Cardiovascular Drugs - Angina, MI & Anti-arrhythmics
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Transcript of Cardiovascular Drugs - Angina, MI & Anti-arrhythmics
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?