05-10-22 - Pharmacological Treatment of Dysrhythmias Flashcards
Learning outcomes
- understand the Vaughan Williams classification of anti-dysrhythmic drugs
- recognise that some drugs are unclassified on this scheme
- know the mechanism of action, and uses of the Class I group of drugs
- recognise the term ““use-dependent”” block
- understand the mechanism of action, and uses of the Class II group of drugs
- know the mechanism of action, and uses of the Class III group of drugs
- understand the mechanism of action, and uses of the Class IV group of drugs
- know the mechanisms of action, and uses of the unclassified drugs
What does membrane potential mean?
What is the resting membrane potential in the cells of the atrium and ventricles?
What are the 5 phases of the cardiomyocyte action potential?
- Membrane potential the potential gradient that forces ions to passively move in 1 direction
- The resting membrane potential in the cells of the atria is typically -65 to -80millivolts (mV)
- The resting membrane potential in the cells of the ventricles is typically -80 to -90mV
- This means the inside of the cells are more negative, so positive ions will want to flow inside
- 5 phases of the atrial/ventricular action potential:
1) Phase 0
* Rapid depolarisation due to increase in Na+ permeability (gNa+) as fast Na+ channels open
2) Phase 1
* Start of repolarisation as fast Na+ channels close
3) Phase 2
* Effect of Ca2+ entry via L-type Dihydropyridine channels
* Calcium coming in from L-type channels can allow channels on the Sarcoplasmic Reticulum to release calcium in a process called calcium induced calcium release
4) Phase 3
* Rapid repolarisation as the in intracellular calcium stimulates K+ channels to open, causing K+ permeability to increase
* Ca2+ L-type channels close
5) Phase 4
* Stable resting membrane potential where gK+ exceeds gNa+ by 50:1
What is the threshold potential of the SA node pacemaker cells?
What are the phases of SA node depolarisation/action potential?
- The threshold potential of the SA node pacemaker cells is around -40mV
- Phases of SA node depolarisation/action potential:
1) Phase 1
* Gradual drift increases in resting membrane potential due to an increase in gNa+ as F-type (funny type) Na+ channels open (opposite to how regular voltage gated sodium channel’s function)
* This is known as the pacemaker potential, which is the slow, positive increase in voltage across the cell’s membrane that occurs between the end of one action potential and the beginning of the next action potential
* As the we get closer to the threshold frequency of the SA node (-40mV), the more likely the F-type Na+ channels are to close
* Transient (T) Ca2+ channels help with the final push towards the threshold potential
* There is also a decrease in gK+ as K+ channels slowly close
* As the potassium tries to repolarise the cell after an action potential, this increases the permeability of the F-type Na+ channels
2) Phase 2
* Moderately rapid depolarisation due to Ca2+ entry via slow (L) channels
3) Phase 3
* Rapid repolarisation as elevated internal Ca2+ stimulates the opening of K+ channels, which leads to an increase in gK+
- We have heart cells that never have a stable resting membrane potential and are constantly oscillating, triggering action potentials, and resetting
- The rate of this is the intrinsic heart rate
How does the Action Potential of the SA node fit over an ECG?
- How does the Action Potential of the SA node fit over an ECG?
What is an Arrhythmia?
What 3 things can arrhythmias be due to?
- An arrhythmia describes conditions where the co-ordinated sequence of electrical activity in the heart is disrupted
- Arrhythmias can be due to:
1) Changes in the heart cells e.g scarred tissue from MI can cause the heart muscle to stiffen
2) Changes in the conduction of the impulse through the heart
3) Combinations of these
What 3 ways can arrhythmias be classified based on site or origin of abnormality?
What are the 2 different types of arrhythmias associated with rhythm?
- 3 ways arrythmias be classified based on site or origin of abnormality:
1) Atrial (supraventricular)
2) Junctional (associated with the AV node)
3) Ventricular - 2 different types of arrhythmias associated with rhythm:
1) Tachycardia
2) Bradycardia
What 4 ways can arrhythmias be generally classified?
- 4 ways can arrhythmias be generally classified:
1) Ectopic pacemaker activity
* The other areas of the conduction system start setting their own rhythm
* This leads to the firing of action potentials when they shouldn’t occur
2) Delayed after-depolarisations
* Due to prolonged elevated calcium
* Calcium tries to get extruded through the Na+ and Ca2+ exchanger
* This leads to too much Sodium moving into the cell, which can cause depolarisation, and an action potential to be generated when it shouldn’t be
3) Circus re-entry
* Block causes electrical signal to re-circulate, which will excite tissues more
4) Heart block
* Prevents signals from passing down conduction pathway
What are the 7 different classes of Antidysrhythmic drugs in the Vaughan Williams system?
What is an example of each type?
Which phases of the cardiac AP do they each affect?
- 7 different classes of Antidysrhythmic drugs in the Vaughan Williams system:
1) 1a: -Sodium channel blockers, disopyramide (class 1 affects phase 0 of Cardiomyocyte AP, 1a also affects phase 3)
2) 1b: -Sodium channel blockers, lignocaine
3) 1c: -Sodium channel blockers, flecainide
4) 2: -b-adrenoreceptor blockers, sotalol (Affects phase 2 and 4 of Cardiomyocyte AP)
5) 3: -Potassium channel block, amiodarone (Affects phase 3 of Cardiomyocyte AP )
6) 4: -Calcium channel blockers, verapamil (Affects phase 2 of Cardiomyocyte AP )
7) Unclassified: adenosine and digoxin
What are class 1 of Antidysrhythmic drugs?
What do they bind to?
What is a use dependent drug?
How does use dependency affect the effectiveness of the drug?
What are the 3 different types of Class A drug?
What effects do these class 1 drugs have on the AP of the cardiomyocyte?
What does depolarisation do to channels?
What does maintained depolarisation cause?
What must cardiomyocytes must do to get back to resting state?
When will the Class 1 drugs work for effectively?
What will this allow them to prevent?
- Class 1 of Antidysrhythmic drugs are Na+ channel blockers
- A use dependent drug is a drug that binds to a channel when in a particular state e.g open, refractory (inactive), or resting (closed)
- Use dependent drugs work more effectively if there is high activity i.e in this case, more effective if there are more open/refractory voltage-gated Na+ channels to bind to
- Class 1 drugs bind to the domains of voltage-gated sodium channels when in an open/refractory state, which makes them use dependent
- Class 1 drugs can be divided into a, b, and c, depending on the properties of the drug
- Class 1 drugs Inhibit action potential propagation and reduce the rate of cardiac depolarisation during phase 0 in cardiomyocytes, as sodium drives this depolarisation
- Depolarisation switches channels from resting to open states - known as activation
- Maintained depolarisation causes the channels to move to a refractory state - known as inactivation, before moving to a resting state
- Cardiac myocytes must repolarise to reset the sodium channels back to resting state.
- These drugs bind to the open and refractory states of the channels and so are viewed as use-dependent i.e. work more effectively if there is high activity and so are more effective against abnormal high frequency activity and not so much against normal beating rates.
- This will mean they are more effective against high frequency activity, with little effect on normal bpm
What is an example of a class 1a, 1b, 1c drug?
What 2 things can class 1a drugs be used for?
What 2 things can class 1b drugs be used for?
What 3 things can class 1c drugs be used for?
- Class 1 drugs:
1) Class 1a drugs
* An example is disopyramide
* Can be used for:
1) Ventricular dysrhythmias
2) Prevention of recurrent atrial fibrillation triggered by vagal over activity
2) Class 1b drugs
* Example is Lignocaine
* Can be used for:
1) Treatment and prevention of ventricular tachycardia
2) Ventricular fibrillation during and immediately after MI
3) Class 1c drugs
* Example is Flecainide
* Can be used for:
1) Suppressing ventricular ectopic beats
2) Preventing paroxysmal atrial fibrillation
3) Preventing recurrent tachycardias associated with abnormal conducting pathways
What type of drugs are class 2 antiarrhythmics?
Describe the 7 steps in the mechanism of Class 2 antiarrhythmics?
- Class 2 antiarrhythmics are Beta Blockers
- Steps in the mechanism of Class 2 antiarrhythmics:
1) Beta 1 and Beta 2 receptors are GPCRs which can be linked to different subtypes (Gs for stimulatory, Gi for inhibitory, and Go, in this case it is the Gs subtype)
2) When catecholamines bind to the GPCR, this stimulates AC (adenylyl cyclase)
3) AC converts ATP to cAMP
4) cAMP activates the kinase PKA
5) PKA phosphorylates calcium channels on the sarcoplasm and SR
6) This increases the activity of the channel
7) When class 2 antiarrhythmics are used, this blocks with pathway, which can slow the heart and decrease cardiac output
What are Class 2 antiarrhythmics?
What 2 things does B1 receptor activation cause?
What 2 things does B1 receptor blocking cause?
How does sympathetic drive link to arrhythmias?
How can we decrease their occurrence?
What are 3 examples of Class 2 antiarrhythmics?
What are the 2 clinical uses of these drugs?
- Class 2 antiarrhythmics are beta blockers
- B1 receptor activation:
1) Increases the rate of depolarisation of the pacemaker cells
2) Enhances calcium entry in phase 2 of the cardiac action potential - B1 receptors blocking:
1) Decreases the rate of depolarisation of pacemaker cells, slowing the heart rate and decreasing cardiac output
2) Increases the refractory period of the AV node which prevent recurrent attacks of supraventricular tachycardias - Increased sympathetic drive and influence tend to promote arrhythmias and so
- Attenuating their influence will slow the heart and decrease their occurrence.
- 3 examples of Class 2 antiarrhythmics:
1) Sotalol (class 2 and 3)
2) Bisoprolol
3) Atenolol - 2 clinical uses of these drugs:
1) Reduce mortality following MI
2) Prevent recurrence of supratachycardias provoked by increased sympathetic activity
What are Class 3 antiarrhythmics?
What effect does this have on cardiomyocyte action potential?
What is an example of a Class 3 antiarrhythmics?
- Class 3 antiarrhythmics are potassium channel blockers
- They prolong the cardiac action potential by prolonging repolarisation
- A prolonged repolarisation prevents another AP from firing by keeping the tissue in are refractory state
- An example of a Class 3 antiarrhythmics is amiodarone
What are 2 examples of Class 3 antiarrhythmics?
What 3 things can amiodarone be used for?
What is WPW syndrome?
What 3 thing is Sotalol used for?
examples of Class 3 antiarrhythmics are Amiodarone and Solatol:
1) Amiodarone
* Used for:
1) Tachycardia associated with the Wolff-Parkinson-White syndrome
* Wolff-Parkinson-White syndrome is a heart condition featuring episodes of an abnormally fast heart rate.
* Episodes can last for seconds, minutes, hours or (in rare cases) days. They may occur regularly, once or twice a week, or just once in a while.
2) Some supraventricular tachyarrhythmias
3) Some ventricular tachyarrhythmias
2) Solatol
* Combines class 3 with class 2 actions
* Used in:
1) Supraventricular dysrhythmias
2) Suppression of ventricular ectopic beats
3) Short runs of ventricular tachycardia.
What are Class 4 antiarrhythmics?
What are 2 example of Class 4 antiarrhythmics?
What 3 effects on cardiomyocyte APs do Class 4 antiarrhythmics have?
- Class 4 antiarrhythmics are Calcium channel blockers
- 2 example of Class 4 antiarrhythmics:
1) Verapamil
2) Diltiazem - 3 effects on cardiomyocyte APs Class 4 antiarrhythmics have:
1) Blocks cardiac voltage gated L-type calcium channels.
2) Slow conduction through the SA and AV nodes where the conduction of the AP relies on the slow calcium (L-type) currents.
3) Shortens the plateau of the cardiac AP and reduces the force of contraction of the heart by preventing CICR (calcium induced calcium release) due to low levels of intracellular calcium
What are the 7 different classes of Antidysrhythmic drugs in the Vaughan Williams system?
What is an example of each type?
Which phases of the cardiac AP do they each affect?
- 7 different classes of Antidysrhythmic drugs in the Vaughan Williams system:
1) 1a: -Sodium channel blockers, disopyramide (class 1 affects phase 0 of Cardiomyocyte AP, 1a also affects phase 3)
2) 1b: -Sodium channel blockers, lignocaine
3) 1c: -Sodium channel blockers, flecainide
4) 2: -b-adrenoreceptor blockers, sotalol (Affects phase 2 and 4 of Cardiomyocyte AP)
5) 3: -Potassium channel block, amiodarone (Affects phase 3 of Cardiomyocyte AP )
6) 4: -Calcium channel blockers, verapamil (Affects phase 2 of Cardiomyocyte AP )
7) Unclassified: adenosine and digoxin
Where is adenosine produced?
What 5 things does adenosine have an effect on?
What condition is adenosine used for?
Describe the 7 Steps in the adenosine’s mechanism for correcting arrhythmias
- Adenosine is produced endogenously (in the body)
- Adenosine has an effect on:
1) Breathing
2) Cardiac
3) Smooth muscle
4) Vagal afferent nerves
5) Platelets - Adenosine is used for terminating SVTs
- 7 Steps in the adenosine’s mechanism for correcting arrhythmias:
1) Adenosine binds to AT1 receptors, which are responsible for the effect on the AV node.
2) The AT1 receptors are GPCRs linked to Gi (inhibitory subunit) and Go
3) The Go subunits can affect K+ channel activity, which can slow HR by prolonging refractory period by prolonging hyperpolarisation (as potassium moves out to repolarise and reset resting potential)
- These receptors are linked to the same cardiac potassium channels that are activated by ACh (main neurotransmitter used in parasympathetics)
4) The Gi subunits can inhibit adenylate cyclase
5) Adenylate cyclase will not convert ATP to cAMP
6) cAMP won activate protein kinase, meaning Calcium channels won’t get phosphorylated and activated
7) In the AV node, it is calcium that drive depolarisation, so these mechanisms this will result in decreased conduction through nodal tissue, and a decreased heart rate
What is digoxin?
Where does this family of compound come from?
What does digoxin do?
What is Parasympathomimetics?
How is this linked to digoxin?
What 2 effects does Digoxin have on the electrical activity of the heart?
What do toxic concentrations of digoxin do?
Describe the 3 steps in this mechanism
- Digoxin is a cardiac glycoside, which are a family of compounds that are derived from the foxglove plant (Digitalis purpurea).
- Increases vagal efferent activity to the heart (by unknown mechanism)
- Parasympathomimetics are a class of medications that activate the parasympathetic nervous system by mimicking or modifying the effects of acetylcholine (main neurotransmitter in parasympathetics)
- Digoxin is a Parasympathomimetic
- 2 effects Digoxin has on the electrical activity of the heart:
1) Reduces sinoatrial firing rate (decreases heart rate)
2) Reduces conduction velocity of electrical impulses through the atrioventricular node - Toxic concentrations of digoxin disturb sinus rhythm by producing ectopic beats
- 3 Steps in this mechanism:
1) Usually, ectopic beats are prevented by pumping sodium out and potassium into SA node cells through the Na+/K+ ATPase
2) Toxic concentrations of Digoxin inhibit the ATPase
3) This leads to the accumulation of Na+ in the cell, which can cause depolarisation that leads to an ectopic heart beat
