Cardiovascular Drugs - Angina, MI & Anti-arrhythmics

1. Cardiovascular Drugs- Angina, MI & Anti-arrhythmics • by Josie Hough and Steven McFarlane

2. 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

3. Treatment Options – Organic Nitrates • Glyceryl Trinate (GTN) & Isosorbide Mononitrate (ISMN) • Mechanism of Action • Nitrovasodilators (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.

4. 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.

5. 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

6. 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 Action • ß-blockers prevent the above from occurring, by blocking action at the ß-receptors.

8. ß-blockers – Side Effects • Increase in left ventricular size – due to increase in LV work. • Bradycardia • Heart failure • Cold periphery

9. Treatment Options – Ca2+ channel blockers • Verapamil & Diltiazem • Mechanism 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.

10. Treatment Options – Ca2+ channel blockers • Nifedipine • Mechanism 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.

11. Ca2+ channel blockers – Side Effects • All: • Flushing • Headaches • Ankle swelling • Diltiazem/Verapamil: • Bradycardia • Heart failure • Nifedipine only: • Reflex techycardia

12. Treatment Options - Other • Nicorandil (K+ channel opener) – vasodilator. • Can cause flushing, dizziness and severe headaches. • Ivabradine (Ifchannel 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.

13. 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.

14. 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

15. Myocardial Infarctions

16. Treatment? • STEMI NSTEMI • Do immediate PCI (or if 90 mins has elapsed give thrombolysis). • Modify risk factors • Within 96 hours do PCI. • Modify risk factors

17. For all acute coronary syndrome: • Reassurance • Oxygen • Morphine + antiemetic • Aspirin • Nitrates – IV or sublingual • Clopidogrel • Enoxaparin (LMW heparin)

18. M.I. • Immediate • M – Morphine • O – Oxygen • N – Nitrates • A – Aspirin • Late • C – Clopidogrel • A – ACEi/ARBs • B – Beta Blockers • S – Statins

19. Clot busters

21. Anti-arrhythmics

22. Cardiac Action Potential

23. Class I Agents

24. 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.

25. 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:

26. Heart Rate

27. 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) Speed Up vs. Slow Down

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

29. 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.

30. Adenosine • Mechanism of Action • Bind to the A1 receptor in pacemaker tissue inhibits adenylyl cyclasereduces cAMPincreases efflux of K+cell hyperpolarisation. • It is primarily used to diagnose and treat AV node dependent tachycardias.

31. 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.

32. Any Questions?