Pharmacological management of Ischaemic heart disease and acute myocardial infarction

1. Pharmacological management of Ischaemic heart disease and acute myocardial infarction October 2006

2. Atherosclerosis The complications of atherosclerosis constitute the greatest cause of morbidity and mortality in the Western World accounting for 40% of all deaths

3. Atherosclerosis • Progressive luminal narrowing - angina pectoris - intermittent claudication • Plaque rupture and thrombosis - acute coronary syndromes - transient ischaemic attack • Aneurysm formation

4. Aims of treatment • Relieve symptoms • Slow disease progression • Reduce risk of acute event • Improve survival

5. Management overview • Pharmacological treatment • Managing risk factors • Interventional procedures

6. Angina pectoris • Myocardial oxygen demand exceeds supply  chest pain • Stable angina - transient myocardial ischaemia - predictable, reproducible - relieved by rest or GTN

7. Principles of treatment • Increase oxygen supply or reduce oxygen demands of myocardium Reduce heart rate Reduce preload Reduce afterload Improve coronary blood flow

8. Symptomatic treatment • Nitrates • Beta blockers • Calcium channel blockers • Potassium channel activators • Selective pacemaker If current inhibitorIvabradine (Procolalan)

9. Describing any drug • MOA and pharmacological properties • Indications • Cautions/Contraindications • Side effects • Important interactions • Dose/overdose

10. Nitrates - Mode of action • Metabolised to release Nitric oxide (NO) •  cGMP • Dephosphorylation of myosin light chains • Increased intracellular calcium • Muscle relaxation

11. Nitrates - Mode of action • Venodilation -  preload • Coronary artery vasodilation -  supply • Moderate arteriolar dilation -  afterload

12. 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

13. Alfred Nobel

14. 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”

15. Indications • Relief of acute angina attack • Prophylaxis of stable angina (prior to exercise GTN or long-acting) • Left ventricular failure

16. Cautions/Contraindications • Hypotension • Aortic stenosis • HOCM • Constrictive pericarditis

17. Side effects • Headache • Flushing • Dizziness • Postural hypotension • Tachycardia • Overdose rarely precipitates methaemoglobinaemia

18. 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

19. Beta blockers

20. 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

21. 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

22. Indications • Symptomatic angina • Hypertension • Acute coronary syndromes • Post myocardial infarction • Stable heart failure • Arrhythmias • Thyrotoxicosis/Benign essential tremor

23. 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

24. Important Interaction • Verapamil and beta blockers  precipitate heart block +- asystole • Must NOT give IV verapamil to beta blocked patients • Extreme caution combined orally

25. 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

26. 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

27. Calcium antagonists

28. 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

29. 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

30. Indications • Symptomatic control of angina • Coronary spasm • Hypertension • Arrhythmias • Subarachnoid haemorrhage (nimodipine)

31. Side effects • Peripheral vasodilation - flushing, headache, ankle oedema • Cardiac effects - AV block, heart failure • Constipation • Short-acting dihydropyridines a/w  mortality and MI

32. Potassium channel activators

33. 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

34. 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)

35. Additional therapy in stable angina • Low-dose aspirin • Lipid lowering therapy • ACE inhibitors • Treat BP and diabetes • Smoking cessation • Weight reduction • Intervention

36. 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

37. Acute coronary syndrome • Angina at rest >20mins • New onset angina severely affecting exercise tolerance • Increasing frequency or duration or occurring with lesser exertion

38. Acute coronary syndromes • Plaque rupture and coronary thrombosis • Unstable angina • Non-ST elevation MI (subendocardial infarction) • Acute transmural myocardial infarction

39. 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

40. 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

41. Definitive treatment-ST 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)

42. Definitive treatment-ST elevation Myocardial infarction Primary PCI not available Thrombolysis 50-60% recanalisation Door to needle time <30mins Effective up to 12 hours

43. Fibrinolytic agents

44. 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

45. Indications • Acute ST elevation myocardial infarction • Acute pulmonary embolism • Acute ischaemic stroke within 3 hours

46. 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)

47. Relative contraindications • Venepuncture (non-compressible site) • Recent invasive procedure • External chest compressions • Pregnancy • Abdominal aortic aneurysm • Diabetic retinopathy • Anticoagulant therapy

48. Side effects • Nausea and vomiting • Bleeding • Reperfusion arrhythmias • Hypotension • Back pain • Allergic reactions (esp streptokinase)

49. 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

50. Reading/Website list • British national formulary BNF • www.uptodate.com • American heart association guidelines