Pharmacological Treatment of Angina

Question 1

What is angina pectoris?

Answer 1

• Chest pain due to inadequate supply of oxygen to the heart.
  
  • Typically severe and crushing.
  • Feeling of pressure and suffocation behind the breastbone.

Question 2

Describe the characteristics of pain distribution in angina.

Answer 2

• Chest
• Arm
• Neck
• Jaw

Question 3

What brings on angina?

Answer 3

• Exertion
• Cold
• Excitement

Question 4

What is thought to cause the pain associated with angina?

Answer 4

• It is thought that chemical factors that cause pain in skeletal muscle (i.e K+, H+​ and adenosine) are responsible.
• Angina can accompany or be a precursor to MI.

Question 5

List the treatments used to reduce chest pain symptoms associated with angina.

Answer 5

• Beta-blockers
• Nitrates
• Calcium channel antagonists
• Nicorandil
• Ivabradine
• Ranolazine

Question 6

List the treatments used to prolong survival in patients with angina.

Answer 6

• Beta-blockers
• Aspirin
• Statins
• Angiotensin converting enzyme inhibitors
• Angiotensin II receptor blockers

Question 7

Describe the coronary blood flow through the left vetricle.

Answer 7

• Left and right coronary arteries feed the blood supply to the heart.
• Most tissues are perfused when the heart contracts.
• Anything that changes the duration of diastole (window for coronary flow) changes the opportunity for perfusion and causes a change in diastolic pressure.
  • If the window is short enough, the base diastolic level rises as the level of blood in the ventricle rises.

Question 8

What factors shrink the window for perfusion?

Answer 8

• Shortening diastole
  
  • Eg. increased heart rate.
• Increased ventricular end diastolic pressure
  
  • Eg. a progressive decline in ventricular emptying; aortic valve stenosis.
• Reduced diastolic arterial pressure
  
  • Eg. mitral or aortic vlve incompetence; heart failure.

Question 9

Describe the issues with coronary blood flow.

Answer 9

• Myocardium cannot function anaerobically
  
  • Anaerobic glycolysis increases in lactic acid production.
• Arterioles close mechanically during systole.
• Decreased diastolic filling period during exercise.
• Increased oxygen demand and increased metabolic demand during exercise.
• Work output of the heart increases by 6-9x during strenuous exercise
  
  • ​Uses 70-80% of coronary blood flow oxygen at rest
    
    • Increased demand must be met by increased flow

Question 10

Describe the autoregulation of arteriolar radius.

Answer 10

• It matches the demand to blood flow by altering flow at arteriolar level.
• Metabolic control:
  
  • ​Muscle cell produces byproducts (eg. adenosine) which trigger vascular smooth muscle cells to relax (potentially via an intermediate produced by endothelial cells).

Question 11

Describe what causes coronary ischaemia.

Answer 11

• Coronary ischaemia is usually the result of atherosclerosis.
• This causes angina.

Question 12

Describe what causes sudden ischaemia.

Answer 12

• Sudden ischaemia is usually caused by thrombosis.
• This may result in cardiac infarction.

Question 13

What is variant angina?

Answer 13

• Angina caused by coronary spasms.
  
  • This is the smooth muscle of the heart spontaneously contracting and relaxing.

Question 14

What is the cellular effect of ischaemia?

Answer 14

• Cellular calcium overload results from ischaemia.
  
  • This may cause cell death and dysrhythmias.

Question 15

Describe the progression of atherosclerosis.

Answer 15

Question 16

What are the classes of angina?

Answer 16

1. Chronic stable angina
   
   • Fixed stenosis
     
     • Demand ischaemia
2. Unstable angina
   
   • Thrombus
     
     • Supply ischaemia
3. Printzmetal’s variant angina
   
   • Vasospasm
     
     • Supply ischaemia

Question 17

Describe stable angina.

Answer 17

• Predictable chest pain on exertion.
• Caused by a fixed narrowing of the coronary arteries.
• Treated by decreased workload of the heart and therefore decreased oxygen requirement.
• Also use drugs to prolong survival (eg. aspirin, statins, ACE inhibitors).

Question 18

Describe unstable angina.

Answer 18

• Occurs at rest and with less exertion than stable angina.
• Associated with a thrombus around a ruptured atheromatous plaque but without complete occlusion of the vessel (similar to MI).

Question 19

Describe variant (Prinzmetal) angina.

Answer 19

• Uncommon
• Caused by coronary artery spasm
• Not completely understood, but sometimes associated with atherosclerosis.

Question 20

Describe the main mechanism of action of antianginal drugs.

Answer 20

Mainly work by reducing the metabolic demand of the heart.

Question 21

Which antianginal drugs are vasodilators?

Describe their mechanism of action.

Answer 21

• Organic nitrates
• Nicorandil
• Calcium antagonists
• These are vasodilators!
• They work by reducing preload or afterload of the heart.

Question 22

Which antianginal drugs slow the heart?

Describe their mechanism of action.

Answer 22

• β-blockers
• Ivabradine
• These slow down the heart.
• They work by decreasing the metabolic demand of the muscle.

Question 23

Define preload.

Answer 23

Venous pressure and venous return to the heart (end diastolic pressure / volume) (EDP/EDV).

Question 24

Define afterload.

Answer 24

Aortic / pulmonary artery pressure.

Question 25

Describe the action of β-blockers in the treatment of angina. Give examples.

Answer 25

* Important (first line) treatment in the prophylaxis and treatment of stable and unstable angina. * Decreases cardiac oxygen consumption by slowing the heart. * Also have an antidysrhythmic action. * Reduces death after MI. * **Bisoprolol** * **Atenolol**

Question 26

Describe the action of calcium antagonists in the treatment of angina. Give examples.

Answer 26

* Preventing opening of voltage-gated L-type Ca²⁺ channels * Therefore block the entry of Ca²⁺ entry. * Mainly affect the heart and smooth muscle to inhibit calcium entry upon muscle cell depolarisation. * Two main types: * Dihydropyridine derivatives * **Amlodipine** * **Lercanidipine** * Rate-limiting * **Verapamil** * **Diltiazem** * Vasodilator effect mainly on resistance vessels * **Therefore reduces afterload** * Also dilates coronary vessels (important in variant angina) * **Verapamil and diltiazem can reduce and impair AV conduction and myocardial contractility.**

Question 27

Describe the depolarisation of the SA node.

Answer 27

* **Phase 1** * **​**Gradual drift upwards in resting membrane potential due to increased gNa⁺ as 'funny' F-type Na⁺ channels open and decreased gK⁺ as K⁺ channels slowly close. * Transient (T) Ca²⁺ channels help with the final push. * **Phase 2** * **​**Moderately rapid depolarisation due to Ca²⁺ entry via slow (L) channels. * **Phase 3** * **​**Rapid repolarisation as elevated internal Ca²⁺ stimulates opening of K⁺ channels and an increase in gK⁺.

Question 28

What are the clinical uses of calcium antagonists in angina?

Answer 28

* Choice depends on comorbidity and drug interactions. * **Amlodipine** or **lercanidipine** safe in patients with heart failure; used instead of a β-blocker in Prinzmetal angina or alongside β-blockers in most angina. * **Diltiazem** or **verapamil** used but contraindicated in heart failure, bradycardia, AV block or in presence of β-blocker. * Side effects include: * Headache * Constipation * Ankle oedema

Question 29

What are the other clinical uses of calcium antagonists?

Answer 29

* Antidysrhythmics * Mainly **verapamil** * Slows ventricular rate in rapid atrial fibrillation. * Prevents recurrence of supraventricular tachycardia (SVT). * No effect on ventricular arrhythmias. * Hypertension * Mainly **amlodipine** or **lercanidipine**.

Question 30

Describe the action of organic nitrates in the treatment of angina.

Answer 30

* **Glyceryl trinitrate** and **isosorbide mononitrate** * **​**Powerful vasodilators * Work by being metabolised to nitric oxide (NO) and relax smooth muscle (particularly vascular smooth muscle). * Act on veins to decrease cardiac preload. * Higher concentrations can affect arteries, therefore decrease afterload. * Decreased cardiac workload is helped by dilation of collateral coronary vessels. * This therefore improves distribution of coronary blood flow towards ischaemic areas. * Dilation of constricted coronary vessels is particularly beneficial in variant angina.

Question 31

Describe the role of the endothelial cells in regulating vascular tone.

Answer 31

Question 32

What are the clinical uses of organic nitrates in angina?

Answer 32

* Stable angina: * Prevention by sublingual glyceryl trinitrate shortly before exertion or isosorbide mononitrate long before. * Unstable angina: * Intravenous glycerly trinitrate (GTN) * Unwanted effects are common; headache and postural hypotension may occur.

Question 33

What are the other clinical uses of organic nitrates?

Answer 33

* Acute heart failure (in specific circumstances) * **Intravenous GTN** * Chronic heart failure (CHF) * **Isosorbide mononitrate** with **hydralazine** in patients of African American origin especially, (or patient cannot tolerate more commonly used CHF drugs).

Question 34

Describe the action of potassium channel activators in the treatment of angina. Give an example.

Answer 34

* **Nicorandil** * ​Combines activation of potassium K⁺_ATP channels with nitrovasodilator actions (has a NO donation effect). * Causes hyperpolarisation of vascular smooth muscle. * Both an arterial and venous dilator. * Causes headaches, flushing and dizziness. * Used for patients who remain symptomatic despite optimal management with other drugs.

Question 35

Give examples of other anti-anginals and state their mechanism of action.

Answer 35

* **Ivabradine** * **​**Inhibits F-type channels in the heart. * Reduces cardiac pacemaker activity. * Therefore inhibits heart rate. * **Ranolazine** * **​**Unique anti-anginal used as a last resort.

Question 36

What is the first-line therapy in pharmacological management of angina?

Answer 36

* β-blockers should be used as first-line therapy for the relief of symptoms of stable angina. * Patients who are intolerant of β-blockers should be treated with either rate limiting calcium channel blockers, long-acting nitrates or nicorandil.

Question 37

Describe drug interventions to prevent new vascular events.

Answer 37

* All patients with stable angina due to atherosclerotic disease should receive long-term standard aspirin and statin therapy. * All patients with stable angina should be considered for treatment with angiotensin-converting enzyme inhibitors.

Question 38

Describe combination therapy in pharmacological management of angina.

Answer 38

* When adequate control of anginal symptoms is not achieved with β-blockade, a calcium channel blocker should be added. * Rate-limiting calcium channel blockers should be used with caution when combined with β-blockers. * Patients whose symptoms are not controlled on maximum therapeutic doses of 2 drugs should be considered for referral to a cardiologist.