Cardiovascular Drugs- Angina, MI & Anti-arrhythmics

by Josie Hough and Steven McFarlane

Angina Prevention/Treatment

• Reduce cardiovascular risk factors:– Reduce BP– Reduce cholesterol– Smoking cessation

• Decrease metabolic demand of LV:– Reduce heart rate– Reduce arterial pressure– Reduce ventricular size

• Increase coronary blood flow

Treatment Options – Organic Nitrates

Glyceryl Trinate (GTN) & Isosorbide Mononitrate (ISMN)

Mechanism of ActionNitrovasodilators (metabolised) NO.NO activates guanylyate cyclase.Guanylate cyclase coverts GTP cGMP.cGMP (via a protein kinase) activates myosin light

chain phosphatase.Myosin light chain phosphatase dephosphorylates

myosin light chain fibres, causing smooth muscle relaxation/preventing constriction.

Organic Nitrates – Extra Info

• Preferential effect on veins (large increase in venous capacitance) – see Starling Curve.

• GTN is inactivated when taken orally – must be delivered sublingually.

• GTN works in 1-2 minutes, for 15-20 minutes.

• ISMN is long-acting, can be taken orally.• Organic nitrates should only be given

intermittently – vascular smooth muscle may become resistant, risk of abnormal constriction on withdrawal.

Organic Nitrates – Side Effects

• Vascular Headaches – caused by dilation of intercranial arteries

• Tachycardia

• Steal Syndrome – healthy blood vessels become dilated, diverting blood away from atheromatous vessels, resulting in less blood supply to these areas than was reaching there previously– Organic nitrates have limited potential for

dilating sites of atheroma

Treatment Options – ß-blockers

Atenolol, etc.The Normal System

Activation of ß-adrenoreceptors (with G-coupled protein) activates adenylate cyclase.Adenylate cyclase activates ATP cAMP.cAMP activates protein kinase A (PKA)PKA causes an increase in heart rate and force of contraction.

Mechanism of Actionß-blockers prevent the above from occurring, by blocking action at the ß-receptors.

ß-blockers – Side Effects

• Increase in left ventricular size – due to increase in LV work.

• Bradycardia

• Heart failure

• Cold periphery

Treatment Options – Ca2+

channel blockersVerapamil & DiltiazemMechanism of Action

Reduce calcium entry to cardiac pacemaker cells, cardiac myocytes and vascular myocytes through L-gated calcium channels.

This causes the heart rate to slow, contraction force to be reduced and blood pressure to fall.

Treatment Options – Ca2+

channel blockersNifedipineMechanism of Action

Reduces calcium entry to vascular myocytes through L-gated calcium channels. Has NO DIRECT EFFECT on cardiac cells themselves.

Nifedipine causes a fall in blood pressure.

Ca2+ channel blockers – Side Effects

• All:– Flushing– Headaches– Ankle swelling

• Diltiazem/Verapamil:– Bradycardia – Heart failure

• Nifedipine only:– Reflex techycardia

Treatment Options - Other

• Nicorandil (K+ channel opener) – vasodilator.– Can cause flushing, dizziness and severe

headaches.

• Ivabradine (If channel blocker) – slows heart rate, relaxes coronary arteries.– Can cause bradycardia, heart block, headaches.

• Ranolazine (reduces intracellular calcium via sodium-dependent calcium channels).– Can cause increased QT interval, vomiting,

constipation, oedema, headaches, hypotension.

Which Treatment When?

For Stable Angina• First line – ß-blocker or Ca2+ channel

blocker• If not tolerated, reverse choice.• If not tolerated try ISMN,

or Nicorandil, or Ivabradine, or Ranolazine – in that order.

Which Treatment When?

For Unstable Angina• Antiplatelet treatment ASAP– Aspirin first line, then clopidrogrel

• Anti-thrombin treatment– Heparin or direct thrombin inhibitor (e.g.

bivalirudin)

• Nitrates

Myocardial InfarctionsSTEMI NSTEMI

Infarct? Yes – dead muscle Yes – dead muscle

Coronary artery

occluded occluded

Pain lasts >30 mins >30 minsPain related to exertion

No No

Pain relieved by relaxing GTN

No No

Thickness of muscle death

Full thickness muscle death

Partial thickness muscle death

ECG changes ST elevation elevation (looks like unstable angina on ECG)

Trop T positive positive

Treatment?

STEMI• Do immediate PCI (or if

90 mins has elapsed give thrombolysis).

• Modify risk factors

NSTEMI• Within 96 hours do PCI. • Modify risk factors

For all acute coronary syndrome:

• Reassurance• Oxygen• Morphine + antiemetic• Aspirin• Nitrates – IV or sublingual• Clopidogrel• Enoxaparin (LMW heparin)

M.I.• Immediate• M – Morphine• O – Oxygen • N – Nitrates• A – Aspirin

• Late• C – Clopidogrel• A – ACEi/ARBs• B – Beta Blockers• S – Statins

Clot bustersStreptokinase Binds circulating plasminogen to

form an activator complex that converts further plasminogen to plasmin

Development of neutralising antibodies therefore avoid re use from 5 days to 1 year after initial treatmentAllergic reaction…

Urokinase As above As aboveTPA (Alteplase) Tissue plasminogen activator… No risk of allergic

reaction, APSAC - Acylated plasminogen streptokinase complex,

Pro-drugPlasminogen-streptokinase

complex activates plasmin

Reteplase recombinant non-glycosylated form of tPAlonger half-life Selective for fibrin-bound plasminogenimproving its ability to penetrate into clots.

Anti-arrhythmics Class Examples Mechanism

Ia Quinidine, Procainamide

Na+ -channel blocker – intermediate association/dissociation

Ib Lidocaine, Phenytoin

Na+ -channel blocker - fast association/dissociation

Ic Flecainide, Propafenone

Na+ -channel blocker – slow association/dissociation

II Atenolol, Propanolol, Bisoprolol

ß-blockers

III Amiodarone, Sotalol

K+ -channel blocker

IV Verapamil, Diltiazem

Ca2+ -channel blocker

V Adenosine, Digoxin, Ivabradine, Atropine

Others

Cardiac Action Potential

Class I Agents

Class III Agents

• Class II – ß-blockers (see earlier slides)

Class III block the potassium channels and thereby prolong repolarisation, but do not affect conduction velocity. They prevent re-entrant arrhythmias.

Class IV Agents

Reduce amplitude and shorten phase 2 of the cardiac AP. As they reduce intracellular Ca2+ they are also

negatively inotropic.

They also have an effect on pacemaker cells, slowing their overall conduction, so that they eventually have this effect:

Heart Rate

Speed Up vs. Slow Down

Atropine•Speed Up: Blocks the effects of Ach, so the heart beats faster•Used to treat Bradycardia!

ß-Blockers•Slow Down: blocks the sympathetic action on the heart•Used to treat atrial fibrillation! (among other things)

Ivabradine

Can also be used to treat arrhythmias. It only works on the SA node, slowing Na+ entry and thereby slowing pacemaker potential.

Digoxin

Inhibits the Na+/K+ ATPase pump increased intracellular Na+ concentration stops passive exchange of Ca2+ for Na+increased intracellular Ca2+ concentration positively inotropic, negatively chronotopic.

Adenosine

Mechanism of ActionBind to the A1 receptor in pacemaker tissue

inhibits adenylyl cyclasereduces cAMPincreases efflux of K+cell hyperpolarisation.

It is primarily used to diagnose and treat AV node dependent tachycardias.

Summary

• Treatment options (and side effects) of main angina drugs.

• MI immediate treatment.

• Anti-arrhythmics – classifications, methods of action and effects of cardiac action potential.

Any Questions?