Arrhythmias and Anti-Arrhythmic Drugs Flashcards
Where do electrical impulses of the heart originate and where do they travel?
SA node is the normal pacemaker for the hear and over-rides other pacemaker activity, normally (OVER-DRIVE SUPPRESSION)
AP spreads through the atria, via anterior, posterior and middle inter-nodal pathways
Impulse arrives at the AV node (allowing a delay for ventricular filling)
Impulse travels down Bundle of His in right and left branches and then into the Purkinje fibres, to spread through the ventricles
Label the regions of the heart, inc. the nodes, inter-nodal pathways, bundles and the fibres
2 classifications and sub-types of electrical dysfunction in the heart?
Defects in IMPULSE FORMATION (give rise to either missed or ectopic beats):
Altered automaticity - SA node automaticity is interrupted
Triggered activity - altered activity
Defects in IMPULSE CONDUCTION:
Re-entry
Conduction block
Accessory tracts
Physiological alteration of automaticity (defect in impulse formation)?
Modulation of SA node activity by the ANS, e.g: sinus tachycardia, sinus arrhythmia (changes due to ventilation, e.g: taking a deep breath)
What is pathological alteration of automaticity?
LATENT PACEMAKER subverts the SA node’s function as the normal pacemaker of the heart (over-drive suppression is lost)
When can pathological alteration of automaticity occur?
If the SA node firing frequency is pathologically low (or when impulse conduction from the SA node is impaired), producing:
Escape beat - latent pacemaker initiates an impulse that occurs later than normal, due to delayed SA node firing
Escape rhythm - series of escape beats
If a latent pacemaker fires at a rate faster than the SA node rate, producing:
Ectopic beat - latent pacemaker initiates an impulse that occurs earlier than normal, due to increased automaticity of myocardial cell
Ectopic rhythm - series of ectopic beats
Causes of ectopic rhythm?
Ischaemia
Hypokalaemia
Increased sympathetic activity
Fibre stretch
What is triggered activity (defect in impulse formation)?
After-depolarisations are triggered by a normal action potential; there can be:
Early after-depolarisation (EAD) - often Purkinje fibres
Delayed after-depolarisation (DAD)
How does EAD occur?
Occurs during the inciting action potential within:
Phase 2 (terminal plateau) - after-depolarisation mediated by Ca2+ channels
Phase 3 (repolarisation) - after-depolarisation mediated by Na+ channels (instead of complete repolarisation, there is a depolarising swing)
Causes of EAD?
Associated with AP prolongation, e.g: sotalol which lengthens Ap by blocking voltage-activated K+ channels.
Drugs that prolong the QT interval
How does DAD occur?
Occurs after complete repolarisation and is associated with Ca2+ overload (opens channels for transient inward movement of Na+, causing depolarisation)
Causes of Ca2+ overload in cells?
Cathecholamines
Digoxin
Heart Failure
What is re-entry?
Self-sustaining electrical circuit that stimulates an area of myocardium repeatedly/rapidly
Describe this image
NORMAL pathway
Conduction pathway divides into branches 1 and 2, between which there is a non-excitable area
AP spreads down branches and again splits to supply heart; the other AP branches try to go around the non-excitable area and they collide (extinguishing each other, as the area behind is refractory and cannot be excited)
Describe this image
ABNORMAL pathway - produces self-sustaining electrical circuit (re-entry): AP, in this image, cannot go down normal branch 2, e.g: it may be ischaemic, so the whole AP goes down branch 1
AP goes in the wrong direction and conducts slowly (from b to a); this mean that branch 1 will have recovered and will no longer be refractory in the next round.
So, conduction can go down branch 1 again without a new impulse - “circus movement”
Requirements for a re-entrant circuit?
Unidirectional block - to prohibit anterograde conduction and allow retrograde conduction
Slowed retrograde conduction velocity
Classifications of conduction block?
May be partial or complete
Partial block:
First-degree block
Second-degree block: Mobitz Type 1 OR Mobitz Type 2
Complete block
What is first degree block?
There is SLOWED CONDUCTION - tissue conducts all impulses but more slowly than usual
There is a LONG PR INTERVAL
What is second degree block and explain the types?
Intermittent block - tissue conducts some impulses but not others:
Mobitz Type 1 - PR interval GRADUALLY INCREASES from cycle to cycle, until AV node fails completely and a QRS complex is MISSING (a ventricular beat)
Mobitz Type 2 - PR interval is CONSTANT but every nth (in variable proportions), a ventricular depolarisation (QRS complex) is MISSING, e.g: 3:1 (3 APs but only 1 gets through)
What is complete block?
No impulses are conducted through the affected area, e.g: third-degree AV block, and the atria and ventricles BEAT INDEPENDENTLY, governed by their own pacemakers (for the ventricles, this is the Purkinje fibres)
Purkinje fibres fire relatively slowly and unreliably - so, bradycardia and low CO
What are accessory tract pathways?
Normally, the AV node is the only point of electrical contact between the atria and ventricles
But some individuals possess electrical pathways that bypass the AV node - a common pathway is the BUNDLE OF KENT
Describe AP conduction in the Bundle of Kent
Impulse through here is conducted more quickly than that through the atria
Ventricles receive impulses from both the normal and accessory pathways - can set up the condition for a RE-ENTRANT LOOP, predisposing to tachyarrhythmias
What do anti-arrhythmic drugs do?
Generally, inhibit specific ion channels with the intention of suppressing abnormal electrical acitivity
Classification of anti-arrhythmic drugs?
Classified PHARMACOLOGICALLY based upon their effects upon the cardiac action potential (Vaughn Williams classification):
Class I - Ia, Ib, Ic
Class II
Class III
Class IV
Flaws with the Vaughn Williams classification?
Many anti-arrhythmic agents are not entirely selective of Na+, K+, or Ca2+ channels, and may block more than one channel type, e.g: amiodarone (class III but affects many different channels)
Some drugs do not fit into the Vaughn Williams classification, e.g: adenosine, digoxin
Difference between class Ia, Ib and Ic?
Different in the rate at which they unbind from Na+ channels
Action of class Ia drugs?
Target: Voltage-activated Na+ channels
Associate with and dissociate from Na+ channels at a moderate rate - prolong repolarisation
Slow rate of rise of AP and a prolonged refractory period
Action of class Ib drugs?
Target: Voltage-activated Na+ channel
Associate with and dissociate from Na+ channels at a RAPID RATE (shortened repolarisation)- prevent premature beats
Action of class Ic drugs?
Target: Voltage-activated Na+ channel
Associate and dissociate from Na+ channels at a SLOW RATE (no change in repolarisation)
Depress conduction
Action of class II drugs?
Target: β-adrenoceptor (as antagonists), i.e: β-blockers
Decrease rate of depolarisation in SA and AV nodes
Action of class III drugs?
Target: Voltage-activated K+ channels (plus others)
Prolong AP duration to increase refractory period
Action of class IV drugs?
Target: Voltage-activated Ca2+ channels
Slow conduction in SA and AV nodes
Decrease force of cardiac contraction
An example of each class of anti-arrhythmic drug?
Class Ia: Disopyramide
Class Ib: Lignocaine
Class Ic: Flecainide
Class II: Metoprolol
Class III: Amiodarone
Class IV: Verapamil
States of Na+ channels?
Open (conducting), inactivated (non-conducting) and resting (non-conducting) states
Depolarising influence causes Na+ channels to open rapidly, from resting. But, if influence continues, channel inactivate and repolarisation (to take the channel to resting state) must occur before the channels can open again
How do Class I agents not kill someone by blocking Na+ channels?
Class I agents block voltage-activated Na+ channels in a use-dependent manner
During high frequency firing, e.g: tachyarrhythmias, Na+ channels spend relatively more time in the open and inactivated states
Class I agents bind preferentially to these, targeting areas of the myocardium in which firing frequency is highest, in a use-dependent manner
They block open state and stabilise inactivated state
When do Class I agents dissociate from Na+ channels?
When it is in the resting state, i.e: during diastole
Steady state block production with Class I agents?
If HR increases, less time is available for unblocking (dissociation) and more time is available for associate (blocking)
Steady state block increases, part. for agents with slow dissociation rates
Feature of myocytes in ischaemic myocardium?
Myocytes are partially depolarised and the action potential is of longer duration, thus:
Inactivated state of the Na+ channel is available to Na+ channel blockers for a greater period of time
Rate of channel recovery from the block is decreased
Why do Class I agents act preferentially on ischaemic tissue?
Higher affinity of Na+ channel blockers for the open and inactivated states of the channel allows them to act preferentially on ischaemic tissue and block an arrhythmogenic focus at its source
Site-based classification of anti-arrhythmic drugs?
Atria (rate control of supre-ventricular tachycardia -SVT) - classes IC and III
Ventricles - classes IA, IB and II
AV node (rhythm control of SVT) - adenosine, digoxin, classes II, IV
Atria and ventricles, AV accessory pathways - amiodarone, sotalol, classes IA, IC
What classes and drugs are used for rhythm control?
Class I, e.g: flecainide, propaferone Class III, e.g: amiodarone, sotalol
What classes and drugs are used for rate control?
Class II, e.g: propranolol, atenolol Class IV, e.g: verapamil, diltiazem
Which drugs are used for supraventricular arrhythmias?
Adenosine (IV bolus)
Digoxin (IV infusion or oral)
Verapamil (Oral)
Mechanism of action of adenosine and uses?
Activates α1-adenosine receptors coupled to Gi/o:
Opens ACh-sensitive K+ channels (GIRK)
Hyperpolarises the AV node briefly, suppressing impulse conduction
Used to terminate paroxysmal supra-ventricular tachcardia (PSVT) - caused by re-entry involving the AV node, SA node, or atrial tissue
Decreases slope of pacemaker potential
Mechanism of action of digoxin and uses?
Slows conduction and prolongs refractory period in AV node and bundle of His
Used to treat AF - chaotic re-entrant impulse conduction through the atrium (could be conducted to ventricles)
Mechanism of action of verapamil and uses?
Class IV agent that blocks L-type voltage-activated Ca2+ channels:
Slows conduction and prolongs refractory period in AV node and bundle of His
Used to treat atrial flutter and fibrillation
Cautions with verapamil?
In high doses, may cause heart block
Should be used with great caution in combination with other drugs that have a negative inotropic effect
Largely replaced by adenosine for acute treatment but it is still used for prophylaxis
Drugs used in ventricular arrhythmias?
Lignocaine (Class Ib agent) - RAPID block of voltage-activated Na+ channels: Blocks inactivated channels with little effect on open channels
Due to rapid unblocking, primarily affect Na+ channels in areas of the myocardium that discharge action potentials at high rate, e.g: an ischaemic zone
Mainly IV in treatment of ventricular arrhythmias following an MI
Drugs used in atrial and ventricular arrhythmias?
Disopyramide and procainamide (Type Ia agents)
Flecainide (Type Ic agent)
Propranolol and atenolol (Type II agents, β-blockers)
Amiodarone and sotolol (Type III agents)
Mechanism of action of disopyramide and procainamide?
Moderate rate of block and unblock of voltage-activated Na+ channels: Blocks open channels and are thus use-dependent
Moderate rate of dissociation results in insufficient time for unblocking if AP frequency is high
Disopyramide is used (orally) to prevent recurrent ventricular arrhythmias, procainamide (IV) to treat ventricular arrhythmias following myocardial infarction
Mechanism of action of flecainide?
Slow rate of block and unblock of voltage-activated Na+ channels:
Strongly depresses conduction in the myocardium and reduces contractility
Mainly used for prophylaxis of paroxysmal atrial fibrillation
Has negative ionotropic action and may trigger serious ventricular arrhythmias
Mechanism of action of propranolol and atenolol?
Control SVT by suppressing impulse conduction through the AV node
Suppress excessive sympathetic drive that may trigger VT
Mechanism of action of amiodarone and sotolol?
Slow repolarization of the AP by block of voltage-activated K+ channels and hence increase action potential duration and the effective refractory period: Supress re-entry
Amiodarone is effective against SVT and VT, probably because it also has class IA, II and IV actions and also blocks β-adrenoceptors
Amiodarone is effective when many other drugs have failed and reduces mortality after MI and in congestive heart failure
However, long term use is compromised by many, serious, adverse effects that include:
Pulmonary fibrosis
Thyroid disorders
Photosensitivity reactions
Peripheral neuropathy
