15) Pharmacology of CVS - Angina

Question 1

What is an Angina and its symptoms?

Answer 1

• The feeling of cramping and severe constriction of the chest that causes pain in the jaw, shoulders, neck and arms
• It is caused by an imbalance between supply and demand of oxygen to the heart
• It may be associated with shortness of breath, sweating, fainting, nausea and heart rate

Question 2

How is pain caused in anginas?

Answer 2

• Angina pain originates from the build up of lactic acid during anaerobic respiration of cardiomyocytes
• This activates myocardial pain receptors which sends signals via sensory neurones to the brain
• This signal causes us to feel pain

Question 3

What is the purpose of pain?

Answer 3

• Pain in the body aids the survival of our body as it alerts us if something has gone wrong

Question 4

What are the traditional classifications of an angina?

Answer 4

• Typical angina: Chest discomfort of characteristic quality and duration which is provoked by exertion or emotional stress. It is relieved through rest and/or nitrates in minutes
• Atypical angina: Presentation of two of the characteristics of a typical angina
• Non-anginal: Presentation of one or none of the characteristics of a typical angina

Question 5

What are the new classifications of an angina?

Answer 5

• Stable angina: Caused by myocardial ischemia or coronary artery disease
• Unstable angina: Caused by further complications of a stable angina
• Prinzmetal angina (Angina Inversa): A cyclic angina in which there are spasms in the coronary artery. Cocaine is the leading cause of prinzmetal angina
• Microvascular angina: Patients may have angina symptoms but no evidence of coronary artery disease. These cannot be seen under a normal/ near-normal coronary angiogram

Question 6

What is the aetiology of a stable angina?

Answer 6

• First the lumen of the coronary arteries are narrowed
• This restricts blood flow to certain areas of the myocardium
• Hence this part of the heart is poorly perfused/ supplied with oxygen when the heart has to work harder
• Thus the myocardium is forced to undergo anaerobic respiration (producing lactic acid in the process)
• This build up of lactic acid is how the pain/angina rises

Question 7

What are the characteristics of Stable Angina?

Answer 7

• They follow a set pattern and so are predictable. They have recurring episodes that have similar initial pattern, duration and intensity
• They last a short duration and radiate from the left arm, neck, jaw or back
• They are caused by exertion or increased O2 demand
• Not life-threatening but can act as a warning for something serious (e.g. heart attacks)
• Relieved by rest or taking medication
• Symptoms are caused by myocardial ischemia

Question 8

What is the aetiology of an unstable angina?

Answer 8

• First thrombosis occurs which blocks arteries making them narrow (stenosis)
• This critically reduces blood flow which means even at rest we suffer from myocardial hypoxia (lack of oxygen supplied to the myocardium)
• This means the myocardium are forced to undergo anaerobic respiration which forms lactic acid
• This lactic acid builds up leading to angina

Question 9

What are the characteristics of an unstable angina?

Answer 9

• Unpredictable
• Pain symptoms are more severe, persistent and can last longer
• Can happen at rest
• May have no trigger
• Not usually relieved by medication or rest
• It is impossible to predict the progression from stable angina to an unstable angina
• It is regarded as an emergency and patients are advised to go to the hospital

Question 10

What is the aetiology of a prinzmetal angina?

Answer 10

• Coronary spasms occur (most commonly due to cocaine use)
• These vasospasms critically restrict blood flow so that parts of myocardium experience hypoxia
• This can occur at rest and forces them to undergo anaerobic respiration which forms lactic acid as a product
• This lactic acid builds up leading to angina

Question 11

What are the characteristics of Prinzmetal Angina?

Answer 11

• Usually occurs while resting at night or early morning
• Episodes tend to last 5-15 mins (and sometimes longer)
• It is rare
• Typically found in younger patients
• Attacks are very severe and painful
• Pain can spread from chest to head, shoulders or arms
• Symptoms include heart burn, nausea, sweating, dizziness, palpitation, migraines and Raynaud’s phenomenon (decreased circulation of blood causes parts of the body to feel cold, sore, numb or change colour)
• It is usually caused by spasms in the coronary arteries and comes in cycles
• Cocaine is the leading cause of Prinzmetal Angina
• Relieved by medication

Question 12

What is the aetiology of microvascular angina?

Answer 12

• Increased vasoconstriction or impaired vasodilation of the coronary arteries causes the coronary circulation to be impaired
• This means there is reduced coronary perfusion causing the myocardium to undergo anaerobic respiration
• This leads to a build up of lactic acid resulting in angina

Question 13

What are the characteristics of microvascular Angina?

Answer 13

• Impaired coronary circulation due to coronary microvascular dysfunction from abnormal vasodilation or increased vasoconstriction
• Patients do not have obstructive coronary artery disease
• Occurs at exertion and at rest but the heart may respond less adequately to nitrates
• Difficult to diagnose early as coronary microvasculature cannot be directly imaged in vivo
• Positron emission tomography (PET) or cardiac magnetic resonance (CMR) may be used to asses cardiac microvascular blood flow
• Treatment varies on type of microvascular angina

Question 14

What are the aims of treating anginas?

Answer 14

• Enhance quality of life by reducing symptoms
• Improve prognosis and prevent complications such as myocardial infarctions and premature death
• Well tolerated and cause minimal side effects

Question 15

How does supply ischemia lead to angina?

Answer 15

• Supply ischemia is when there is a decreased coronary blood flow
• This decrease in flow is caused by vasospasms (Prizmetal angina) or a thrombus/blockage (unstable angina)

Question 16

How does demand ischemia lead to angina?

Answer 16

• Demand ischemia is caused by increased oxygen requirement

- This increased requirement can be caused by fixed stenosis (chronic/stable angina)

Question 17

What are the precipitating factors of ischemia?

Answer 17

• Increased sympathetic activity increases heart rate which means there is less diastolic time. The heart is only perfused during diastole as during systole the blood is unable to move. Hence by reducing diastolic time there is less coronary artery perfusion
• Increased contractility (e.g. during exercise, expressing emotions and stress) can increase oxygen demand
• Increased vasoconstriction to redirect blood flow to areas where there are needed (e.g. after a large meal blood is diverted to the GI tract) and this affects coronary circulation

Question 18

What strategies are used to treat anginas?

Answer 18

• Improve perfusion: We can increase oxygen delivery by improving coronary blood flow using coronary vasodilators
• Reduce metabolic demand: We can reduce oxygen demand by decreasing cardiac work using vasodilators (to reduce preload and afterload) and cardiac depressants (reduce heart rate and contractility)
• Prevention: Prophylactics can reduce the risk of episodes. These are lipid lowering drugs, anticoagulants, fibrinolytic and anti-platelet

Question 19

How do nitrates (-nitrate) treat anginas?

Answer 19

• Nitrates mimic endogenous NO.
• They form Guanylyl cyclase which reacts with GTP to from cGMP
• cGMP activates protein kinase G which dephosphorylates Myosin light chain
• This increases the uptake of Ca2+ by the SR causing a decrease of Ca2+ in the cytoplasm
• They also activate K+ channels causing hyperpolarisation and closing VGCC
• They cause peripheral venodilation which decreases intravascular pressure to decrease preload
• They also cause arterial dilation to decrease Total Peripheral Resistance (TPR) which reduces afterload
• These lower oxygen demand by decreasing the amount of work the heart needs to do

Question 20

What adverse effects can nitrates cause?

Answer 20

• Throbbing headache, flushing and syncope (due to arterial dilation)
• Postural hypotension (due to venodilation)
• Reflex tachycardia (due to sympathetic outflow)

Question 21

How do beta-blockers (-olol) treat anginas?

Answer 21

• They reduce sympathetic activity caused by noradrenaline and adrenaline.
• This means the amount of adenylate cyclase made is reduced and so cAMP levels decrease
• Firstly less Na+ enters the cell so it takes longer for depolarisation to occur.
• This means is harder for Voltage gated calcium channels to open
• Hence heart rate decreases as it lengthens diastole time and gives more time for coronary perfusion.
• Furthermore less cAMP means less active Protein Kinase A and therefore a further decrease in Calcium influx so less CICR occurs
• It also reduces the force of cardiac contractions which improves exercise tolerance

Question 22

What are the side effects of beta-blockers?

Answer 22

• Fatigue, postural hypotension
• Asthma as they block beta-2 receptors so can cause contraction in lungs and bronchospasms
• Heart block when atrial-ventrical conduction is poor as they may block the AV node

Question 23

How do Calcium channel blockers (-ines) treat anginas?

Answer 23

• They reduce Ca2+ entry into cardiac myocytes and smooth muscle cells by blocking VGCC after an action potential is fired.
• This means there is little to no Ca2+ influx into the cell and so there is decreased CICR.
• As a result there is an overall decrease in Ca2+ which reduces contractility and thus less Oxygen consumption
• They also cause coronary vasodilation which causes more coronary blood flow
• They reduce BP/ TPR/ afterload and so the heart works less hard to eject blood

Question 24

What are the side effects of Ca2+ channel blockers?

Answer 24

• Lower limb oedema as there is increased pressure in the capillary in the lower limbs
• Flushing and headaches due to excessive vasodilation
• Reflex tachycardia as vasodilation causes increased sympathetic activity (baroreflex) and increases HR and contractility
• Blocking Ca2+ channels in the heart can alter electrical conductivity and contractility

Question 25

What are the prophylactic drugs for angina?

Answer 25

• Aspirin: inhibits COX. As a result it reduces thromboxane A2 and platelet aggregation
• Clopidogrel: inhibits ADP receptors on platelets to reduce aggregation
• Statins: HMG Co-A reductase inhibitor which causes a decrease in cholesterol levels

(Aspirin and Clopidogrel can be used together to reduce thrombosis as they have different mechanisms)

Question 26

What are some anti-anginals?

Answer 26

• Nicorandil: A potassium channel activator which promotes hyperpolarisation. This inhibits VGCC and Ca2+ influx goes down. As a result we get coronary vasodilation. Part of its vasodilator action is due via generation of NO
• Ivabradine: A specific inhibitor of the pacemaker current in the SAN. This slows sinus heart rate and decreases the frequency of pacemaker potentials being fired. Hence there is a decreased heart rate to reduce the myocardial O2 demand
• Ranolazine: Late sodium current inhibitor which reduces Ca2+ in ischaemic myocardial cells. This reduces oxygen demand and reduces the compression of small intramyocardial coronary vessels which improves myocardial perfusion