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Pharmacological management of Ischaemic heart disease and acute myocardial infarction October 2006 Atherosclerosis The complications of atherosclerosis constitute the greatest cause of morbidity and mortality in the Western World accounting for 40% of all deaths Atherosclerosis Progressive luminal narrowing - angina pectoris - intermittent claudication Plaque rupture and thrombosis - acute coronary syndromes - transient ischaemic attack Aneurysm formation Aims of treatment Relieve symptoms Slow disease progression Reduce risk of acute event Improve survival Management overview Pharmacological treatment Managing risk factors Interventional procedures Angina pectoris Myocardial oxygen demand exceeds supply chest pain Stable angina - transient myocardial ischaemia - predictable, reproducible - relieved by rest or GTN Principles of treatment Increase oxygen supply or reduce oxygen demands of myocardium Reduce heart rate Reduce preload Reduce afterload Improve coronary blood flow Symptomatic treatment 1. 2. 3. 4. 5. Nitrates Beta blockers Calcium channel blockers Potassium channel activators Selective pacemaker If current inhibitorIvabradine (Procolalan) Describing any drug MOA and pharmacological properties Indications Cautions/Contraindications Side effects Important interactions Dose/overdose Nitrates - Mode of action Metabolised to release Nitric oxide (NO) cGMP Dephosphorylation of myosin light chains Increased intracellular calcium Muscle relaxation Nitrates - Mode of action Venodilation - preload Coronary artery vasodilation - supply Moderate arteriolar dilation - afterload Pharmacological properties Glyceryl trinitrate (GTN) short acting, first pass metabolism sublingual/intravenous/patch administration Isosorbide dinitrate intermediate acting sublingual/intravenous/oral administration Isosorbide mononitrate long acting oral administration Alfred Nobel Pharmacological properties Tolerance (tachyphylaxis) - reduced therapeutic effects “Monday morning sickness” ? due to depletion of free tissue –SH Long-acting preparations /infusions/transdermal patches “Nitrate free period” Indications Relief of acute angina attack Prophylaxis of stable angina (prior to exercise GTN or long-acting) Left ventricular failure Cautions/Contraindications Hypotension Aortic stenosis HOCM Constrictive pericarditis Side effects Headache Flushing Dizziness Postural hypotension Tachycardia Overdose rarely precipitates methaemoglobinaemia Important interaction Phosphodiesterase inhibitors eg sildenafil Inhibits cGMP breakdown severe hypotension – nitrates contraindicated if taken within the previous 24 hours Infusion reduces anticoagulant effect of heparin Beta blockers Mode of action Competitive inhibitors of catecholamine at beta-adrenoceptor sites Inhibit sympathetic stimulation of heart and smooth muscle HR contractility β1 Vasoconstriction & bronchoconstriction β2 Pharmacological properties Cardioselective – eg atenolol metoprolol Non selective – eg propranolol Intrinsic sympathomimetic (partial agonist) activity – eg celiprolol pindolol Alpha-blocking activity eg carvedilol Lipid soluble (eg propranolol) versus water soluble (eg atenolol) Up-regulation of receptors – withdrawal syndrome Indications Symptomatic angina Hypertension Acute coronary syndromes Post myocardial infarction Stable heart failure Arrhythmias Thyrotoxicosis/Benign essential tremor Cautions/Contraindications C/I in asthma Uncontrolled heart failure Bradycardia Heart block Phaeochromocytoma without prior alpha blockade Caution coronary spasm/COPD/PVD Avoid abrupt withdrawal Important Interaction Verapamil and beta blockers precipitate heart block +- asystole Must NOT give IV verapamil to beta blocked patients Extreme caution combined orally Side effects Beta-1 effects – Bradycardia, heart block, heart failure Beta-2 effects – bronchospasm, worsening PVD, Raynaud’s phenomenon Fatigue, depression, nightmares, impotence May mask hypoglycaemia and worsen glycaemic control in IDDM Dose Rational choice - long-acting cardioselective beta blocker od or bd Anti-anginal effects are dose related Titrate to resting heart rate 50-60 bpm Calcium antagonists Mode of action Prevent opening of voltage-gated calcium channels Bind to -1 subunit of cardiac and smooth muscle L-type calcium channels Vasodilator effect on resistance vessels afterload Coronary artery dilation Negative chronotropic Negative inotropic effects Pharmacological properties 3 classes Phenylalkylamines eg verapamil - relatively cardioselective - -ve chronotropic and inotropic Dihydropyridines eg nifedipine amlodipine - relatively smooth muscle selective - potent vasodilator Benzothiazepines eg diltiazem - intermediate Indications Symptomatic control of angina Coronary spasm Hypertension Arrhythmias Subarachnoid haemorrhage (nimodipine) Side effects Peripheral vasodilation - flushing, headache, ankle oedema Cardiac effects - AV block, heart failure Constipation Short-acting dihydropyridines a/w mortality and MI Potassium channel activators Potassium channel activators - nicorandil Activates K ATP channel NO donor effects Arterial and venodilator S/E Flushing, dizziness, headache Usually 3rd or 4th line agent Selective pacemaker If current inhibitor Ivabradine (Procolalan) reduces spontaneous beating rate of the sinus node by slowing the diastolic depolarization slope of the action potential selective and prolonged reduction in heart rate, both at rest and during exercise Indicated for angina where cannot give a beta blocker Ongoing trials (Beautiful trial) Additional therapy in stable angina Low-dose aspirin Lipid lowering therapy ACE inhibitors Treat BP and diabetes Smoking cessation Weight reduction Intervention Antiplatelet agents Aspirin – inhibits cyclo-oxygenase and thromboxane A2 synthesis Theinopyridines – clopidogrel – block binding of ADP to platelet receptor Glycoprotein IIb/IIIa inhibitors (abciximab) – inhibit cross-bridging of platelets by fibrinogen Acute coronary syndrome Angina at rest >20mins New onset angina severely affecting exercise tolerance Increasing frequency or duration or occurring with lesser exertion Acute coronary syndromes Plaque rupture and coronary thrombosis Unstable angina Non-ST elevation MI (subendocardial infarction) Acute transmural myocardial infarction Goals of treatment Relief of ischaemic pain Assess haemodynamic state Anti-platelet therapy to prevent further thrombosis Initiate reperfusion therapy with percutaneous angioplasty or thrombolysis if appropriate Secondary prevention Initial Management Oxygen Aspirin 150-300mg chewed/dispersible Nitrates GTN 0.4mg sublingual +- IV Intravenous morphine 2.5-10mg+ antiemetic cyclizine 50mg Decide on definitive treatment Beta-blocker atenolol 5mg over 5 mins repeated after 10-15 mins Clopidogrel 300mg if undergoing PCI Glycoprotein IIb/IIIa inhibitors (abciximab) if undergoing PCI ACE inhibitor within 24 hours Tight glycaemic control Optimise potassium and magnesium Definitive treatmentST elevation Myocardial infarction Primary coronary angioplasty 90% recanalisation Door to balloon time <90mins ? up to 3hrs Ideal where cardiogenic shock and when thrombolytics contraindicated clopidogrel 300mg loading dose then 75mg od Glycoprotein IIb/IIIa inhibitors (abciximab) Definitive treatmentST elevation Myocardial infarction Primary PCI not available Thrombolysis 50-60% recanalisation Door to needle time <30mins Effective up to 12 hours Fibrinolytic agents Mode of action Activate plasminogen to form plasmin which degrades fibrin breaking up thrombi Streptokinase, alteplase, reteplase, tenecteplase Streptokinase – antibodies within 4 days Alteplase, reteplase followed by heparin for 48 hours Indications Acute ST elevation myocardial infarction Acute pulmonary embolism Acute ischaemic stroke within 3 hours Contraindications Recent haemorrhage trauma or surgery Recent dental extraction Coagulation defects;bleeding disorders Aortic dissection History of cerebrovascular disease Active peptic ulceration Severe menorrhagia Severe hypertension Active cavitating lung disease Acute pancreatitis Severe liver disease Oesophageal varices Previous reaction to streptokinase (Streptokinase) Relative contraindications Venepuncture (non-compressible site) Recent invasive procedure External chest compressions Pregnancy Abdominal aortic aneurysm Diabetic retinopathy Anticoagulant therapy Side effects Nausea and vomiting Bleeding Reperfusion arrhythmias Hypotension Back pain Allergic reactions (esp streptokinase) Unstable angina/NSTEMI “MONA” – morphine; O2; nitrate; aspirin Heparin eg enoxaparin 1mg/kg 12 hourly Beta-blocker atenolol 5mg over 5 mins repeated after 10-15 mins Clopidogrel Glycoprotein IIb/IIIa inhibitors (abciximab) if undergoing PCI ACE inhibitor if indicated Tight glycaemic control Optimise potassium and magnesium Reading/Website list British national formulary BNF www.uptodate.com American heart association guidelines