Anti-Arrhythmics Flashcards
How do pacemaker cells in the heart differ from other myocardial cells?
They show a slow, spontaneous depolarisation during diastole
What causes the slow, spontaneous depolarisation of pacemaker cells in diastole?
Inward movement of sodium and calcium ions causing a positive current
How does the speed of pacemaker depolarisation vary throughout different locations in the heart?
It is fastest in the SA node, and decreases throughout the normal conduction pathway through the AV node to the bundle of His and Purkinje system
Draw the pacemaker action potential
What can dysfunction of impulse generation or conduction in the heart lead to?
Abnormalities in cardiac rhythm
How can arrhythmia be organised into groups?
Based on the site of the abnormality in impulse generation or conduction - the atria, the AV node, or the ventricles
What are the categories of causes of arrhythmias?
- Abnormal automaticity
- Abnormalities in impulse conduction
Which site in the heart normally shows the fastest rate of phase 4 depolarisation?
The SA node
What is the result of the SA node normally showing the fastest rate of phase 4 depolarisation?
It exhibits a higher rate of discharge than that occuring in other pacemaker cells, and so sets the pace for contraction of the myocardium
What happens if cardica sites other than the SA node show increased automaticity?
They may generate competing stimuli for myocardial contraction, and arrythmias may arise
How do anti-arrhythmic agents suppress automaticity?
By blocking either sodium or calcium channels, to reduce the ratio of these ions to potassium.
How does blocking sodium or calcium channels suppress abnormal automaticity?
- It decreases the slope of the phase 4 depolarisation
- It raises the threshold of discharge to a less negative voltage
This causes the frequency of discharge to decrease
This effect is more pronouced in cells with ectopic pacemaker activity than in normal cells
Describe the pathways that impulses from higher pacemaker centres are normally conducted down
Pathways that bifurcate to active the entire ventricular surface
When might re-entry occur?
If a unidirectional block caused by myocardial injury or a prolonged refractory period results in an abnormal conduction pathway
At what level of the cardiac conduction system can re-entry occur?
Any
How does a re-entry loop result in arrhythmias?
It results in re-excitation of the ventricular muscle, causing premature contraction of sustained ventricular arrhythmias
How do anti-arrhythmic drugs prevent re-entry?
- Slow conduction
- Increase the refractory period
This converts a unidirectional block into a bi-directional block down the abnormal pathway
What is the problem with many anti-arrhythmic agents?
They are known to have dangerous polyarrhythmic actions - they cause arrhythmias
What effect can inhibition of potassium channels have?
Can widen the action potential, and thus prolong the QT interval
What can result from excessive QT prolongation?
Can increase the risk of developing life threatening ventricular tachycardia (torsades de pointes)
What can cause QT prolongation?
Most common cause is drug induced, however other conditions, including ischaemia and hypokalaemia, and genetic profiles may laso contribute
What drugs can cause QT prolongation?
- Class III anti-arrhythmic drugs
- Macrolide antibiotics
- Antipsychotics
What caution should be taken to reduce the risk of excessive and dangerous QT prolongation?
- Shouldn’t combine drugs with additive effects on the QT interval
- Should be careful when giving drugs that can prolong QT interval alongside drugs known to affect their metabolism
How do class I anti-arrythmic drugs work?
By blocking voltage-sensitive sodium channels
What effect do class 1A anti-arrythmic drugs have?
They slow phase 0 depolarisation in ventricular muscle fibres
What effect do class 1B anti-arrhythmic drugs have?
They shorten phase 3 repolarisation in ventricular muscle fibres
What effect do class 1C anti-arrhythmic drugs have?
They markedly slow phase 0 depolarisation in ventricular muscle fibres
How do class II anti-arrhythmic agents work?
They block ß-adrenoreceptors
What effect do class II anti-arrhythmic agents have on the pacemaker action potential?
They inhibit phase 4 depolarisation in the SA and AV node
How do class III anti-arrhythmic agents work?
They block potassium channels
What effect do class III anti-arrhythmic agents have on the pacemaker action potential?
They prolong phase 3 repolarisation in ventricular muscle fibres
How do class IV anti-arrhythmic agents work?
They block calcium channels
What effect do class IV anti-arrhythmic agents have on the pacemaker action potential?
They inhibit the action potential in SA and AV nodes
Why is the classification of anti-arrhythmic drugs not always clear cut?
Because many drugs have actions relating to more than one class, or may have active metabolites with a different class of action
Why has the use of class I anti-arrhythmic agents declined?
Due to their proarrhythmic effects, particularly in patients with reduced left ventricular function and ischaemic heart disease
What is meant by ‘use dependance’ in class I anti-arrhythmic agents?
Class I drugs bind more rapidly to open or inactivated sodium channels than to channels that are fully repolarised following recovery from the previous depolarisation cycle. Therefore, these drugs show a greater degree of blockade in tissues that are frequently depolarising
What is the clinical importance of the ‘use dependant’ property of class IA agents?
It enables the drugs to block cells that are discharging at an abnormally high frequency, without interfering with the normal, low frequency beating of the heart
Give an example of a class 1A anti-arrhythmic agent
Quinidine
What is the mechanism of action of class 1A anti-arrhythmic agents such as quinidine?
- Binds to open and inactivated sodium channels, and prevents sodium influx, thus slowing the rapid upstroke in phase 0.
- Decreases the slope of phase 4 spontaneous depolarisation
- Inhibits potassium channels
- Blocks calcium channels
These actions cause a slowing of conduction velocity and increased refraction period.
What are the therapeutic uses of class 1A anti-arrhythmic agents?
Used in the treatment of a variety of arrythmias, including atrial, AV junctional, and ventricular tachycardias.
What are the adverse effects of class 1A anti-arrhythmic agents such as quinidine?
- Large doses might induce symptoms of cinchonism, including blurred vision, tinnitus, headache, disorientation, and psychosis
- Anti-cholinergic effects, e.g. dry mouth, urinary retention, blurred vision, constipation
When are the actions of class 1B anti-arrythmic agents manifested?
When the cardiac cell is depolarised, or firing rapidly
Why are the actions of class 1B anti-arrhythmic drugs manifested when the cardiac cell is depolarised, or firing rapidly?
Because they rapidly associate and dissociate from sodium channels
Give two examples of class 1B anti-arrhythmic agents
- Lidocaine
- Mexiletine
What is the mechansim of action of class 1B anti-arrhythmic agents?
- Sodium channel blockade
- Shorten phase 3 repolarisation
- Decrease duration of action potential
What are the therapeutic uses of lidocaine?
- Alternative to amiodarone in ventricular fibrillation, or pulseless ventricular tachycardia
Polymorphic VT
Why is lidocaine not used in atrial or AV junction arrhythmias?
Because it does not markedly slow conduction, and therefore has little effect in these arrhythmias
How is lidocaine administered?
IV
Why is lidocaine given IV?
Because of extensive first-pass metabolism by the liver
When should lidocaine be monitored?
When given in combination with drugs affecting CYP1A2 and CYP3A4
When might lidocaine dose adjustment be required?
When given with drugs that lower hepatic blood flow
Does lidocaine have a wide or narrow therapeutic index?
Fairly wide
What are the ADRs of lidocaine?
- Nystagmus
- Drowsiness
- Slurred speech
- Paresthesia
- Agitation
- Confusion
- Convulsions
Why do class 1C anti-arrhythmic drugs have prominent effects even at normal heart rates?
Because they dissociate slowly from resting sodium channels
What is the problem with class 1C anti-arrhythmic drugs?
Several studies have shown the potential for serious safety issues, especially in those with structural heart disease
Give an example of a class 1C anti-arrhythmic drug
Flecainide
What is the mechanism of action of flecanide?
- It suppresses the phase 0 upstroke in the Purkinje and myocardial fibres, causing a marked slowing of conduction in all cardiac tissue, with a minor effect on the duration of the action potential and refractory period
- Blocks potassium channels, leading to an increased AP duration
How does flecanide decrease automaticity?
By increasing the threshold potential, rather than causing a decrease in the slope of phase 4 depolarisation
What are the therapeutic applications of flecainide?
- Maintenance of sinus rhythm in atrial flutter or fibrillation in patients without tural heart disease
- Treating refractory ventricular arrythmias
What conditions are included in tural heart disease?
- Left ventricular hypertrophy
- Heart failure
- Atherosclerotic heart disease
Why can’t flecinide be used in heart failure?
Because it has a negative inotropic effect, and can aggrevate chronic heart failure
How is flecainide administered?
Orally
How is flecainide eliminated?
Mainly renally
When might dose adjustment for flecainide be required?
In renal disease
What are the adverse effects of flecainide?
- Blurred vision
- Dizziness
- Nausea
What is the effect of class II antiarrhythmic agents?
They diminish phase 4 depolarisation, and thus depress automaticity, prolong AV conduction, and decrease heart rate and contractility
What are the indications of class II antiarrhythmic agents?
- Tachycardias caused by increased sympathetic activity
- Atrial flutter
- Atrial fibrillation
- AV nodal re-entrant tachycardia
- Ventricular arrhythmias following MI
What is the most widely used class II anti-arrhythmic agent?
Metoprolol
What is the advantage of metoprolol compared to non-selective class II agents, such as propanolol?
It reduces the risk of bronchospasm
What is esmolol?
A very short-acting ß-blocker (class II antiarrhythmic agent) used for IV administration in acute arrhythmias that occur during surgery or emergency situations
What is the mechanism of action of class III antiarrhythmic agents?
They block potassium channels, and so diminish the outwards potassium current during repolarisation of cells
What is the effect of class III anti-arrhythmic agents?
They prolong the duration of the action potential without altering phase 0 of depolarisation or the resting membrane potential. Instead, they prolong the effective refractory period
What adverse effect to all the class III anti-arrythmic agents have the potential to cause?
Induce arrhythmias
Give an example of a class III anti-arrhythmic
Amiodarone
What is the mechanism of action of amiodarone?
Complex - shows class I, II, III, and IV actions, as well as alpha-blocing activity.
Dominant effect is prolongation of the action potential duration and the refractory period by blocking potassium channels
What are the therapeutic uses of amiodarone?
- Treatment of severe refractory supraventricular and ventricular tachycardia
- Atrial fibrillation or flutter
Describe the oral absorption of amiodarone
Incomplete
What is the half life of amiodarone?
Several weeks
What is the result of the long half life of amoidarone?
It can take months for full clinical effects to be achieved, unless loading doses are used
Where does amiodarone distribute extensively?
Adipose tissue
What are the adverse effects of amiodarone?
- Pulmonary fibrosis
- Neuropathy
- Hepatotoxicity
- Corneal deposits
- Optic neuritis
- Blue-gray skin discolouration
- Hypo- or hyperthyroidism
How can amiodarone toxicity be reduced?
Use of low doses and close monitoring
Why is amiodarone subject to numerous drug interactions?
Because it is metabolised by CYP3A4, and serves as an inhibitor of numerous CYP enzymes and P-glycoprotein
What are class IV antiarrhythmic drugs?
Non-dihydropyridine calcium channel blockers
Give two examples of class IV antiarrhythmic drugs
- Verapamil
- Diltiazem
What is the mechanism of action of class IV anti-arrhythmic agents?
They bind to open depolarised voltage sensitive calcium channels, thus decreasing the inward current carried by calcium. They prevent repolarisation until the drug has dissociated from the channel, resulting in a decreased rate of phase 4 spontaneous depolarisation.
They also slow conduction in tissues that are depedant on calcium currents, such as the AV and SA nodes
What are the therapeutic applications of class IV antiarrhythmic drugs?
- Treating re-entrant supraventricular tachycardias
- Reducing the ventricular rate in atrial flutter and fibrillation
What is adenosine?
A naturally occuring nucleoside
What is the effect of adenosine at high doses?
- Decreases conduction velocity
- Prolongs refractory period
- Decreases automaticity of AV node
How is adenosine administered in the treatment of arrhythmias?
Intravenously
What is the therapeutic application of intravenous adenosine?
Supraventricular tachycardia treatment
What are the ADRs of adenosine?
- Flushing
- Chest pain
- Hypotension
What is the duration of action of adenosine?
10 to 15 seconds
Why does adenosine have such a short half life?
Due to rapid uptake by erythrocytes and endothelial cells
