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?
- Membrane potential the potential gradient that forces ions to passively move in 1 direction
What is the resting membrane potential in the cells of the atrium and ventricles?
- 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
What are the 5 phases of the cardiomyocyte 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?
The threshold potential of the SA node pacemaker cells is around -40mV
What are the 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
the spontaneous electrical discharge of the SAN is from a combined effect of what?
- decrease in K flow
- “funny” Na current
- slow inward Ca current
what type of channels are Na and Ca channels?
Na channels = fast acting channels
Ca channels = slow nodal conducting channels
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?
- An arrhythmia describes conditions where the co-ordinated sequence of electrical activity in the heart is disrupted
What 3 things can arrhythmias 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?
- 3 ways arrythmias be classified based on site or origin of abnormality:
1) Atrial (supraventricular)
2) Junctional (associated with the AV node)
3) Ventricular
What are the 2 different types of arrhythmias associated with rhythm?
- 2 different types of arrhythmias associated with rhythm:
1) Tachycardia
2) Bradycardia
what are the 4 ways arrhythmias can be classified?
- ectopic pacemaker activity
- delayed after depolarisations
- circus re entry
- heart block
how many classes of antidysrythmIc drugs are there?
5
1- has a,b,c (all sodium channel blockers)
2 = beta adrenoreceptor blocker, sotalol
3= potassium channel blocker (amiodarone)
4 = calcium channel blockers (verapamil)
unclassified = adenosine ad digoxin
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 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?
- 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.
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 Class 4 antiarrhythmics?
What are 2 example of Class 4 antiarrhythmics?
- Class 4 antiarrhythmics are Calcium channel blockers
- 2 example of Class 4 antiarrhythmics:
1) Verapamil
2) Diltiazem
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?
- 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
What is digoxin?
Where does this family of compound come from?
What does digoxin do?
What is Parasympathomimetics?
How is this linked to digoxin?
- 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
