Pharmacological Pharmacological management of management of Ischaemic heart Ischaemic heart

disease and acute disease and acute myocardial infarctionmyocardial infarction

October 2006October 2006

AtherosclerosisAtherosclerosis

The complications of The complications of

atherosclerosis constitute the atherosclerosis constitute the

greatest cause of morbidity and greatest cause of morbidity and

mortality in the Western World mortality in the Western World

accounting for 40% of all deathsaccounting for 40% of all deaths

AtherosclerosisAtherosclerosis

Progressive luminal narrowingProgressive luminal narrowing

- angina pectoris- angina pectoris

- intermittent claudication- intermittent claudication Plaque rupture and thrombosisPlaque rupture and thrombosis

- acute coronary syndromes- acute coronary syndromes

- transient ischaemic attack- transient ischaemic attack Aneurysm formationAneurysm formation

Aims of treatmentAims of treatment

Relieve symptomsRelieve symptoms

Slow disease progressionSlow disease progression

Reduce risk of acute eventReduce risk of acute event

Improve survivalImprove survival

Management overviewManagement overview

Pharmacological treatmentPharmacological treatment

Managing risk factorsManaging risk factors

Interventional proceduresInterventional procedures

Angina pectorisAngina pectoris

Myocardial oxygen demand Myocardial oxygen demand

exceeds supply exceeds supply chest pain chest pain Stable angina Stable angina

- transient myocardial ischaemia- transient myocardial ischaemia

- predictable, reproducible- predictable, reproducible

- relieved by rest or GTN- relieved by rest or GTN

Principles of treatmentPrinciples of treatment

Increase oxygen supply or reduce Increase oxygen supply or reduce oxygen demands of myocardiumoxygen demands of myocardium

Reduce heart rateReduce heart rate

Reduce preloadReduce preload

Reduce afterloadReduce afterload

Improve coronary blood flowImprove coronary blood flow

Symptomatic Symptomatic treatmenttreatment

1.1. NitratesNitrates

2.2. Beta blockersBeta blockers

3.3. Calcium channel blockersCalcium channel blockers

4.4. Potassium channel activatorsPotassium channel activators

5.5. Selective pacemaker If current Selective pacemaker If current inhibitorIvabradine (Procolalan)inhibitorIvabradine (Procolalan)

Describing any drugDescribing any drug

MOA and pharmacological MOA and pharmacological propertiesproperties

IndicationsIndications Cautions/ContraindicationsCautions/Contraindications Side effectsSide effects Important interactionsImportant interactions Dose/overdoseDose/overdose

Nitrates - Mode of Nitrates - Mode of actionaction Metabolised to release Nitric oxide Metabolised to release Nitric oxide

(NO)(NO) cGMPcGMP Dephosphorylation of myosin light Dephosphorylation of myosin light

chainschains Increased intracellular calciumIncreased intracellular calcium Muscle relaxationMuscle relaxation

Nitrates - Mode of Nitrates - Mode of actionaction Venodilation - Venodilation - preload preload Coronary artery vasodilation - Coronary artery vasodilation -

supplysupply Moderate arteriolar dilation - Moderate arteriolar dilation -

afterloadafterload

Pharmacological Pharmacological propertiesproperties Glyceryl trinitrate (GTN)Glyceryl trinitrate (GTN) short acting, first pass metabolismshort acting, first pass metabolism sublingual/intravenous/patch administrationsublingual/intravenous/patch administration Isosorbide dinitrateIsosorbide dinitrate intermediate actingintermediate acting sublingual/intravenous/oral administrationsublingual/intravenous/oral administration Isosorbide mononitrateIsosorbide mononitrate long actinglong acting oral administration oral administration

Alfred NobelAlfred Nobel

Pharmacological Pharmacological propertiesproperties

Tolerance (tachyphylaxis)Tolerance (tachyphylaxis)

- reduced therapeutic effects- reduced therapeutic effects ““Monday morning sickness”Monday morning sickness” ? due to depletion of free tissue –SH? due to depletion of free tissue –SH Long-acting preparations Long-acting preparations

/infusions/transdermal patches/infusions/transdermal patches ““Nitrate free period”Nitrate free period”

IndicationsIndications

Relief of acute angina attackRelief of acute angina attack Prophylaxis of stable anginaProphylaxis of stable angina

(prior to exercise GTN or long-(prior to exercise GTN or long-acting)acting)

Left ventricular failureLeft ventricular failure

Cautions/Cautions/ContraindicationsContraindications

HypotensionHypotension Aortic stenosisAortic stenosis HOCMHOCM Constrictive pericarditisConstrictive pericarditis

Side effectsSide effects

HeadacheHeadache FlushingFlushing DizzinessDizziness Postural hypotensionPostural hypotension TachycardiaTachycardia Overdose rarely precipitates Overdose rarely precipitates

methaemoglobinaemiamethaemoglobinaemia

Important interactionImportant interaction

Phosphodiesterase inhibitors eg Phosphodiesterase inhibitors eg sildenafil sildenafil

Inhibits cGMP breakdownInhibits cGMP breakdown

severe hypotension – severe hypotension –

nitrates contraindicated if taken nitrates contraindicated if taken within the previous 24 hourswithin the previous 24 hours

Infusion reduces anticoagulant effect Infusion reduces anticoagulant effect of heparinof heparin

Beta blockersBeta blockers

Mode of actionMode of action

Competitive inhibitors of Competitive inhibitors of catecholamine at beta-adrenoceptor catecholamine at beta-adrenoceptor sitessites

Inhibit sympathetic stimulation of Inhibit sympathetic stimulation of heart and smooth muscleheart and smooth muscle

HR HR contractility contractility ββ11 Vasoconstriction & Vasoconstriction &

bronchoconstriction bronchoconstriction ββ22

Pharmacological Pharmacological propertiesproperties Cardioselective – eg atenolol metoprololCardioselective – eg atenolol metoprolol Non selective – eg propranololNon selective – eg propranolol Intrinsic sympathomimetic (partial Intrinsic sympathomimetic (partial

agonist) activity – eg celiprolol pindololagonist) activity – eg celiprolol pindolol Alpha-blocking activity eg carvedilolAlpha-blocking activity eg carvedilol Lipid soluble (eg propranolol) versus Lipid soluble (eg propranolol) versus

water soluble (eg atenolol)water soluble (eg atenolol) Up-regulation of receptors – withdrawal Up-regulation of receptors – withdrawal

syndromesyndrome

IndicationsIndications

Symptomatic anginaSymptomatic angina HypertensionHypertension Acute coronary syndromesAcute coronary syndromes Post myocardial infarctionPost myocardial infarction Stable heart failureStable heart failure ArrhythmiasArrhythmias Thyrotoxicosis/Benign essential Thyrotoxicosis/Benign essential

tremortremor

Cautions/Cautions/ContraindicationsContraindications

C/I in asthmaC/I in asthma Uncontrolled heart failureUncontrolled heart failure BradycardiaBradycardia Heart blockHeart block Phaeochromocytoma without prior Phaeochromocytoma without prior

alpha blockadealpha blockade Caution coronary spasm/COPD/PVDCaution coronary spasm/COPD/PVD Avoid abrupt withdrawalAvoid abrupt withdrawal

Important InteractionImportant Interaction

Verapamil and beta blockers Verapamil and beta blockers precipitate heart block +- precipitate heart block +- asystoleasystole

Must NOT give IV verapamil to Must NOT give IV verapamil to beta blocked patientsbeta blocked patients

Extreme caution combined orallyExtreme caution combined orally

Side effectsSide effects

Beta-1 effects – Bradycardia, heart Beta-1 effects – Bradycardia, heart block, heart failureblock, heart failure

Beta-2 effects – bronchospasm, Beta-2 effects – bronchospasm, worsening PVD, Raynaud’s worsening PVD, Raynaud’s phenomenonphenomenon

Fatigue, depression, nightmares, Fatigue, depression, nightmares, impotenceimpotence

May mask hypoglycaemia and worsen May mask hypoglycaemia and worsen glycaemic control in IDDMglycaemic control in IDDM

DoseDose

Rational choice - long-acting Rational choice - long-acting cardioselective beta blocker od or cardioselective beta blocker od or bdbd

Anti-anginal effects are dose Anti-anginal effects are dose relatedrelated

Titrate to resting heart rate 50-60 Titrate to resting heart rate 50-60 bpmbpm

Calcium antagonistsCalcium antagonists

Mode of actionMode of action

Prevent opening of voltage-gated Prevent opening of voltage-gated calcium channelscalcium channels

Bind to Bind to -1 subunit of cardiac and -1 subunit of cardiac and smooth muscle L-type calcium channelssmooth muscle L-type calcium channels

Vasodilator effect on resistance vessels Vasodilator effect on resistance vessels afterload afterload

Coronary artery dilationCoronary artery dilation Negative chronotropicNegative chronotropic Negative inotropic effectsNegative inotropic effects

Pharmacological Pharmacological propertiesproperties 3 classes3 classes PhenylalkylaminesPhenylalkylamines eg verapamil eg verapamil - relatively cardioselective- relatively cardioselective - -ve chronotropic and inotropic- -ve chronotropic and inotropic Dihydropyridines Dihydropyridines eg nifedipine eg nifedipine

amlodipineamlodipine - relatively smooth muscle selective- relatively smooth muscle selective - potent vasodilator- potent vasodilator BenzothiazepinesBenzothiazepines eg diltiazem eg diltiazem - intermediate- intermediate

IndicationsIndications

Symptomatic control of anginaSymptomatic control of angina Coronary spasmCoronary spasm HypertensionHypertension ArrhythmiasArrhythmias Subarachnoid haemorrhage Subarachnoid haemorrhage

(nimodipine)(nimodipine)

Side effectsSide effects

Peripheral vasodilation Peripheral vasodilation

- flushing, headache, ankle oedema- flushing, headache, ankle oedema Cardiac effectsCardiac effects

- AV block, heart failure- AV block, heart failure ConstipationConstipation Short-acting dihydropyridines a/w Short-acting dihydropyridines a/w

mortality and MImortality and MI

Potassium channel Potassium channel activatorsactivators

Potassium channel Potassium channel activators - nicorandilactivators - nicorandil Activates K ATP channelActivates K ATP channel NO donor effectsNO donor effects Arterial and venodilatorArterial and venodilator S/E Flushing, dizziness, headacheS/E Flushing, dizziness, headache Usually 3Usually 3rdrd or 4 or 4thth line agent line agent

Selective pacemaker If Selective pacemaker If current inhibitorcurrent inhibitor Ivabradine (Procolalan)Ivabradine (Procolalan) reduces spontaneous beating rate of the reduces spontaneous beating rate of the

sinus node by slowing the diastolic sinus node by slowing the diastolic depolarization slope of the action depolarization slope of the action potential potential

selective and prolonged reduction in selective and prolonged reduction in heart rate, both at rest and during heart rate, both at rest and during exercise exercise

Indicated for angina where cannot give a Indicated for angina where cannot give a beta blockerbeta blocker

Ongoing trials (Beautiful trial)Ongoing trials (Beautiful trial)

Additional therapy in Additional therapy in stable anginastable angina

Low-dose aspirinLow-dose aspirin Lipid lowering therapyLipid lowering therapy ACE inhibitorsACE inhibitors Treat Treat BP and diabetesBP and diabetes Smoking cessationSmoking cessation Weight reductionWeight reduction InterventionIntervention

Antiplatelet agentsAntiplatelet agents

Aspirin – inhibits cyclo-oxygenase Aspirin – inhibits cyclo-oxygenase and thromboxane A2 synthesisand thromboxane A2 synthesis

Theinopyridines – clopidogrel – Theinopyridines – clopidogrel – block binding of ADP to platelet block binding of ADP to platelet receptorreceptor

Glycoprotein IIb/IIIa inhibitors Glycoprotein IIb/IIIa inhibitors (abciximab) – inhibit cross-(abciximab) – inhibit cross-bridging of platelets by fibrinogenbridging of platelets by fibrinogen

Acute coronary Acute coronary syndromesyndrome Angina at rest >20minsAngina at rest >20mins New onset angina severely New onset angina severely

affecting exercise toleranceaffecting exercise tolerance Increasing frequency or duration Increasing frequency or duration

or occurring with lesser exertionor occurring with lesser exertion

Acute coronary Acute coronary syndromessyndromes

Plaque rupture and coronary Plaque rupture and coronary thrombosisthrombosis

Unstable anginaUnstable angina Non-ST elevation MI (subendocardial Non-ST elevation MI (subendocardial

infarction)infarction) Acute transmural myocardial Acute transmural myocardial

infarctioninfarction

Goals of treatmentGoals of treatment

Relief of ischaemic painRelief of ischaemic pain Assess haemodynamic stateAssess haemodynamic state Anti-platelet therapy to prevent Anti-platelet therapy to prevent

further thrombosisfurther thrombosis Initiate reperfusion therapy with Initiate reperfusion therapy with

percutaneous angioplasty or percutaneous angioplasty or thrombolysis if appropriatethrombolysis if appropriate

Secondary preventionSecondary prevention

Initial ManagementInitial Management

OxygenOxygen Aspirin 150-300mg chewed/dispersibleAspirin 150-300mg chewed/dispersible Nitrates GTN 0.4mg sublingual +- IVNitrates GTN 0.4mg sublingual +- IV Intravenous morphine 2.5-10mg+ antiemetic cyclizine Intravenous morphine 2.5-10mg+ antiemetic cyclizine

50mg50mg Decide on definitive treatmentDecide on definitive treatment

Beta-blocker atenolol 5mg over 5 mins repeated after Beta-blocker atenolol 5mg over 5 mins repeated after 10-15 mins10-15 mins

Clopidogrel 300mg if undergoing PCIClopidogrel 300mg if undergoing PCI Glycoprotein IIb/IIIa inhibitors (abciximab) if undergoing Glycoprotein IIb/IIIa inhibitors (abciximab) if undergoing

PCIPCI ACE inhibitor within 24 hoursACE inhibitor within 24 hours Tight glycaemic controlTight glycaemic control Optimise potassium and magnesiumOptimise potassium and magnesium

Definitive treatment-Definitive treatment-ST elevation Myocardial ST elevation Myocardial infarctioninfarction

Primary coronary angioplasty Primary coronary angioplasty

90% recanalisation90% recanalisation

Door to balloon time <90mins ? up to Door to balloon time <90mins ? up to 3hrs3hrs

Ideal where cardiogenic shock and when Ideal where cardiogenic shock and when thrombolytics contraindicatedthrombolytics contraindicated

clopidogrel 300mg loading dose then clopidogrel 300mg loading dose then 75mg od75mg od

Glycoprotein IIb/IIIa inhibitors (abciximab)Glycoprotein IIb/IIIa inhibitors (abciximab)

Definitive treatment-Definitive treatment-ST elevation Myocardial ST elevation Myocardial infarctioninfarction

Primary PCI not availablePrimary PCI not available

Thrombolysis Thrombolysis

50-60% recanalisation50-60% recanalisation

Door to needle time <30minsDoor to needle time <30mins

Effective up to 12 hoursEffective up to 12 hours

Fibrinolytic agentsFibrinolytic agents

Mode of actionMode of action

Activate plasminogen to form plasmin Activate plasminogen to form plasmin which degrades fibrin breaking up which degrades fibrin breaking up thrombithrombi

Streptokinase, alteplase, reteplase, Streptokinase, alteplase, reteplase, tenecteplasetenecteplase

Streptokinase – antibodies within 4 Streptokinase – antibodies within 4 daysdays

Alteplase, reteplase followed by Alteplase, reteplase followed by heparin for 48 hoursheparin for 48 hours

IndicationsIndications

Acute ST elevation myocardial Acute ST elevation myocardial infarctioninfarction

Acute pulmonary embolismAcute pulmonary embolism Acute ischaemic stroke within 3 Acute ischaemic stroke within 3

hourshours

ContraindicationsContraindications Recent haemorrhage trauma or surgery Recent haemorrhage trauma or surgery Recent dental extractionRecent dental extraction Coagulation defects;bleeding disordersCoagulation defects;bleeding disorders Aortic dissectionAortic dissection History of cerebrovascular diseaseHistory of cerebrovascular disease Active peptic ulcerationActive peptic ulceration Severe menorrhagiaSevere menorrhagia Severe hypertensionSevere hypertension Active cavitating lung diseaseActive cavitating lung disease Acute pancreatitisAcute pancreatitis Severe liver diseaseSevere liver disease Oesophageal varicesOesophageal varices Previous reaction to streptokinase (Streptokinase)Previous reaction to streptokinase (Streptokinase)

Relative Relative contraindicationscontraindications Venepuncture (non-compressible Venepuncture (non-compressible

site)site) Recent invasive procedureRecent invasive procedure External chest compressionsExternal chest compressions PregnancyPregnancy Abdominal aortic aneurysmAbdominal aortic aneurysm Diabetic retinopathyDiabetic retinopathy Anticoagulant therapyAnticoagulant therapy

Side effectsSide effects

Nausea and vomitingNausea and vomiting BleedingBleeding Reperfusion arrhythmiasReperfusion arrhythmias HypotensionHypotension Back painBack pain Allergic reactions (esp Allergic reactions (esp

streptokinase)streptokinase)

Unstable Unstable angina/NSTEMIangina/NSTEMI

““MONA” – morphine; O2; nitrate; aspirinMONA” – morphine; O2; nitrate; aspirin Heparin eg enoxaparin 1mg/kg 12 hourlyHeparin eg enoxaparin 1mg/kg 12 hourly

Beta-blocker atenolol 5mg over 5 mins Beta-blocker atenolol 5mg over 5 mins repeated after 10-15 minsrepeated after 10-15 mins

Clopidogrel Clopidogrel Glycoprotein IIb/IIIa inhibitors (abciximab) if Glycoprotein IIb/IIIa inhibitors (abciximab) if

undergoing PCIundergoing PCI ACE inhibitor if indicatedACE inhibitor if indicated Tight glycaemic controlTight glycaemic control Optimise potassium and magnesiumOptimise potassium and magnesium

Reading/Website listReading/Website list

British national formulary BNFBritish national formulary BNF www.uptodate.comwww.uptodate.com American heart association American heart association

guidelinesguidelines