Pharmacology of the CVS - Angina Flashcards
What are the 3 main symptoms of angina?
- Feeling of cramping in the chest
- Referred pain- shoulders, neck and arms
- May be associated with shortness of breath, sweating, and nausea
What is angina?
Chest pain due to insufficient blood flow to heart muscle.
How does anginal pain form?
- Ischaemia causes build-up of lactic acid during anaerobic respiration of cardiomyocytes.
- Activates myocardial pain receptors which sends signals via sensory neurones to the brain. These signals trigger pain.
FPATH RECAP
What is the purpose of pain?
- Protective response
- Warning to stop person doing whatever they are about to do
How was angina traditionally classified?
- Typical angina
- Atypical angina
- Non-anginal
What are the three characteristics of typical angina?
- substernal chest discomfort of characteristic quality + duration
- provoked by exertion or emotional stress
- relived by rest and/or nitrates within minutes
What do atypical and non-anginal pain have in common with typical angina?
Focus on the three characteristic of typical angina
ATYPICAL - shares at least two of the characteristics
NON-ANGINAL -presentation of one or none of the characteristic
What is the new classification of angina?
- Stable Angina
- Unstable Angina
- Prinzmetal Angina
- Microvascular Angina
What is stable angina commonly attributed to?
- Myocardial ischaemia
- Coronary artery disease
What is unstable angina commonly attributed to?
- Stable angina complications
What is prinzmetal angina attributed to?
- Cyclical coronary spasms commonly induced by cocaine
What is unique about microvascular angina?
- Angina symptoms but no signs or evidence of coronary heart disease
- Coronary angiograms will present as normal
Outline the aetiology of stable angina.
- Narrowed coronary artery lumen
- Restricted blood flow to myocardium so reduced oxygen delivery
- Oxygen received is insufficient when the heart has to work harder
- Leads to anaerobic respiration which forms lactic acid - leads to pain.
What are the characteristics of stable angina? PART 1
- Follow a set pattern and so are predictable. They have recurring episodes that have similar initial pattern, duration and intensity
- Last a short duration and radiate from the left arm, neck, jaw or back
- Caused by exertion or increased O2 demand
What are the characteristics of stable angina? PART 2
- Not life-threatening but can act as a warning for serious cardiovascular events (e.g. heart attacks)
- Relieved by rest or taking medication
- Symptoms are attributed to myocardial ischemia
Outline the aetiology of unstable angina
- Clot formation occludes artery (following plaque rupture)
- Leads to reduction in blood flow so reduced oxygen delivery to myocardium
- Oxygen supply is inadequate even at rest
- Anaerobic respiration occurs forming lactic acid - causes pain
What are the characteristics of unstable angina? PART 1
- Unpredictable
- Pain symptoms are more severe and last longer
- Happens at rest with little exertion
- May not have a trigger
What are the characteristics of unstable angina? PART 2
- Not usually relived by medications
- Progression from stable angina – not possible to predict who will progress
- Serious, regarded as emergency - requires hospital admission
Outline the aetiology of prinzmetal angina
- Coronary Spasm (induced by drugs)
- Reduced blood flow so reduced oxygen delivery
- Oxygen supply is inadequate even at rest
- Anaerobic respiration occurs forming lactic acid - causes pain
What are the characteristics of prinzmetal angina. PART 1
- Usually occurs while resting at night or early morning
- Episodes tend to last 5-15 mins (and sometimes longer)
- Rare
- Typically found in younger patients
- Attacks are very severe and painful
What are the characteristics of prinzmetal angina. PART 2
- Symptoms include heart burn, nausea, sweating, dizziness and Raynaud’s phenomenon
- It is usually caused by spasms in the coronary arteries and comes in cycles
- Cocaine is the leading cause
- Relieved by medication
Outline the aetiology of microvascular angina.
- Increased vasoconstriction/impaired vasodilation of the coronary arteries
- Coronary circulation to be impaired
- Reduced coronary perfusion
- Myocardium undergoes anaerobic respiration
- Build up of lactic acid resulting in angina
What are the characteristics of microvascular angina. PART 1
- Impaired coronary circulation due to coronary microvascular dysfunction
- Patients do not have obstructive coronary artery disease
- Occurs at exertion and at rest but the heart may respond less adequately to nitrates
What are the characteristics of microvascular angina. PART 2
- 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
What are the aims of anginal treatment?
- Enhance quality of life by reducing symptoms
- Improve prognosis
- Prevent complications such as myocardial infarctions and premature death
- Treatment should have minimal side effects
How does supply ischemia lead to angina?
- Decreased coronary blood flow
- Caused by vasospasms (Prizmetal angina) or a thrombus/blockage (unstable angina)
How does demand ischaemia lead to angina?
- Increased oxygen requirement
- Caused by fixed stenosis (chronic/stable angina)
What are the three precipitating factors for ischaemia?
- Increased sympathetic activity
- Increased contractility
- Increased vasoconstriction
Describe how increasing sympathetic activity is a precipitating factor for ischaemia.
- Increases heart rate
- Reduced diastolic time.
- The heart is only perfused during diastole as during systole the blood is unable to move.
- Therefore lower diastolic time means reduced perfusion
Describe how increasing contractility is a precipitating factor for ischaemia.
Increases oxygen demands
Describe how increasing vasoconstriction is a precipitating factor for ischaemia.
- Required to redirect blood flow to areas where there are needed (e.g. after a large meal blood is diverted to the GI tract)
- Affects coronary circulation
How do angina treatments aim to improve perfusion?
- Increasing oxygen delivery by improving coronary blood flow
EXAMPLE: Coronary vasodilators
How do angina treatments aim to reduce metabolic demand?
- Reduce oxygen demands
EXAMPLES: Vasodilators and coronary depressants
How do angina treatments aim to reduce the risk of subsequent anginal episodes?
- Use of prophylactics
- This is where treatment becomes a form of prevention rather than symptom reduction
EXAMPLE: Anticoagulants and lipid-lowering drugs
RECAP: How does smooth muscle contraction occur?
- Increase in cytoplasmic calcium from interstitial fluid
- Calcium binds to calmodulin
- Causes activation of myosin light chain kinase
- Myosin is phosphorylated
- Cross bridge formation occurs
RECAP: How does cardiac muscle contraction occur?
- Increase in cytoplasmic calcium from SR
- Calcium binds to troponin C
- Causes movement of tropomyosin - so myosin binding sites exposed
- Cross bridge formation occurs
How can nitrates be used to treat angina, focussing on its mechanism of action?
- Mimic endogenous NO.
- Form Guanylyl cyclase - cGMP forms
- cGMP activates protein kinase G which dephosphorylates the myosin light chain
- Increases the uptake of Ca2+ by the SR causing a decrease of Ca2+ in the cytoplasm
- Activate K+ channels causing hyperpolarisation and closing VGCC
What are the main effects of nitrates?
- Cause peripheral venodilation - decreases intravascular pressure to decrease preload
- Cause arterial dilation - decreases TPR - reduces afterload
- Lower oxygen demands
What are the adverse effects of nitrates?
- Syncope (due to arterial dilation)
- Postural hypotension (due to venodilation)
- Reflex tachycardia (due to sympathetic outflow)
What is the mechanism of action for beta blockers?
- Reduce sympathetic activity caused by noradrenaline and adrenaline.
- Reduced activation of adenylate cyclase
- Intracellular cAMP levels decrease so reduced activation of PKA so reduced phosphorylation and opening of sodium ion channels
- Reduced sodium ion influx so it takes longer for depolarisation to occur.
- Harder for voltage-gated calcium channels to open
What are the effects of beta-blockers e.g atenolol?
- Inhibits pacemaker current in SAN so heart rate goes down
- Heart rate decreases - lengthens diastole time, more time for coronary perfusion.
- Reduced force of cardiac contraction so improved exercise tolerance
- Myocardial oxygen supply is improved
What are the adverse effects of beta-blockers?
- Fatigue
- Bronchospasm
List two contraindications of taking beta-blockers
ASTHMA - blocking of the beta receptor causes bronchospasm
HEART BLOCK - blocking of the AVN
What is the mechanism of action for calcium channel blockers e.g dihydropyridines - amlodipine?
- Reduced Ca2+ influx into cardiac myocytes and smooth muscle cells
- Decreased CICR.
- Overall decrease in intracellular Ca2+
- Reduced 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
What are the effects of calcium channel blockers?
- Cause coronary vasodilation - more coronary blood flow
- Reduce BP/ TPR/ afterload - the heart works less hard to eject blood
What are the adverse effects of calcium channel blockers?
- Lower limb oedema - increased pressure in the capillary in the lower limbs
- Flushing and headaches - 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
Give examples of prophylactic drugs for angina.
- Aspirin: inhibits COX. As a result, it reduces platelet aggregation
- Clopidogrel: inhibits ADP receptors on platelets to reduce aggregation
- Statins: HMG CoA reductase inhibitor - causes decrease in cholesterol levels
Aspirin and clopidogrel can be used together. Explain why.
Both have different mechanisms
Outline the mechanism of action of nicorandil (anti-anginal)
- Potassium channel activator which promotes hyperpolarisation.
- Inhibits VGCC
- Reduced calcium influx
- Coronary vasodilation occurs.
- Part of its vasodilator action is due to generation of NO
Outline the mechanism of action of ivabradine (anti-anginal)
- Inhibitor of the pacemaker current in the SAN.
- Slows sinus heart rate
- Decreases the frequency of pacemaker potentials being fired.
- Decreased heart rate to reduce the myocardial O2 demand
Outline the mechanism of action of ranolazine
- Sodium current inhibitor
- Reduces Ca2+ in ischaemic myocardial cells.
- Reduces oxygen demand
- Reduces the compression of small intramyocardial coronary vessels
- Improves myocardial perfusion
