Pharmacology - Drugs for Myocardial Ischaemia

Question 1

Difference between infarct and ischaemia?

Answer 1

Infarct - Die

Ischaemia - Reduced

Question 2

Which coronary artery is most commonly effected?

Answer 2

Left AnterIor Descending - Widow maker

Question 3

Where can coronary artery vasodilators dilate ?

Answer 3

coronary arteriolar vasodilators will only dilate areas proximal to the plaque, and reduce rather than increase perfusion to the ischaemic area.

So how do drugs improve the balance between oxygen supply and demand in the relief of angina pain?

Question 4

What is the first line medication for angina?

Answer 4

GTN

Question 4

What route is GTN given ?

Answer 4

Sublingually

Question 5

Why is GTN given sublingually ?

Answer 5

The sublingual route avoids extensive liver metabolism.

Question 6

What is the mechanism of action for GTN ?

Answer 6

GTN maybe considered as a prodrug, converted by aldehyde dehydrogenase in mitochondria of the blood vessel wall generating NO, an endogenous vasodilator (they have been used for this purpose for over 100 years, prior to the discovery of endogenous NO). The NO generated, stimulates a cytoplasmic guanylate cyclase in smooth muscle to generate cGMP which in turn activates a cGMP kinase to reduce intracellular calcium resulting in vasodilation. Mechanisms involved lowering intracellular calcium include inhibiting the removal of calcium from the cell by a Ca ATP-ase or increasing the uptake into intracellular stores. GTN relieves angina pain by reducing oxygen demand firstly through venodilation (increasing venous capacitance, reducing preload) and secondly through peripheral arteriolar dilation reducing the afterload. Arterial vasodilation improving collateral blood flow and vasospasm, may also increase oxygen supply.

Question 7

What medications can be used for relied of anginal pain ?

Answer 7

1- β-Blockers (treatment of Angina Pectoris)
and/or
2) Calcium Channel Blockers (treatment of Variant form)
3) long acting nitrate/nicorandil (Reduces intracellular Na-Ca = improves diastolic function)

Question 8

Explain use of B-Blockers in Angina

Answer 8

Act by blocking β1 receptors and decreasing
Heart rate
Contractility (Force of contraction)
Cardiac output
Blood pressure
Act on area of heart stimulated by sympathetic nervous system and circulating adrenaline

Will result into
Decrease oxygen demand of myocardium during exercise and rest

What beta blockers do
Reduce frequency of anginal attack
Increases exercise duration and tolerance with efforts induced angina
Reduced risk of death and MI in patient who have had prior MI
Improve mortality of patient with hypertension and reduced ejection fraction

Selective B1 blockers are
Metoprolol
Atenolol

To be monitored and used in
DM
PVD
COPD

To remember
Do not suddenly stop
Gradually tapered over 2-3 weeks to prevent rebound angina, MI , HT

Question 9

Explain the mechanism of action of B-Blockers in Angina

Answer 9

Mecahnism of balance of oxygen in Angina Pectoris
Negative inotrope (O2 demand )
Negative chronotrope -Reduces heart rate (distribution of O2 supply)
Antihypertensive - reduces afterload (O2 demand )- arterial pressure

They alter the balance of oxygen supply and demand in
3 separate ways:-

Oxygen demand is reduced by inhibiting myocardial contractility (negative inotrope) and reducing the afterload on the heart by lowering systemic blood pressure.
The distribution of oxygen supply to the inner myocardium is improved by slowing the heart rate (negative chronotrope) increasing time for blood to perfuse from the outside to the inside of the heart within each heart beat.

The major benefit of Beta Blockers will be in the relief of angina pain due to angina pectoris and atheroma rather than coronary vasospasm.

Question 10

What are the two groups of Ca channel blockers ?

Answer 10

Dihydropyridine
Nondihydropyridine

Question 11

Explain why Calcium channel blockers are used in relieving angina pain

Answer 11

Dihydropyridines
Most effective in coronary vasospasm
L-form calcium channel (present in vascular Smooth muscles)
Inhibits all channel states
Works from outside cell

In Angina - Arteries are bettered perfuses than arterioles (Different than Hypertension)

Potential B-Blocker combination
Once daily
amlodipine or nifedipine (sustained release)

Ca Channel Blockers - Not used in Angina
Diltiazem –most effective CCB in angina pectoris modest decrease in heart rate and blood pressure.

• Verapamil – do not use in angina, reduces CO, causes heart block, -ve negative inotrope, problem with beta blockers and heart failure

Question 12

What are some nitrate alternatives ?

Answer 12

Glyceryl trinitrate itself may be delivered continuously, rather than intermittently, using either skin patches or a 2% ointment. Tolerance can be avoided by day-time treatment with removal of the skin patch at night.

An oral sustained release form of nitrate, isosorbide mononitrate, unlike GTN, is not a substrate for 1st pass metabolism by the liver. Twice daily administration uses a 7 hour dosage interval (at 8am and 3pm) to avoid the development of tolerance.

A second agent, nicorandil has a dual mode of action. It is a nitrate vasodilator which at higher doses also opens ATP K+ channels to cause hyperpolarisation of vascular smooth muscle which contributes to the vascular effect.

Nicorandil, unlike GTN does appear to induce tolerance and may activate guanylate cyclase directly.

Question 13

Explain how Ivabrine works

Answer 13

Ivabradine - slows heart rate without affecting force of cardiac contraction

This improves inner myocardial perfusion and oxygen supply. It does so by slowing the unstable resting membrane potential (pacemaker) in the SA node (phase 4 of the action potential). This pacemaker potential (depolarisation) is due to the inward movement of Na through the so-called ‘funny channel’ (If) named because it is activated by hyperpolarisation rather than depolarisation. Blockade of If by ivabradine, slows the inward flow of Na, slowing the heart rate, improving myocardial perfusion and hence oxygen supply.

Question 14

Explain how ranolazine works

Answer 14

Ranolazine - Inhibits force of cardiac contraction without affecting heart rate

Ranolazine - Inhibition of late sodium current
Reduction in elevated intracellular calcium,
Reduction of muscle tension and oxygen demand

Metabolised by CYP3A4, inhibits CYP2D6
Prolongs QT interval

Ranolazine, in a way does the opposite of ivabradine, it inhibits the force of contraction of cardiac muscle without affecting heart rate reducing oxygen demand by the heart (opposite to digoxin). Ranolazine inhibits another cardiac sodium channel (Ina), a late sodium current shortening the action potential reducing total calcium entry which in turn reduces myocardial contractility and thereby oxygen demand.

Question 15

What are fibrinolytic drugs used for ?

Answer 15

Involvement of drug use in the re-canalisation of occluded vessels. The use of clot-busting fibrinolytic drugs is being replaced by the use of percutaneous coronary intervention (PCI) with balloon angioplasty.

Question 16

When can fibrinolytic drugs be given and why ?

Answer 16

Fibrinolytic drugs can reduce mortality when given within 12h of acute ST elevation MI
Enzymatic activation of plasminogen
Superceded by PCI + stent + drug coating

We can’t deal with the whole vascular cascade, but endogenous clots are degraded by the action of a tissue plasminogen activator (tPA) activating plasminogen to plasmin which proteolytically cleaves the fibrin threads to break up the clot.
Fibrinolytic drugs stimulate the activation of plasminogen into plasmin, resulting in re-canalising an occluded coronary vessel.
Fibrinolytic drugs reduce mortality when given within 12h of an MI (the earlier the better).
Agents include streptokinase and recombinant versions of the endogenous tPA, tissue plasmogen activator.

Question 17

What type of drug is streptokinase ?

How is it given ?

Answer 17

Fibrinolytic

Streptokinase is a protein originally derived from B-haemolytic streptococci which binds to plasminogen inducing plasmin cleavage.

Given by IV by a loading dose to produce immediate effect has a Synergistic effect with asprin

Works only one time. Within 3-4 hours of MI (derived from antibiotics – act as an antigen and leaves antibodies in the body)
Influence in body – bleeding, bruises

Problem - development of antibodies

Question 18

What type of drug is Altesplase (rtPA)

Explain how it works

How is it given

Advanataged/ Disadvantages

Answer 18

• Used to treat clots

-Loading dose followed by IV infusion

-Advantage
Activates ONLY fibrin bound plasminogen
Not antigenic

-Disadvantage
Short half-life (4-8min)
Nausea, mild hypotension, risk of intracranial haemorrhage

To try and avoid the systemic activation of plasmin, a recombinant tPA (alteplase) is used which only binds to plasminogen bound to fibrin, producing a much more selective effect on the coronary artery avoiding the systemic bruising seen chronically with streptokinase. Alteplase however has a short half-life and two alternative tPA-type proteins, reteplase and tenecteplase both have a longer duration of action

Question 19

What type of drug is Tenecteplase

Explain how it works

How is it given

Advantages/ Disadvantages

Answer 19

Use in clots

Tenecteplase
Modification of 3 amino acids
Advantages
Longer half-life, higher affinity
Greater resistance to endogenous metabolism

Tenecteplase is recombinant tPA but 3 amino acid modifications make it much less susceptible to endogenous metabolism. Reteplase, in contrast, has a shorter amino acid chain, producing better clot penetration and is given as a double IV bolus dose rather than an IV infusion

Question 20

Whats PCI

Answer 20

Percutaneous coronary intervention

Question 21

When should a stent be used during angiplast ?

Answer 21

A stent should normally be used during balloon angioplasty in a person who has angina or has had a heart attack.

A drug-eluting stent should be used if the person has angina, and the inside diameter of the artery is less than 3 mm across, or the narrowed area is more than 15 mm long.

There are several different drug-eluting stents, which contain different drugs. NICE recommends stents that contain either a drug called sirolimus, or one called paclitaxel, because most of the research has been on these.

Question 22

Explain why the drug-eluting stent Sirolimus (rapamycin) is often used

Answer 22

Sirolimus is coated onto stents with a polymer to retain it on the stent framework. Sirolimus inhibits mTOR to reduce the proliferative effects of cytokines such as IL-2, inhibiting the synthesis of cell cycle proteins preventing cell proliferation.

Question 23

What is meant by secondary prevention of MI ?

Answer 23

The third area to consider would be maintenance therapy to prevention the occurrence of further heart attacks.

Question 23

What medications are included in the secondary prevention of an MI according to NICE guidance?

Answer 23

Dual antiplatelet therapy (aspirin plus a second antiplatelet agent)
Beta-blocker
ACE (angiotensin-converting enzyme) inhibitor
Statin

Important : Calcium channel blockers/nicorandil are not recommended for secondary prevention

Question 24

What is the COX inhibator that reduced platlet aggregation ?

Answer 24

Aspirin is the only COX inhibitor which reduces platelet aggregation and is used following an MI (other COX inhibitors may increase the risk of CVS).

Question 25

What are the doses for asprin for a MI ?

Answer 25

For immediate effect an oral 300mg loading dose is given followed by 75mg per day. Treatment is recommended to be maintained indefinitely. Aspirin isn’t recommended for primary prevention in the absence of symptoms.

Question 25

What are the reccomended doses dor asprin with a stroke ?

Answer 25

Stroke

300mg for 2 weeks then 75mg/day
NICE - Antiplatelet therapy with aspirin no longer recommended in atrial fibrillation to reduce blood clots and prevent stroke – use anticoagulants

Question 26

What should you offer to people following an MI who has asprin sensitivity ?

Answer 26

For patients with aspirin hypersensitivity - use clopidogrel monotherapy

Question 27

Explain how clopidogrel works

Answer 27

Introduced 1998 (Thienopyridine class)
Prodrug activated by CYP2C19 in the liver
Irreversible purine receptor antagonist
Binds to P2Y12 receptor for ADP (disulphide bridge)
Synergistic with aspirin – different mechanisms
Onset of action 2h, loading dose required
Loading dose required for early effect 300mg, maintain on 75mg/day
Wear off- takes 7-10 days (life span of platelet)
Platelet infusion maybe required in an emergency to stop bleeding

Question 28

When clopidogrel be used ?

What are its adverse effects ?

Answer 28

Therapeutic Use

1- Secondary prevention of MI – monotherapy if history of gastric ulceration. Dual therapy with aspirin for 12 months
2- Acute coronary syndrome – limits arterial thrombosis
3- Drug eluting coronary stents – treatment started 14 days prior to surgery

Adverse Effects
1- Bleeding – effect potentiated by aspirin
1- Dyspepsia/diarrhoea
3- Consider stopping 7 days prior to elective surgery
4- Monotherapy – lower incidence of gastrointestinal haemorrhage than aspirin
5- Prodrug (CYP2C19) interactions – efficacy reduced by CYP inhibitors
(ie proton pump inhibitors, avoid omeprazole)

Question 29

Explain the use of Ticagrelor

How it works

Advantages/Disadvantages

Answer 29

Ticagreclor is a second generation P2Y12 receptor antagonist, structurally related to the nucleoside, adenosine. It has two major differences from clopidogrel. Firstly it is not a prodrug and secondly, by binding to an allosteric site on the receptor it is a reversible rather than irreversible antagonist.

Advantage
Not a prodrug - no hepatic activation
Faster onset, shorter duration than clopidrogel
Easier to stop prior to elective surgery

Disadvantage
Twice daily oral administration
Dyspnea (14%) and bleeding

Question 30

Explain the mechanism of statins

Answer 30

Statin therapy has been shown to reduce mortality and morbidity following MI however, the mechanism involved however may not be due to the reduction in plasma cholesterol. Many intracellular protein are transported within the cell using lipid tags also synthesised, like cholesterol via the production of mevalonate, the synthesis of which is inhibited by statins. This may explain how statins can produce cardiovascular benefit in patients with both high and normal levels of cholesterol.

Question 31

When should ACE inhibitors be given in regards to an MI?

Answer 31

Offer people who present acutely with an MI an ACE inhibitor as soon as they are haemodynamically stable. Continue the ACE inhibitor indefinitely
Dose Titration - titrate the ACE inhibitor dose upwards at short intervals every 12–24h until the maximum tolerated or target dose is reached (within 4–6weeks of discharge)
Alternative therapy : Offer people after an MI who are intolerant to ACE inhibitors an ARB.
Do not offer combined treatment, ACE inhibitor plus ARB after an MI.
Monitoring : Renal function, serum electrolytes and blood pressure, more frequently if risk of deterioration in renal function

Question 32

When can an aldosterone antagonist be given after an MI?

What are examples?

Answer 32

Aldosterone Antagonists
(spironolactone or eplerenone)
may be used if there is evidence of left ventricular dysfunction
after an MI, ideally after beginning treatment with an ACE inhibitor

Question 33

When should Beta blockers be given after an ACS event ?

How long for ?

Answer 33

Offer people a beta-blocker as soon as possible after an MI, when the person is haemodynamically stable (no acute heart failure or heart block)

Titrate beta-blockers up to the maximum tolerated or target dose
Continue a beta-blocker for at least 12months after an MI in people without left ventricular systolic dysfunction or heart failure.
Continue a beta-blocker indefinitely in people with left ventricular systolic dysfunction.
Offer all people who have had an MI more than 12 months ago, who have left ventricular systolic dysfunction, a beta-blocker whether or not they have symptoms.

Do not offer people without left ventricular systolic dysfunction or heart failure, who have had an MI more than 12 months ago, treatment with a beta-blocker unless there is an additional clinical indication for a beta-blocker.