EXPOSURE TO RANOZALINE DRUG-DRUG INTERACTION CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) DECREASED EXPOSURE TO RANOZALINE ADVERSE DRUG REACTIONS Mild to moderate in severity Common ADRs: dizziness, headache, constipatin, vomiting, nausea, ECG effects: ↑QTc, ↓T wave amplitude, T wave notching CONTRAINDICATIONS Hypersensitivity to the drug Severe renal impairment (CrC < 30ml/min) Moderate or severe hepatic impairment Co-administration of potent CYP 3A4 inhibitors LQTS Co-administration QT-prolonging drugs (quinidine, dofetilide, sotalol) HEART-RATE LOWERING DRUGS Ivabradin (Procoralan 5 mg, 7,5 mg tablets) Selective and specific inhibitor of If current that controls the spontaneous diastolic depolarisation in the sinus node Dose-dependent reduction in heart rate and MO2 INDICATIONS Symptomatic treatment of chronic stable angina pectoris 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 pts inadequately controlled with an optimal betablocker dose and whose rate is > 60 bpm Treatment of chronic heart failure PHARMACOKINETICS S-enantiomer, highly water-soluble Rapidly and completely absorbed from the gut C max after 1 hour under fasting condition Food delays absorption by 1 h and increases plasma contrentation by 20 to 30% Plasma protein bounding 70% Half-life 11 hours BIOTRANSFORMATION Metabolised by CYP 3A4 only Active metabolite – N-desmethlated derivative Very low affinity for CYP 3A4 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 BIOTRANSFORMATION 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 CONTRAINDICATIONS Hypersensitivity to the active substance Resting heart rate below 60 bpm prior to treatment Acs, cardiogenic shock, severe hypotension Severe hepatic insufficiency Sick sinus syndrom, sino-atrial block A-V block of 3rd degree Combination with strong CYP 3A4 inhibitors Pregnancy, lactation UNDESIRABLE EFFECTS Headache Dizziness Bradycardia – 3,3% Luminous phenomena (phosphenes) – 14,5% Uncontrolled blood pressure Combinations of antianginal drugs COMBINATION BENEFICIAL Nitrates + b-blocker X Nitrates + diltiazem, verapamil X Nitrates + dihydropyridine b-blockers + dihydropyridine b-blockers + diltiazem, verapamil SHOULD BE AVOIDED OR IS RELATIVELY CONTRAINDICATED X X X Thienopyridines Ticlopidine (2 x 250 mg) Clopidogrel (1 x 75 mg) P2Y12 adenosine diphosphate receptor blocker For 1 year after NSTEMI, STEMI, PCI + DES GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY 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 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 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 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: 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 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY Esomeprazol and pantoprazol are preferred PPIs in patients treated with clopidogrel Omeprazol is not recommended due to a risk of significant interaction with clopidogrel EUROPA TRIAL EUropean trial on Reduction Of cardiac evens with Perindopril in stable coronary Artery disease • Randomized, placebo controled, duble blind study • 4 years follow-up • 12218 patients at low risk; perindopril 8 mg vs placebo EUROPA TRIAL - RESULTS • The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% • Risk of MI ( fatal + nonfatal ) ↓ 24% • Hospitalisation for HF ↓ 39% PERTINENT TRIAL PERindopril, Thrombosis, INflammation, Endothelial dysfunction and Neurohormonal activaTion • • • • • • • Rate of apoptosis of EC Activity and expression of NOS Proapoptotic protein Bax Antiapoptotic protein Bcl-2 Von Willebrand factor Levels of AT II, bradykinin, TNF Assesment at baseline and after 1 year of treatment 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 LIPID-LOWERING THERAPY Statins – HMG-CoA reductase inhibitors Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin Significant LDL reduction, relatively small reduction in TG, minor increas in HDL Lower is better ( LDL < 70 mg%) Fibrates – fenofibrate (↑ HDL) Ezetimib (Ezetrol 10mg) STATINS Natural (fungal fermentation): lovastatin, simvastatin, pravastatin Synthetic: fluvastatin, atorvastatin, rosuvastatin Metabolized by CYP 3A4: lovastatin, simvastatin, atorvastatin CYP 2C9 for fluvastatin Pravastatin does not use CYP P450 Hydrophilic statins: pravastatin, fluvastatin ADVERSE EFFECTS OF STATINS All statins are well tolerated 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) 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 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 quality of life by reducing symptoms of angina and occurrence of ischemia 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: 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) Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) ACE inhibitor (level of evidence: A) 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: 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 in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B). TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS I correction of risk factors, nitroglycerin sl aspirin 75 mg CLASS II as above+ chronic therapy with LA nitrates or ß1-blockers or LA Calcium antagonists or Trimetazidine or combination of these drugs TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS III and IV As above and establish indications for invasive treatment