Pharmacological treatment of angina

Question 1

What is angina pectoris?

Answer 1

Chest pain

Question 2

Where does the chest pain experienced during angina originate and what is it caused by?

Answer 2

Originates in the heart muscle and is caused by a part of the heart muscle not getting enough oxygen causing it to respire anaerobically. This then causes the build up of lactic acid which is what actually causes the pain.

Question 3

How does the heart sense the heart muscle isn’t receiving enough oxygen?

Answer 3

Low pH (high H+ conc.) stimulates Nociceptive chemoreceptors on the heart which send signals through the CVS to the brain.

Question 4

What are some of the symptoms of angina?

Answer 4

Feeling of severe constriction/ cramping in chest
Referred pain
Shortness of breath
Sweating

Question 5

What are the 3 old classifications of angina?

Answer 5

Typical angina
Atypical angina
Non-anginal

Question 6

What is the more modern classification of angina?

Answer 6

Stable Angina
Unstable Angina
Prinzmetal Angina

Question 7

What are some of the characteristics of stable angina?

Answer 7

Follows a set/stable pattern - pain episodes have a set duration and intensity
Pain has short duration - usually 2-5 mins
Relieved by rest or taking medication
Occurs during exertion as a result of increased Cardiac 02 demand

Question 8

Describe the process that leads to the development of stable angina

Answer 8

Plaque formation leads to narrowing of the coronary artery lumen (atherosclorosis) and stiffening of the region where the plaque is (stenosis) beyond a critical value (critical stenosis).
This leads to blood flow to the myocardial tissue perfused by the artery in that region becoming limited and not being able to deliver enough oxygen to meet the metabolic needs of the myocardium particularly during times of increased need.
This lack of oxygen means the myocardial tissue has to respire anaerobically leading to a build up of lactic acid.
This lactic acid is what results in the angina pain.

Question 9

What are some characteristics of unstable angina?

Answer 9

Unpredictable (May not have a trigger)
Pain more severe and can lasts longer than stable angina
Happens at rest with little exertion
Not usually relieved by medications

Question 10

Describe the process that leads to the development of unstable angina?

Answer 10

Plaque rupture leads to thrombosis occuring with the resulting blood clot leading to partial occlusion of the artery.
This partial occlusion leads to a critical reduction in blood flow meaning that blood flow to the myocardial tissue perfused by the artery in insufficient even at rest.
Again the lack of oxygen results in myocardial tissue respiring anaerobically and producing lactic acid.
The only real difference is this process occurs even at rest with unstable angina.

Question 11

Why is it that the vessel is unable to stop a blood clot from forming during the development of unstable angina?

Answer 11

Because endothelium is unable to produce nitric oxide and prostacyclin that inhibit platelet aggregation and clot formation

Question 12

What are some characteristics of Prinzmetal Angina (variant angina)?

Answer 12

Usually occurs during sleep or at rest
Rare - about 1 in 100 Angina cases are Prinzmetal angina
Associated symptoms include heart burn, sweating, dizziness
Usually occurs in younger patients
Pain may spread from chest to other body parts e.g. head or shoulder (referred pain)

Question 13

Describe the process that leads to the development of unstable angina?

Answer 13

A vasospasm occurs leading to temporary vasoconstriction of a part of the vessel.
This leads to a reduction in blood flow meaning oxygen supply to the myocardial tissue perfused by this artery meaning is inadequate.

Question 14

All the processes the produce angina lead to a decrease in the oxygen supply/demand ratio of that part of myocardial tissue but how do these processes cause this decrease?

Answer 14

Cause an imbalance between oxygen supply (decreased coronary blood flow) and oxygen demand (increased myocardial oxygen consumption), which leads to the decrease in the oxygen supply/demand ratio.

Question 15

What are the 2 types of ischaemia that result in angina pain?

Answer 15

Supply Ischaemia - When oxygen supply decreases thereby decreasing the oxygen supply/demand ratio.

Demand Ischaemia - When oxygen demand increases also decreasing the oxygen supply/demand ratio.

Question 16

What types of angina occur due to supply ischaemia?

Answer 16

Prinzmetal angina

Unstable angina

Question 17

What types of angina occur due to demand ischaemia?

Answer 17

Stable angina

Question 18

What are the 3 main precipitating factors for angina?

Answer 18

Increased sympathetic activity - Increases heart rate meaning less diastolic time. This means less time for coronary arteries to be perfused as blood only flows through them during diastole.

Increased contractility - heart does’t have enough oxygen it needs to contract

Increased vasoconstriction - less blood can flow through restricted vessel meaning heart gets less oxygen

Question 19

What are the main treatment strategies for angina?

Answer 19

To improve perfusion - Increase oxygen delivery by increasing coronary blood flow
To reduce metabolic demand - Reduce oxygen demand by reducing cardiac work
Prevention - reduce risk of subsequent episodes

Question 20

Give examples of medications that can be used to improve perfusion

Answer 20

Coronary vasodilators

Question 21

Give examples of medications that can be used to reduce metabolic demand

Answer 21

Vasodilators (reduces preload and afterload)
Cardiac depressants (reduces heart rate and contractility)

Question 22

Give examples of medications that can be used to prevent subsequent episodes of angina

Answer 22

Anti-coagulants

Lipid lowering drugs

Question 23

What effects do Organic nitrates produce to combat the effects of angina?

Answer 23

Act on vascular smooth muscle of peripheral veins to promote Venodilation.
This reduces the intraventricular pressure within the veins meaning that venous return is reduced.
This results in a decrease in cardiac preload.

They also cause modest vasodilation of arterioles which causes a decrease in TPR.
Decrease in TPR reduces afterload.

Reduction in preload and afterload decreases the workload of the heart and lowers myocardial oxygen demand.

Question 24

Why don’t the organic nitrates really work on the coronary vessels themselves?

Answer 24

Atherosclerosis limits coronary dilation due to stenosis of the coronary vessels meaning they are less compliant

Question 25

What are some adverse effects of using organic nitrates to treat angina?

Answer 25

Throbbing headaches
Postural hypotension
Reflex tachycardia

Question 26

Why do organic nitrates lead to throbbing headaches?

Answer 26

Arterial dilation of arteries leading to the brain leads to increased blood flow. This causes the vessel to compress pain receptors within the brain leading to the throbbing headache.

Question 27

Describe the mechanism of action of organic nitrates

Answer 27

Organic nitrates mimic nitric oxide produced by endothelium.
L-arginine is converted to Nitric oxide via nitric oxide synthase
Nitric oxide then diffuses from the endothelium into the smooth muscle
In smooth muscle nitric oxide binds and activates guanylyl cyclase.
Guanylyl cyclase catalyses the reaction that causes GTP to be converted into cGMP
cGMP then activates protein kinase G which produces a number of different effects which all cause smooth muscle relaxation.

Question 28

Why is nitric oxide able to freely diffuse from the endothelium to the smooth muscle cells?

Answer 28

Nitric oxide is lipophilic so is easily able to diffuse the phospholipid bilayer of the endothelial membrane and the smooth muscle membrane.

Question 29

What are the effects that protein kinase G produces that leads to smooth muscle relaxation?

Answer 29

Activates myosin light chain phosphatase which de-phosphorylates myosin light chain kinase.
No myosin light chain kinase means myosin isn’t phosphorylated and so can’t bind ATP and cause smooth muscle contraction.

Increases uptake of calcium by SR of smooth muscle cells - less calcium in cytoplasm means calmodulin isn’t activated meaning myosin light chain kinase is also not activated.

Activates potassium channels leading to hyperpolarisation and closing the voltage gated calcium channels.
This means no calcium influx from SR to cytoplasm

Question 30

What effects do β blockers produce to combat angia?

Answer 30

Inhibits pacemaker current produced by the sinoatrial node.
This causes a decrease in heart rate - this increases the time for diastole which increases the amount of time available for the coronary arteries to be perfused thus increasing myocardial oxygen supply.

Also reduces the force of cardiac contractions which improves exercise tolerance.

Question 31

What are some adverse effects of using β blockers?

Answer 31

Bronchospasm
Fatigue
Postural hypotension

Question 32

Why might someone suffering angina not be prescribed a β blocker?

Answer 32

Because some β blockers act on β2 receptors on the lungs rather than the β1 receptors on the heart.
Blocking of β2 receptors causes constriction of lungs and bronchospasm.

Question 33

Describe the mechanism that causes β blockers to reduce heart rate

Answer 33

β blockers binds to β1 receptor preventing noradenaline from binding.
This prevents receptor being activated meaning αGs subunit doesn’t bind GTP instead of GDP.
This means Adenylate cyclase isn’t activated meaning ATP isn’t converted to cAMP.
No cAMP means influx of K+ and Na+ through funny channel doesn’t occur.
This means the funny/pacemaker current isn’t produced.

Question 34

Describe the mechanism that causes β blockers to reduce force of contraction

Answer 34

Same mechanism for how β blockers to reduce heart rate except no cAMP means protein kinase A isn’t activated.
This means voltage gated calcium channels aren’t phosphorylated so no calcium influx.
Without calcium influx ryanodine receptors aren’t activated so they don’t release calcium into the cytopasm.
This means calcium-induced calcium release doesn’t occur so the force of contraction decreases.

Question 35

What effects do calcium channel blockers produce to combat angina?

Answer 35

Reduces calcium entry into the cardiac myocytes and the vascular smooth muscle cells which reduces contractility

Causes direct coronary vasodilation which increases coronary blood flow.

Reduces TPR/blood pressure/afterload which means heart has to work less hard to eject blood

Reduces force of contraction which means myocardial tissue doesn’t need as much oxygen.

Question 36

What are some adverse effects of using calcium channel blockers?

Answer 36

Lower limb oedema - due to increase in capillary pressure in lower limbs
Flushing and headaches - excess vasodilation
Reflex tachycardia - vasodilatation triggers baroreflex

Question 37

Describe the mechanism that causes calcium channel blockers to reduce the force of contraction

Answer 37

Exact same mechanism that also causes β blockers to reduce force of contraction

Question 38

Describe the mechanism that causes calcium channel blockers to cause vasodilation of the vascular smooth muscle

Answer 38

Noradrenaline binds to α1 adrenoreceptor causing Gαq subunit to bind GTP.
This causes Gαq subunit to dissociate from rest of receptor and activate phopholipase C.
Phospholipase C cleaves PIP2 into IP3 and DAG.
However, IP3 isn’t able to bind to it’s receptor on the SR because it’s blocked by the calcium channel blocker. This means there’s no calcium influx from the SR.

Also, calcium channel blockers bind to the voltage gated calcium channels which prevents calcium influx into the vascular smooth muscle.
No calcium influx means the mechanism for vascular smooth muscle contraction ca not occur meaning the muscle remains relaxed.

Question 39

Give some examples of other anti anginal drugs

Answer 39

Nicorandil
Ivabradine
Ranolazine

Question 40

How does Nicorandil combat effects of angina?

Answer 40

Nicorandil opens K+channels, which leads to hyperpolarisation of the cell and closes voltage-gated L-type Ca2+channels causing coronary vasodilation.

Question 41

How does Ivabradine combat effects of angina?

Answer 41

Ivabradine inhibits the If current (pacemaker current) produced by the sinoatrial node.
This causes a decrease in heart rate allowing for more time for coronary diffusion as lower heart rate means more diastole.

Question 42

Give examples of some prophylactic drugs, drugs used to prevent a disease from occuring, used to treat angina

Answer 42

Aspirin
Clopidogrel
Statins

Question 43

How does Aspirin help to prevent angina?

Answer 43

Inhibits COX enzyme from synthesising thromboxane A2 precursors.
No thromboxane A2 means no platelet aggregation meaning thrombus can’t form in coronary artery. This means blood flow to myocardial tissue not reduced by partial occulsion.

Question 44

How does Clopidogrel help to prevent angina?

Answer 44

Clopidogrel inhibits ADP receptor on platelets which again reduces aggregation.

Question 45

How do Statins help to prevent angina?

Answer 45

Statins act as HMG reductase inhibitors thus inhibiting synthesis of LDL.
Lower LDL levels means atherosclerosis reduced so no plaque to rupture and thrombosis doesn’t then occur.