Module 4 Section 2 (Angina)

Question 1

What is coronary artery disease (CAD)?

Answer 1

It’s characterized by narrowing of the coronary arteries and reduced blood flow to the heart (i.e. ischemia).

Question 2

What is the most common condition resulting from ischemia?

Answer 2

The most common condition resulting from ischemia is angina pectoris, while advanced coronary artery disease and ischemia can lead to heart failure.

Question 3

What is angina pectoris? What are the symptoms associated with it?

Answer 3

Angina pectoris is usually due to atherosclerosis of the coronary arteries, or the buildup of lipid deposits within the arteries that causes the vessel to narrow, hindering blood flow.

Symptoms include a sudden, severe pressing pain in the chest.
- The pain arises from diminished blood flow and therefore diminished oxygen supply to an area of the heart muscle.

Question 4

How is pain reduced for angina pectoris?

Answer 4

To reduce the pain, the oxygen requirement of the heart must be decreased and/or the oxygen supply to oxygen deficient areas of the heart muscle must be increased.

Question 5

Angina pectoris is precipitated by the four “E’s.” What are they?

Answer 5

• Eating
• Exercise
• Excitement
• Exposure to cold

All of these activities increase the oxygen demand on the heart muscle.

Question 6

What occurs when the oxygen requirements of the heart increase? How is it treated?

Answer 6

The oxygen requirements of the heart increase when there is an increase in heart rate, force of contraction, arterial pressure, and volume of blood to be pumped.

These conditions are all precipitated during exercise.
- The aim of therapy is to either reduce the work load on the heart, or increase the delivery of oxygen to the affected area of heart muscle.

Question 7

What are the 2 types of angina?

Answer 7

1) Typical (exertional) angina: characterized by chest pain with exertion. Typical angina is often due to coronary obstruction (e.g. atherosclerosis).

2) Variant (Prinzmetal’s) angina: chest pain is experienced during rest.
- Variant angina is thought to be due to coronary vasospasm without obstruction (i.e. a temporary, sudden narrowing of one of the coronary arteries).

Question 8

What are the 3 major classes of antianginal drugs?

Answer 8

1) Organicnitrates: these include the short-acting nitroglycerin and the long-acting isosorbide dinitrate.

2) β-adrenergicantagonists: β-blockers antagonize β adrenergic receptors.
- Propranolol is the prototypical drug.

3) Calcium channel blockers: calcium channel blockers are vasodilators.
- Nifedipine is the prototypical drug.

Question 9

The mechanism of action of organic nitrates (nitroglycerin) has been studied for many years and a great deal of argument has been provoked by proponents of different theories. The general consensus now is that organic nitrates relax the smooth muscle of blood vessels and exert their therapeutic effect by two mechanisms? What are the mechanisms?

Answer 9

1) Relaxation of large capacitance vessels (veins), leading to vasodilation.
- This effect results in a decrease in venous blood returning to the heart, leading to a decrease in cardiac output and blood pressure.
- As a result, there is a decrease in the workload and energy expenditure of the heart, and thus a decrease in the oxygen requirements of the heart.

2) Dilation of large coronary arteries.
- This causes blood to be diverted to areas of the heart with low blood flow, thereby enhancing oxygen supply to areas of the heart deficient in oxygen.

Question 10

How does nitric oxide (NO) work in the body?

Answer 10

Normally in the body, the enzyme nitric oxide synthase (NOS) catalyses the conversion of arginine into citrulline and nitric oxide (NO).

NO passes from the endothelial cells into smooth muscle cells where it activates the enzyme guanylyl cyclase, and leads through a series of steps to relax the blood vessel.
- As such, NO is an endogenous vasodilator.

Question 11

What occurs to nitroglycerin (GTN) in the body?

Answer 11

Within the body, nitroglycerin (GTN) is converted into the endogenous chemical nitric oxide (NO).

Nitroglycerin initiates this mechanism by entering blood vessels and moving into smooth muscle cells, where it is converted into nitric oxide. Nitroglycerin therefore owes its effectiveness to its conversion into a normal body constituent, namely nitric oxide.

Question 12

What are some adverse effects off organic nitrates?

Answer 12

Adverse effects of organic nitrates include a throbbing headache, flushing, hypotension, tachycardia, and dizziness.

Question 13

What is sublingual nitroglycerin (glyceryl trinitrate, GTN) and how is it administered?

Answer 13

It’s used to treat angina pectoris.

The effects of GTN are much more intense when given by the sublingual route, as opposed to oral administration. This is because GTN is rapidly broken down in the GI tract, decreasing the amount of GTN that can be absorbed.

• When placed under the tongue, GTN dissolves in the fluids and is absorbed into the blood vessels very rapidly.
• Thus, the peak level of GTN is achieved in plasma within five minutes. The plasma level of GTN drops after five minutes, so it is not surprising that the action of the drug is terminated within 20-30 minutes.

Question 14

Is the sublingual use of GTN appropriate?

Answer 14

Not really.

Sublingual use of GTN is appropriate to abort or control acute episodes of angina, but is of limited value in preventing episodes of angina, as it would need to be administered every 30 minutes.

Question 15

What is the alternative to the sublingual use of GTN? How does it work?

Answer 15

The drug industry designed a GTN patch, which conveniently administers GTN transdermally.

The GTN patch contains a reservoir of GTN that has been impregnated into a polymer.

• The polymer is bonded to a membrane to control the rate of GTN movement across the skin, and the membrane is attached to an adhesive bandage which is placed on the skin.
• This provides a convenient method to obtain a long lasting effect from GTN (approximately 24 hours).

Question 16

What is the downside to transdermal GTN?

Answer 16

Tolerance to GTN develops over a 24-hour period

Question 17

Compare the tolerance for sublingual and transfermal GTN.

Answer 17

When GTN is taken sublingually several times a day, reproducible pharmacological effects are observed (there is no development of tolerance).

However, tolerance does develop to transdermal GTN after several hours. For this reason, a transdermal GTN patch is applied to the skin for 12 hours and then removed for a 12-hour period (overnight) to allow the patient time to recover sensitivity to GTN.

Question 18

What are the therapeutic uses of GTN?

Answer 18

1) For termination of an individual attack: GTN, given sublingually, is the most frequently used drug.
- GTN would be ineffective if swallowed, as it would be inactivated in its passage through the intestine and liver before reaching the general circulation.
- GTN, taken sublingually, acts in approximately two minutes to relieve pain.
- The termination of pain is usually sudden and complete.

2) Prevention of individual attack: GTN, taken sublingually, increases the exertion tolerated by a patient before the amount of oxygen in the heart muscle drops to the level that pain is experienced.
- Therefore, a patient can take sublingual GTN prior to undertaking additional exercise that would normally precipitate angina, and thereby prevent the angina from developing.
- The protective effect would last for approximately 30 minutes.

3) Chronic prophylaxis: if a patient has numerous anginal attacks a day, and has to consume many GTN tablets sublingually, the physician may prescribe a long-acting organic nitrate preparation with the aim of decreasing the number of anginal attacks.
- Such a preparation is isosorbide dinitrate, which when given orally two to three times daily, will cut down on the number of anginal attacks and the need to take GTN sublingually.
- Transdermal GTN is an alternative.

Question 19

In a few sentences, describe the mechanism of action of nitroglycerin and its clinical use.

Answer 19

Nitroglycerin is commonly administered sublingually and is rapidly absorbed by the blood vessels under the tongue.

Within the smooth muscle, GTN is converted into NO, which is an endogenous vasodilator.

NO activates the enzyme guanylyl cyclase and via a cascade of events, leads to dilation of the blood vessel.

GTN can be used to stop or prevent an angina attack, or it can be used prophylactic

Question 20

What are β- adrenergic blocking agents and what do they do? Give an example.

Answer 20

An alternative drug used for chronic prophylaxis of angina pectoris is a β-adrenergic blocking agent.

β-blockers decrease the activation of the sympathetic nervous system and therefore can be used for long term prophylaxis of typical angina, but are often avoided in variant angin

Ex: propranolol

Question 21

True or false: angina is precipitated by factors that increase sympathetic nervous system (SNS) activity (e.g. stress and exercise.

Answer 21

True

Increased SNS activity results in an increase in heart rate and an increase in myocardial contractility. This in turn leads to an increase in cardiac output, and an increase in myocardial oxygen requirement, resulting in the pain of angina.

Question 22

How do calcium channel blocking drugs work? What are some adverse effects?

Answer 22

Calcium channel blocking drugs decrease the amount of extracellular calcium reaching sites inside cells of vascular smooth muscle, leading to a relaxation of arterioles, a decrease in resistance of the arterioles, and a reduced workload on the heart.

Coronary arteries are particularly sensitive to the action of calcium channel blockers.
- Additionally, these drugs block the calcium channels in cardiac muscle, reducing the force of myocardial contraction, and in turn, reducing the workload and oxygen demand on the heart.

Common adverse effects of calcium channel blockers include hypotension (nifedipine), flushing, ankle swelling, and headach

Question 23

True or false: calcium channel blockers are chosen over β blockers for long term prophylaxis of variant angina.

Answer 23

True

Question 24

What is the most likely medication to be chosen for chronic prophylaxis of typical angina that is not adequately controlled with an organic nitrate?

Answer 24

β blockers are the recommended drug for chronic prophylaxis of typical angina.

Question 25

What is the most common cause of heart failure (HF)?

Answer 25

The most common cause of heart failure is coronary artery disease, however, other conditions, such as hypertension, also contribute to the development of heart failure. Edema is often, but not always present with heart failure. The term congestive heart failure is used when edema is present.

Question 26

What leads to heart failure? What are the symptoms?

Answer 26

Heart failure is a progressive disease that can involve one or both ventricles, and is characterized by a decline in cardiac performance that manifests as reduced cardiac output and decreased oxygen to the tissues. This results in symptoms such as shortness of breath, fatigue, tachycardia (increased heart rate), and an enlarged heart (cardiomegaly). - Fatigue is a direct consequence of the decline in cardiac performance that characterizes heart failure. - However, the other symptoms of heart failure are a result of the body trying to compensate for the failing heart through two main mechanisms: • increasing the sympathetic nervous system, thus increasing the heart rate and force of contraction • activating the RAS, increasing blood pressure.

Question 27

Discuss the development of heart failure.

Answer 27

Prolonged activation of β1 receptors in the heart due to increased sympathetic nervous system activation increases the amount of caspases in the cells, which initiate cardiac cell death. In addition, increased angiotensin II leads to remodeling (i.e. dilation and other slow structural changes) of both the heart and the vessels. Ultimately, these factors cause increased cardiac cell death, resulting in less cardiac cells to do the work of the heart and thereby increasing the stress on the heart. The heart compensates for this decrease in cardiac cells by increasing muscle mass to maintain cardiac output. While this is initially beneficial to the heart, in the long run it is detrimental to the heart and contributes to the worsening of heart failure.

Question 28

Cardiac performance is determined by four factors, and each of these factors are affected in heart failure. What are those factors?

Answer 28

1) Preload: the initial stretching of the heart cells prior to contraction. Preload is usually increased in heart failure because of increased blood volume. 2) Afterload: the resistance against which the heart must pump blood. As cardiac output falls, a compensatory increase in vascular resistance occurs (because of increased sympathetic nervous system outflow), leading to increased resistance and hence increased afterload. 3) Contractility: the heart muscle in patients with heart failure have reduced muscle contractility, as the muscle is damaged. 4) Heart Rate: heart rate is a major determinant of cardiac output. In heart failure, as the heart function decreases, compensatory mechanisms increase the heart rate to maintain cardiac output, leading to tachycardia, one of the first symptoms of heart failure.

Question 29

Why is the incidence of heart failure increasing?

Answer 29

The incidence of heart failure is increasing, partly due to the fact that treatment for other cardiovascular conditions, such as myocardial infarctions, has improved. As such, more patients are surviving long enough for heart failure to develop.

Question 30

What are the goals of heart failure treatment?

Answer 30

1) To reduce the symptoms and slow the progression of heart failure. 2) To manage acute episodes of decompensated failure (i.e. an episode where the patient’s condition worsens, resulting in the need for urgent therapy or hospitalization).

Question 31

How can heart failure be managed?

Answer 31

Heart failure can be managed with both non-pharmacological and pharmacological treatments. The two main non-pharmacological treatment options include behavioural modifications and surgery. - Behavioural modifications includes gradually increasing the amount of physical activity and instituting dietary control (e.g. salt restriction). In terms of surgery, depending on the severity of the disease, patients may be candidates for coronary revascularization (e.g. coronary artery bypass), or cardiac transplantation. Pharmacological treatment of heart failure can consist of: - Diuretics - Inhibitors of RAS (e.g. ACE inhibitors, ARBs) - Vasodilators - Positive inotropic agents (i.e. cardiac glycosides such as digitalis).

Question 32

Describe the mechanism of action of diuretics.

Answer 32

Diuretics function by increasing the amount of salt and water expelled in the urine, thereby decreasing blood pressure, cardiac output, and overall workload on the heart. The different classes of diuretics - loop diuretics, thiazide diuretics, and potassium sparing diuretics - act on different locations in the nephron.

Question 33

Describe the mechanism of action of vasodilators, using calcium channel blockers as an example.

Answer 33

Calcium channel blockers decrease the amount of calcium inside vascular smooth muscle cells and cardiac muscle cells. Calcium is required for these cells to contract, and therefore the vascular smooth muscle cells and cardiac muscle cells will be in a relaxed state reducing blood pressure and workload on the heart.

Question 34

Describe the mechanisms of action of the drugs that influence the RAS - ACE inhibitors and ARBs.

Answer 34

ACE inhibitors block angiotensin converting enzymes, and therefore angiotensin I cannot be converted into angiotensin II. Angiotensin II normally results in vasoconstriction, however, the lack of angiotensin II in the presence of ACE inhibitors will promote vasodilation. ARBs block the receptor for angiotensin II, and thus angiotensin II cannot bind and induce vasoconstriction. Both of these classes of drugs decrease blood pressure and hence decrease workload on the heart.

Question 35

What are cardiac glycosides and why are they used?

Answer 35

Diuretics, inhibitors of the RAS, and vasodilators are the primary treatments for heart failure. Cardiac glycosides may be used as second line treatment. The major cardiac glycoside used in Canada is digoxin. Cardiac glycosides such as digoxin have a specific and powerful action on the myocardium.

Question 36

How do cardiac glycosides, specifically Digoxin, work?

Answer 36

1) Digoxin binds specifically to the enzyme sodium-potassium-ATPase, thereby inhibiting the extrusion of sodium from cardiac cells. 2) This results in an increase in the intracellular concentration of sodium, thereby decreasing the extrusion of calcium via the sodium-calcium exchanger. 3) The increased intracellular concentration of calcium ultimately leads to an increase in myocardial contractility. Thus, by increasing myocardial contractility, digoxin decreases heart size, venous congestion, and edema, while increasing renal perfusion.

Question 37

What are the therapeutic uses of digoxin?

Answer 37

Extensive research has shown that drugs aimed at non-cardiac tissues (e.g. ACE inhibitors and diuretics) are more effective in prolonging life than the cardiac glycosides (e.g. digoxin). However, some clinical applications of digoxin do exist: 1) Patients with heart failure and atrial fibrillation: Only about 50% of patients with normal sinus rhythm will have relief of heart failure from digoxin. - However, better results are seen with digoxin in patients who also have atrial fibrillation. 2) Treatment of disordered electrical rhythms of the heart (arrhythmias): Digoxin causes changes in the electrical properties of the heart. - An important therapeutic action of digoxin is its ability to decrease the number of electrical impulses passing from the atria to the ventricles and to slow the rate of beating of the ventricles in disordered rhythms arising in the atria.

Question 38

What are the adverse effects of digoxin?

Answer 38

Digoxin has a narrow therapeutic index of just 2; therefore, levels of digoxin in the blood are often monitored. Digoxin also accumulates in the body. - As a result of these two factors, approximately 25% of hospitalized patients taking digoxin show some signs of toxicity. - An early sign of digoxin toxicity is gastrointestinal symptoms (e.g. diarrhea). Other adverse effects are listed below: - Disordered rhythms in the heart (arrhythmia): While digoxin preparations are used to treat some disordered rhythms of the heart, these preparations can also cause fatal rhythm disturbances. A disordered rhythm of the ventricle (ventricular fibrillation) is the most common cause of death in digoxin poisoning. - Disturbances of vision: Vision is often blurred, and white halos may appear on dark objects. Colour vision can also be disturbed, with objects often appearing yellow or green. - Neurological effects: Headache, fatigue, muscle weakness, and confusion.

Question 39

What are the drug interactions that occur when taking digoxin?

Answer 39

Changes in intracellular potassium: changes in intracellular concentrations of potassium will affect the activity of digoxin. - Ex: a decrease in intracellular potassium, as occurs with most diuretics, will increase digoxin activity. This is because digoxin and potassium compete for the same spot on the sodium-potassium-ATPase. Antibiotics such as erythromycin: Digoxin can interact with antibiotics, such as erythromycin. - Erythromycin interacts with the gut flora that function to break down and inactivate digoxin, leading to an increase in digoxin levels in the blood.

Question 40

Which one of the drugs listed is correctly matched with its mechanism of action? a) Beta blockers – blocks beta receptors increasing heart rate and contractility b) Organic nitrates – dilates large veins, increasing venous return c) Digoxin – decreases heart rate and contractility d) Calcium channel blockers – increase dilation of coronary arteries

Answer 40

d) Calcium channel blockers – increase dilation of coronary arteries

Question 41

Which one of the drugs listed can be used in the treatment of heart failure but not hypertension? a) Cardiac glycosides b) Diuretics c) Vasodilators d) Angiotensin receptor blockers

Answer 41

a) Cardiac glycosides