Ischaemic Heart DiseaseIschaemic Heart Disease

Clinical PharmacologyClinical Pharmacology

AnginaStableUnstablePrinzmetal’s

Myocardial InfarctionNSTEMISTEMI

AnginaStableUnstablePrinzmetal’s

Myocardial InfarctionNSTEMISTEMI

Ischaemic Heart DiseaseIschaemic Heart Disease

AnginaAngina

Clinical syndrome – exertional central chest tightness radiating to arms & neck

Oxygen demand exceeds supply

Factors contributing: HR, preload(venous return), afterload, aortic impedance all

determine myocardial O2 requirements

Clinical syndrome – exertional central chest tightness radiating to arms & neck

Oxygen demand exceeds supply

Factors contributing: HR, preload(venous return), afterload, aortic impedance all

determine myocardial O2 requirements

Management of stable anginaManagement of stable angina Relieved/prevented by: Slowing HR Reducing preload (impacts on LV wall stress thru LVEDP) Reducing afterload - BP Dilating coronary arteries Reducing myocardial contractility Also- Correct anaemia, tachyarrhythmias Modify CV risk factors: Hypertension, DM, smoking cessation, Wt loss,

graded exercise Prophylaxis before exercise

Relieved/prevented by: Slowing HR Reducing preload (impacts on LV wall stress thru LVEDP) Reducing afterload - BP Dilating coronary arteries Reducing myocardial contractility Also- Correct anaemia, tachyarrhythmias Modify CV risk factors: Hypertension, DM, smoking cessation, Wt loss,

graded exercise Prophylaxis before exercise

NitratesNitrates Reduce preload by venodilation, dilates coronaries, reduces afterload by systemic

vasodilatation

Different modes of delivery: Spray, buccal, long acting, short acting, IV, patch

Tachyphylaxis

Lethal interaction with PDE5 inhibitors: profound hypotension

Adverse effects:

Headache

Drug free period to prevent tolerance – LA preps - 12 hours free

Indications:

Angina, treatment of LVF

Reduce preload by venodilation, dilates coronaries, reduces afterload by systemic vasodilatation

Different modes of delivery: Spray, buccal, long acting, short acting, IV, patch

Tachyphylaxis

Lethal interaction with PDE5 inhibitors: profound hypotension

Adverse effects:

Headache

Drug free period to prevent tolerance – LA preps - 12 hours free

Indications:

Angina, treatment of LVF

ß blockersß blockers Reduce HR and contractility

Less cardiac demand for O2

Myocardium has ß1 & 2 receptors, coronary and peripheral arteries ß2 (sm. muscle dilation). Theoretic benefit for cardioselective agents – but no significant differences. Nebivolol may have additional NO effects.

Adv Effects:

Worsen/ precipitate heart blocks

Lethargy

Worsening acute cardiac failure – but used in chronic stable heart failure

Worsening COPD/asthma

Worsening peripheral vascular disease

Reduced mood / dreams – CNS penetrating drugs

Indications: Primary prophylaxis of angina, secondary prevention (post MI – ISIS 1 trial – where reduction in deaths due to EMD). Not those with ISA, arrhythmias, HOCM, thyrotoxicosis,hypertension, stable mod to severe heart failure, phaeochromocytoma, migraine prophylaxis

Reduce HR and contractility

Less cardiac demand for O2

Myocardium has ß1 & 2 receptors, coronary and peripheral arteries ß2 (sm. muscle dilation). Theoretic benefit for cardioselective agents – but no significant differences. Nebivolol may have additional NO effects.

Adv Effects:

Worsen/ precipitate heart blocks

Lethargy

Worsening acute cardiac failure – but used in chronic stable heart failure

Worsening COPD/asthma

Worsening peripheral vascular disease

Reduced mood / dreams – CNS penetrating drugs

Indications: Primary prophylaxis of angina, secondary prevention (post MI – ISIS 1 trial – where reduction in deaths due to EMD). Not those with ISA, arrhythmias, HOCM, thyrotoxicosis,hypertension, stable mod to severe heart failure, phaeochromocytoma, migraine prophylaxis

Calcium channel blockersCalcium channel blockers 2 main types: Dihydropyridines – Nifedipine, Amlodipine, Lercanidipine Reduce afterload by arteriolar dilation, dilate coronaries Non-dihydropyridines – Diltiazem, Verapamil As above & negative chronotropy by acting on SA & AV nodes.

Most are negative inotropes (non DH >> DH) except Amlodipine which is definitely safe in LV impairment

Adverse effects: Flushing, dizziness – esp instant release preparations of Nifedipine Tachycardia (esp short acting preps - reflex tachycardia) Ankle oedema – not heart failure. No indication for diuretics Non-DH: SOB, heart block (esp with concomitant ß-blockers) Indications: Angina, hypertension, post SAH, Raynaud’s

Useful in vasospastic angina

2 main types: Dihydropyridines – Nifedipine, Amlodipine, Lercanidipine Reduce afterload by arteriolar dilation, dilate coronaries Non-dihydropyridines – Diltiazem, Verapamil As above & negative chronotropy by acting on SA & AV nodes.

Most are negative inotropes (non DH >> DH) except Amlodipine which is definitely safe in LV impairment

Adverse effects: Flushing, dizziness – esp instant release preparations of Nifedipine Tachycardia (esp short acting preps - reflex tachycardia) Ankle oedema – not heart failure. No indication for diuretics Non-DH: SOB, heart block (esp with concomitant ß-blockers) Indications: Angina, hypertension, post SAH, Raynaud’s

Useful in vasospastic angina

Potassium channel activatorsPotassium channel activators Vasodilatory properties (arterial and venous) Similar to other agents – may have additional benefits as an adjunct

(ie 3rd or 4th line) Nicorandil – has a nitrate component Adv effects: Headache esp on initiation Indications: Angina IONA study : When added to standard medications, nicorandil

reduced death, NFMI by 17%

Vasodilatory properties (arterial and venous) Similar to other agents – may have additional benefits as an adjunct

(ie 3rd or 4th line) Nicorandil – has a nitrate component Adv effects: Headache esp on initiation Indications: Angina IONA study : When added to standard medications, nicorandil

reduced death, NFMI by 17%

If channel inhibitorIf channel inhibitor New anti-anginal - Ivabradine Blocks If (ionic funny channel) – an mixed Na-K inward current

activated by hyperpolarization and autonomic nervous system - lowers pacemaker activity in the SA-node

Slows heart rate – different mechanism from beta-blockers Adverse effects: Luminous phenomena (retinal Ih channels

similar to If channels) – self-limiting Indications: Angina

Restricted use

New anti-anginal - Ivabradine Blocks If (ionic funny channel) – an mixed Na-K inward current

activated by hyperpolarization and autonomic nervous system - lowers pacemaker activity in the SA-node

Slows heart rate – different mechanism from beta-blockers Adverse effects: Luminous phenomena (retinal Ih channels

similar to If channels) – self-limiting Indications: Angina

Restricted use

Management Strategy for Stable Angina Management Strategy for Stable Angina

1.ASA 2.Lipid lowering agent 3. S/L GTN 4. ß-blocker or CCB which controls rate eg non-DH 5. Add CCB to ß-blocker or nitrate to CCB 6. CCB + ß-blocker(DH) + nitrate 7.Nicorandil 8. Coronary intervention – PCI or CABG

1.ASA 2.Lipid lowering agent 3. S/L GTN 4. ß-blocker or CCB which controls rate eg non-DH 5. Add CCB to ß-blocker or nitrate to CCB 6. CCB + ß-blocker(DH) + nitrate 7.Nicorandil 8. Coronary intervention – PCI or CABG

Acute Coronary SyndromesAcute Coronary Syndromes

Stable AnginaUnstable Angina

STEMI NSTEMI

Character of pain

Exertional pain Rest pain Rest pain Rest pain

RelieversResponds to

GTNNo GTN effect No GTN effect No GTN effect

Enzymes Normal Normal Elevated Elevated

ECG Often normalOften ST

depressionST segment

elevationNo ST segment

elevation

Acute Inferior MIAcute Inferior MI

Acute coronary syndromes - managementAcute coronary syndromes - management

Bed rest Oxygen Low molecular weight heparin Aspirin Clopidogrel IV nitrate Optimise oral therapy Stratify risk - ETT, stress imaging ± angiography Consider

Tirofiban Intervention if pain fails to settle

Bed rest Oxygen Low molecular weight heparin Aspirin Clopidogrel IV nitrate Optimise oral therapy Stratify risk - ETT, stress imaging ± angiography Consider

Tirofiban Intervention if pain fails to settle

Myocardial Infarction- management

Myocardial Infarction- management

Bed rest Oxygen ASA 300mg od stat Analgesia: Diamorphine 2.5 – 5 mg IV (if no asthma/COPD) +

antiemetic Metoclopramide 10mg IV Thrombolysis – SK, tPA If typical pain within 12 hours of presentation at any age New ST elevation or LBBB Adv effects: haemorrhage, hypotension, bradycardia,

reperfusion arrythmias, anaphylaxis

Bed rest Oxygen ASA 300mg od stat Analgesia: Diamorphine 2.5 – 5 mg IV (if no asthma/COPD) +

antiemetic Metoclopramide 10mg IV Thrombolysis – SK, tPA If typical pain within 12 hours of presentation at any age New ST elevation or LBBB Adv effects: haemorrhage, hypotension, bradycardia,

reperfusion arrythmias, anaphylaxis

Myocardial InfarctionMyocardial Infarction SK first choice, tPA for patients < 60 within first 6 hours and anterior

changes, cardiogenic shock, prev anaphylaxis with SK IV heparin to follow tPA Contraindications to thrombolysis: Within 28 days of bleed, trauma,traumatic resuscitation Uncontrolled hypertension SBP > 200, DBP > 120 mmHg - Rx IV GTN Aortic dissection Coma Known / suspected active peptic ulcer disease Recent CVA Defective haemostasis (warfarin per se is OK, unless INR very high -

consult seniors) Severe renal/liver disease Acute pancreatitis Pregnancy / lactation Within 3 months of vascular surgery

SK first choice, tPA for patients < 60 within first 6 hours and anterior changes, cardiogenic shock, prev anaphylaxis with SK

IV heparin to follow tPA Contraindications to thrombolysis: Within 28 days of bleed, trauma,traumatic resuscitation Uncontrolled hypertension SBP > 200, DBP > 120 mmHg - Rx IV GTN Aortic dissection Coma Known / suspected active peptic ulcer disease Recent CVA Defective haemostasis (warfarin per se is OK, unless INR very high -

consult seniors) Severe renal/liver disease Acute pancreatitis Pregnancy / lactation Within 3 months of vascular surgery

AntithrombogensAntithrombogens

Aspirin – inhibits cyclo-oxygenase, prevents syntheses of TxA2 (pro-thrombotic)

Thienopyridines (clopidogrel, ticlopidine) – irreversibly inhibit binding of ADP during platelet activation. Used with Aspirin with drug eluting stents & in NSTEMI. Expensive!!

Glycoprotein 2b3a antagonists – potent inhibitors of platelet aggregation eg. abciximab, eptifibatide, tirofiban

Aspirin – inhibits cyclo-oxygenase, prevents syntheses of TxA2 (pro-thrombotic)

Thienopyridines (clopidogrel, ticlopidine) – irreversibly inhibit binding of ADP during platelet activation. Used with Aspirin with drug eluting stents & in NSTEMI. Expensive!!

Glycoprotein 2b3a antagonists – potent inhibitors of platelet aggregation eg. abciximab, eptifibatide, tirofiban

IV ß-blockade - indications IV ß-blockade - indications

Indication as for thrombolysisAtenolol 5-10mg IV slowContraindications: Pulse < 50, SBP <100 mmHg,

Asthma/COPD, conduction defects/sick sinus, uncontrolled CCF, severe PVD, poor LV function

Indication as for thrombolysisAtenolol 5-10mg IV slowContraindications: Pulse < 50, SBP <100 mmHg,

Asthma/COPD, conduction defects/sick sinus, uncontrolled CCF, severe PVD, poor LV function

Secondary prophylaxis for IHDSecondary prophylaxis for IHDAspirin to all patientsß-blocker to all patientsACE inhibition – meta-analyses of SAVE, AIRE, TRACE

in patients with LV dysfunction, HOPE in patients without LV dysfunction

Lipid lowering for all patients

Aggressive risk factor management – hypertension, DM ,smoking cessation, cardiac rehabilitation

Aspirin to all patientsß-blocker to all patientsACE inhibition – meta-analyses of SAVE, AIRE, TRACE

in patients with LV dysfunction, HOPE in patients without LV dysfunction

Lipid lowering for all patients

Aggressive risk factor management – hypertension, DM ,smoking cessation, cardiac rehabilitation

EBM - MIEBM - MI

ISIS (International Study of Infarct Survival) 1 : Atenolol reduces early mortality post MI (mainly due to reduction in EMD)

ISIS 2 : SK and ASA reduces 5 week mortality in patients with AMI

ISIS 3 : SK = rtPA but rtPA associated with more cerebral bleeds

ISIS 4 : Captopril has a small but significant reduction in mortality post MI. IV Mg and nitrates – no benefit

ISIS (International Study of Infarct Survival) 1 : Atenolol reduces early mortality post MI (mainly due to reduction in EMD)

ISIS 2 : SK and ASA reduces 5 week mortality in patients with AMI

ISIS 3 : SK = rtPA but rtPA associated with more cerebral bleeds

ISIS 4 : Captopril has a small but significant reduction in mortality post MI. IV Mg and nitrates – no benefit

EBMEBM IHD CURE (Clopidogrel in Unstable Angina to prevent recurrent events): In ACS,

clopidogrel + ASA significantly reduces death from CV, non-fatal MI & stroke compared to ASA alone

HOPE (Heart Outcome Prevention Evaluation Study) : Ramipril reduced MI, stroke, CV death in high risk patients

Lipids: 4S (Scand Simvastatin Survival Study) : Simvastatin reduces risk of all major

coronary events (relative risk reduction of 35%) in patients with CAD & mild-mod hypercholesterolemia (2º prevention)

WOSCOPS (West of Scotland Coronary Prevention Study) : Pravastatin reduced deaths from CHD, all cardiovascular causes and nonfatal MI in patients with hypercholesterolemia and no previous IHD (1 º prevention)

IHD CURE (Clopidogrel in Unstable Angina to prevent recurrent events): In ACS,

clopidogrel + ASA significantly reduces death from CV, non-fatal MI & stroke compared to ASA alone

HOPE (Heart Outcome Prevention Evaluation Study) : Ramipril reduced MI, stroke, CV death in high risk patients

Lipids: 4S (Scand Simvastatin Survival Study) : Simvastatin reduces risk of all major

coronary events (relative risk reduction of 35%) in patients with CAD & mild-mod hypercholesterolemia (2º prevention)

WOSCOPS (West of Scotland Coronary Prevention Study) : Pravastatin reduced deaths from CHD, all cardiovascular causes and nonfatal MI in patients with hypercholesterolemia and no previous IHD (1 º prevention)