Pharmacological management of Ischaemic heart disease and acute myocardial infarction

Hamid Shamsolkottabi MD Cardiologist Sina Heart Center, Esfahan, IRAN

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. Nitrates 2. Beta blockers 3. Calcium channel blockers 4. Potassium channel activators 5. 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 Moderate arteriolar dilation   supply 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 - relatively cardioselective - -ve chronotropic and inotropic Dihydropyridines eg nifedipine amlodipine - relatively smooth muscle selective - potent vasodilator Benzothiazepines - intermediate eg verapamil eg diltiazem

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 3 rd or 4 th 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 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)

Definitive treatment ST 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