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Stage 2: Supporting Life > Pharmacology of Angina > Flashcards

Pharmacology of Angina Flashcards

1
Q

What are the aims of angina drug treatment?

A

1) Limit the number, severity and sequelae of angina attacks, thereby improve QoL
2) Protect against future, potentially more lethal ischaemic syndromes e.g. MI and lower the risk of atherosclerosis progression e.g. to unstable

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2
Q

What is the main mechanism for the pharmacological treatment of angina of effort?

A

To decrease cardiac oxygen demand bc can’t dilate stenosis so difficult to get more blood to affected part of heart (except in some types using a vasodilator)

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3
Q

What is a secondary mechanism for pharmacological treatment of angina?

A

To increase the oxygen supply to the ischaemic zone by decreasing the HR and increasing the blood flow in coronary arteries

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4
Q

How do we protect against future, potentially more lethal ischaemic syndromes?

A

1) Decrease risk factors (smoking/BP/cholesterol)
2) Aspirin
3) Beta blockers
4) ACE inhibitors
5) Statins

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5
Q

What drug is used for immediate relief/short term prevention?

A

Sublingual glyceryl trinitrate (GTN) - short acting nitrate

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6
Q

What is the NICE treatment pathway for ongoing prophylaxis?

A

1) Beta blocker OR calcium channel blocker (CCB)
2) Beta blocker + vascular selective CCB
3) Beta blocker + vascular selective CCB + long acting nitrate/ivabradine/nicorandil/ranolazine
(which one depends on type of angina and co-morbidities)

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7
Q

What is cardiac oxygen demand a function of?

A

Wall tension, contractility and HR

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8
Q

What is calcium transport vital for?

A

Regulation of vascular smooth muscle tone

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9
Q

How do organic nitrates work?

A

They dilate and relax veins and venules, lowering CVP, cardiac wall tension and cardiac oxygen demand (F-S mechanism)

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10
Q

What is the cellular mechanism of organic nitrates?

A

NO donor e.g. in GTN, one of the nitrate groups is enzymatically cleaved off the molecule to form NO

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11
Q

What is the haemodynamic mechanism of organic nitrates?

A

Low CVP/preload, increased coronary blood flow

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12
Q

What is the main example of an organic nitrate?

A

GTN

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13
Q

How is GTN taken and why?

A

Sublingually → it has a v rapid effect as it is absorbed by vasculature in the tongue within a minute (if taken orally it is broken down)

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14
Q

What is GTN used for?

A

For cutting short an angina attack or preventing an anticipated attack

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15
Q

What is an example of a longer acting organic nitrate?

A

Isosorbide dinitrate

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16
Q

How are longer acting organic nitrates taken?

A
  • On an ongoing basis e.g. pills, ointments, patches
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17
Q

What is the problem with longer acting organic nitrates and how can this be avoided?

A
  • Their effectiveness is limited by the development of tolerance after roughly 12 hours
  • This can be avoided by a daily 8 hour drug-free period (typically at night when don’t really get angina anyway as usually brought on by exercise)
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18
Q

What are the minor haemodynamic effects of nitrates?

A
  • Dilate larger coronary arteries, increasing blood flow through coronary collaterals
  • Lower TPR and afterload, thus lowering oxygen demand
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19
Q

What are side effects of organic nitrates and what are they due to?

A

Due to vasodilation → headache, facial flushing, lower BP, reflex increase of HR

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20
Q

What does the heart do to bypass stenosis and slow down the course of angina and why might vasodilators aid this?

A

Grow new blood vessels = coronary collaterals (inter-arterial anastomoses) → vasodilators can increase blood flow in these collaterals

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21
Q

Explain why GTN is not a good vasodilator in arteries by how it is metabolised

A

1) GTN is metabolised by mitochondrial enzyme Mt ALDH-2
2) This also generates a superoxide which increases release of endothelin-1 by the endothelium
3) Endothelin-1 is a vasoconstrictor and also increases the ability of the arteries to respond to other vasoconstrictors nearby e.g. NA
4) Superoxide also inhibits guanylate cyclase (involved in how NO leads to vasodilation)
5) So any vasodilating effect of GTN is counteracted

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22
Q

How does tolerance to GTN form?

A

1) Superoxide combines with NO to form peroxynitrate which inhibits Mt ALDH-2
2) So the build up of peroxynitrate over a long time causes tolerance to GTN

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23
Q

Why is superoxide generally not good for the CV system?

A

Oxidative stress

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24
Q

How do beta blockers work?

A
  • They inhibit sympathetic stimulation of the heart so reduce cardiac contractility
  • They also increase coronary blood flow and reduce oxygen demand
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25
Q

What is the aim when dosing beta blockers?

A
  • Aim for a resting HR of 55-60 bpm and an increase of <75% of the rate causing ischaemia during exercise
  • So aiming to give a dose that will reduce the increase in rate by at least 75%
26
Q

Why are beta blockers contraindicated in vasospastic angina?

A

Tend to make vasospasm worse

27
Q

Why do beta blockers increase life expectancy post-MI?

A

They reduce the risk of developing chronic heart failure as you spend more time in diastole (?)

28
Q

What is an example of a beta blocker?

A

Bisoprolol

29
Q

To what beta receptor do you want beta blockers to be selective to and why?

A

Beta-1 selective e.g. bisoprolol so it has fewer effects on the lungs bc doesn’t block beta-2 receptors v much but does to same extent

30
Q

What other effect do beta blockers have on the kidneys?

A

They reduce renin release bc stimulation of renin is via beta-1 receptors in the kidney (sympathetic stimulation)

31
Q

What are 3 examples of calcium channel blockers (CCBs)

A

1) DHPs (dihydropyridine)
2) Diltiazem
3) Verapamil

32
Q

How do CCBs work?

A
  • They block L-type calcium channels which initiate constriction → arterial vasodilation
  • They reduce afterload, reducing work of the heart
  • They dilate coronary arteries
33
Q

In which types of angina is the coronary vasodilation of CCBs most useful?

A

1) Angina associated with coronary vasoconstriction e.g. Prinzmetal’s
2) Mixed angina

34
Q

How do DHPs mainly act?

A

By vasodilation, reducing afterload and therefore cardiac work

35
Q

How does verapamil mainly act?

A

By direct negative inotropic effect, with some reduction in afterload as it is also a vasodilator

36
Q

Which drug has the middle action of DHP and verapamil?

A

Diltiazem

37
Q

Give the order of effectiveness of CCBs at vasodilation

A

DHPs > diltiazem > verapamil

38
Q

Give the order of effectiveness of CCBs at negative inotropy

A

Verapamil > diltiazem > DHPs

39
Q

What are some other potentially beneficial actions of CCBs?

A

1) Reduced reperfusion injury (cardiac damage occurring after ischaemia) - increase in oxidative stress
2) Endothelial ‘protection’
3) Reduced atheroma progression
4) Reduction of left ventricular hypertrophy

40
Q

What is an example of a DHP?

A

Amlodipine

41
Q

What is an example of a potassium ATP channel activator?

A

Nicorandil

42
Q

What is the dual cellular action of nicorandil?

A

1) Opens ATP-sensitive K+ channels in vascular smooth muscle cells → vasodilating influence, as K channels open, membrane potential becomes more negative so less voltage-gated calcium channels are open (like CCBs)
2) Stimulates guanylate cyclase (activated by NO)

43
Q

What effects does nicorandil have?

A

1) Relaxation of vascular smooth muscle through muscle mechanisms incl. hyperpolarisation, removal of calcium from the cytoplasm, calcium desensitisation
2) As a result, this leads to venous and arterial vasodilation → decreased preload and afterload → decreased cardiac work and oxygen demand

44
Q

Why are KATP channel blockers not used v wildly?

A

Don’t seem to be any better than CCBs and were released after

45
Q

How does ranolazine work?

A

1) Acts by inhibiting the late Na current in myocytes caused by ischaemia which triggers the action potential by opening calcium channels, causing contraction in the heart
2) Therefore it reduces cardiac wall tension → reduces cardiac work

46
Q

What happens in ischaemia and reactive oxygen species due to the late sodium current?

A

1) Calcium concentration increases due to late sodium current (lack of proper sodium calcium exchange)
2) Therefore the heart is stiff in diastole (not relaxed), so using energy when it shouldn’t be and can’t receive all the blood that it is supposed to

47
Q

What type of angina is ranolazine the most effective drug for?

A

Microvasculature angina

48
Q

Why is the funny current funny?

A
  • Because it is activated by hyperpolarisation and is a mixed sodium and potassium current → causes inwards current
  • This + inactivation of the potassium current causes depolarisation
49
Q

How does ivabradine work?

A

1) Blocks the funny current (not completely) which is involved in SAN pacemaking by entering the open channel from inside the cell and then it gets trapped when the channel shuts
2) This leads to a reduced HR

50
Q

Why is ivabradine an open channel blocker and what does this mean for the effectiveness of the drug?

A

1) Because the binding of ivabradine in the channel builds up when the channel is opening more frequently
2) This ‘use-dependency’ means that ivabradine tends to block more when the HR goes up (good)
3) Therefore, the faster the heart is beating and the channel is opening, the better ivabradine works as the more chances it has to act on the open channels

51
Q

How does the slowing action of ivabradine treat angina?

A

Slows down heart → increasing length of diastole → allows more time to perfuse myocardium

52
Q

What are the haemodynamic effects of ivabradine?

A

1) Lower HR allows more time for blood to perfuse the myocardium which reduces ischaemia
2) Lower HR → lower afterload → lower oxygen demand

53
Q

What are statins used for?

A

They are used long term in people with elevated LDL cholesterol levels to reduce the risk of developing coronary heart disease

54
Q

How do statins work?

A

1) They block the rate-limiting enzyme which produces cholesterol
2) Less LDL is taken up from the plasma by the liver

55
Q

What is revascularisation?

A

Opening up the blocked coronary artery e.g. percutaneous coronary intervention (PCI) using an inflated balloon

56
Q

What is the problem and solution with PCI?

A 
Problem = restenosis in 30% over 6 months so symptoms return 
Solution = stents
57
Q

Describe coronary artery bypass grafting

A
  • Uses pieces(s) of saphenous vein or diverted internal mammary artery
  • Used in preference to PCI in patients with more serious/advanced coronary artery disease
  • Much more invasive than PCI → chest must be opening, patient is usually on cardiopulmonary bypass
  • Unlike PCI it improves survival
  • e.g. triple bypass (look at diagram)
58
Q

What is stable angina?

A

Chest pain or discomfort which occurs when the presence of atherosclerotic plaque in one or more coronary arteries prevent the heart from receiving enough blood when its metabolic needs increase

59
Q

What is the main aim of drug treatment?

A

To reduce the number and seriousness of episodes of angina

60
Q

How is the main aim of drug treatment for angina achieved?

A

1) Mist if the drugs used act by reducing one or more of the 4 factors which determine CO and therefore work → preload, afterload, HR and cardiac contractility
2) Vasodilating drugs may also increase coronary perfusion, but this is seen as a secondary mechanism for treating angina

61
Q

How else can angina be treated?

A
  • Angina can also be treated using percutaneous intervention and stunting or in more severe disease, coronary bypass
  • The former approach is much more common, but is generally not more effective than drug treatment in the long term

Stage 2: Supporting Life (30 decks)

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