Pharmacological Treatment of Dysrhythmias Flashcards
(34 cards)
Describe the Vaughan Williams classification of anti-dysrhythmic drugs.
- 1a: -Sodium channel blockers, disopyramide
- 1b: -Sodium channel blockers, lignocaine
- 1c: -Sodium channel blockers, flecainide
- 2: -b-adrenoreceptor blockers, sotalol
- 3: -Potassium channel block, amiodarone
- 4: -Calcium channel blockers, verapamil
- Unclassified: adenosine and digoxin
where: Class 1 = Sodium Channel Blockers Class 2 = Beta Blockers Class 3 = Potassium Channel Blockers Class 4 = Calcium Channel Blockers
Explain the mechanism of action of Class I anti-dysrhythmic drugs.
- Inhibit action potential propagation and reduce the rate of cardiac depolarisation during phase 0.
- 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. Cardiac myocytes must repolarise to reset the sodium channels back to resting state.
- These drugs bind to the open and refractory states of voltage gated Sodium channels (from the intracellular side of the channel) 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.
What is the difference between class Ia, Ib, and Ic ?
Subdivision to class a, b and c is based on the properties of the drugs in binding to sodium channels in their various states such as open, refractory and resting.
Where on the channels do class I anti-dysrhythmic drugs bind ?
On the drug binding domains of voltage-gated sodium channels.
Give an example of class I anti-dysrhythmic drugs.
1a: disopyramide
1b: lignocaine
1c: flecainide
Describe some clinical uses of class I anti-dysrhythmic drugs.
Class 1a. Disopyramide (resembles quinidine)
• Ventricular dysrhythmias, prevention of recurrent atrial fibrillation triggered by vagal over activity.
Class 1b. Lignocaine (given by IV)
• Treatment and prevention of ventricular tachycardia and fibrillation during and immediately after MI.
Class 1c. Flecainide
• Suppresses ventricular ectopic beats. Prevents paroxysmal atrial fibrillation and recurrent tachycardias associated with abnormal conducting pathways.
Explain the mechanism of action of Class 2 anti-dysrhythmic drugs.
- Block b-1 receptors slow the heart and decrease cardiac output.
- b-1 receptor activation increases the rate of depolarisation of the pacemaker cells so blocking them decreases this.
- b-1 receptor activation enhances calcium entry in phase 2 of the cardiac action potential so blocking them reduces this.
- b-blockers increase the refractory period of the AV node so prevent recurrent attacks of supraventricular tachycardias.
- Basically increased sympathetic drive and influence tend to promote dysrhythmias and so attenuating their influence will slow the heart and decrease their occurrence.
Give an example of class 2 anti-dysrhythmic drugs.
Sotalol, bisoprolol, atenolol
Describe some clinical uses of class 2 anti-dysrhythmic drugs.
Sotalol, bisoprolol, atenolol. Clinical uses are to reduce mortality following MI and to prevent recurrence of tachycardias provoked by increased sympathetic activity.
Explain the signal transduction pathway of β adrenoceptors, and hence explain how beta blockers have an effect on dysrythmias.
Beta adrenoreceptor is a G protein coupled receptor. The stimualtory Gs protein it is coupled with can increase activity of effector molecule (Adenylate Cyclate). AC can in turn increase production of cAMP, which is a substrate for the enzyme PKA. PKA causes phosphorylation of calcium channels, which results in their increased activity. By blocking this pathway using beta blockers, we are effectively decreasing the activity
of calcium channels, which is especially important for nodal tissue where calcium is the ion driving the depolarisation (rather than sodium).
Explain the mechanism of action of Class 3 anti-dysrhythmic drugs.
- prolongs the cardiac action potential by prolonging the refractory period (delays repolarisation by blocking potassium channels)
- Drug gets from extracellular space to cytosol, at which point the activation gate opens, and the drug enters the vestibule. Closing of the gate traps the drug. Channel inactivation stabilizes drug binding.
Give examples of Class 3 anti-dysrhythmic drugs.
- Amiodarone, tachycardia associated with the Wolff- Parkinson-White syndrome. The combination of Wolff-Parkinson-White syndrome and atrial fibrillation can be life-threatening.
- Amiodarone is also effective in many other supreventricular and ventricular tachyarrhythmias.
- Sotalol combines class 3 with class 2 actions. It is used in supraventricular dysrhythmias and suppresses ventricular ectopic beats and short runs of ventricular tachycardia.
Define 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.
Describe the mechanism of action of Class 4 drugs.
- Blocks cardiac voltage- gated L-type calcium channels.
- Slow conduction through the SA and AV nodes where the conduction of the AP relies on the slow calcium currents.
- They shorten the plateau of the cardiac AP and reduce the force of contraction of the heart.
Give examples of Class 4 drugs.
Verapamil and diltiazem.
Illustrate, in graphical fashion, the effect of a class 3 drug on a ventricular AP.
Refer to slide page 15 in lecture on “Pharmacological Treatment of Dysrhythmias”
Illustrate, in graphical fashion, the effect of a class 4 drug on a ventricular AP.
Refer to slide page 17 in lecture on “Pharmacological Treatment of Dysrhythmias”
Describe the clinical uses of class 4 drugs.
- Verapamil is used to prevent recurrence of supraventricular tachycardias (SVTs) + to reduce the ventricular rate in patients with atrial fibrillation provided they do not have Wolff-Parkinson-White syndrome BUT IT IS INEFFECTIVE AND DANGEROUS in ventricular dysrhythmias.
- Diltiazem is similar to verapamil but has more effect on smooth muscle calcium channels and has less bradychardia.
Identify the main phases of a cardiac AP.
Phase 0: Rapid depolarisation Phase 1: Partial repolarisation Phase 2: Plateau Phase 3: Repolarisation Phase 4: Pacemaker potential
What ions drive the different phases of a cardiac AP ?
Phase 0- Sodium channels Phase 1- Potassium channels Phase 2- Calcium channels (and Potassium channels) Phase 3- Potassium channels Phase 4- Potassium channels
Will the AP profile be the same depending on where along the conduction pathway you are taking the measurement from ?
No, AP profile is different dependent on which part of the conduction pathway you are looking at.
Briefly state where each class of anti-dysrhythmic drug will act along the cardiac AP.
Class 1: (decreases) Phase 0
Class 2: (decrease) phases 2 and (decreases slope of) phase 4
Class 3 (and 1a): (decreases) Phase 3
Class 4: (decreases) Phase 2
Identify two unclassified anti-dysrhythmic drugs.
Adenosine and Digoxin
Describe the mechanism of action of Adenosine.
- Adenosine outside the cell binds to A1 receptor (receptor responsible for the effect on the AV node). A1 receptor is coupled with Gi (inhibitory) and Go (other) proteins. Upon adenosine binding, the Gi protein will result in inhibition of Adenylate Cyclase which will in turn reduce production of cAMP. This will in turn reduce phosphorylation and thereby activity of Calcium channels. Since these channels drive depolarisation of nodal tissue, blocking them will slow the pacemaker potential down.
- These receptors are linked to the same cardiac potassium channels that are activated by ACh. and so it hyperpolarises cardiac conducting tissue (by opening Potassium channels) and slows the heart rate. It decreases pacemaker activity.
