How can an arrhythmia occur?
To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity
Relaxation must occur between contractions (not true for other types of muscle [skeletal muscle exhibits tetany => contracts and hold contraction for certain length of time])
Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues.
Arrhythmias: heart condition where disturbances in
Pacemaker impulse formation
Contraction impulse conduction
Combination of the two
This results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO).
Describe how arrhythmias can affect the cardiac cycle and explain about atrial and ventricular arrhythmias
Cardiac arrhythmias can affect the cardiac cycle by being too fast (e.g. atrial fibrillation, AV re-entry tachycardia, ventricular tachycardia or Torsades de Pointes) or too slow (e.g. Sinus Bradycardia or 1o-3o heart block). Cardiac arrhythmias can be caused due to enhanced automaticity, delayed after-depolarisations, early after-depolarisation or re-entry circuits.
In atrial arrhythmias such as in atrial fibrillation, there is chaotic activity in the atria. The sinoatrial node is ‘switched off’.
Ventricular arrhythmias are common in most people and are usually not a problem but they are the most common cause of sudden death
- Ventricular arrhythmias are the most common cause of sudden death.
- Majority of sudden death occurs in people with neither a previously known heart disease nor history of ventricular arrhythmias.
- ECG shows abnormal ectopic beat (could be a sign of automaticity or scar tissue formation after an MI). The depolarisations could be too early or too late.
Describe the electrophysiology of the cardiac action potential. What would you seen on a normal ECG?
A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell.
Caused by unequal distribution of ions inside vs outside cell
- Na+ higher outside than inside cell
- Ca2+ much higher outside than inside cell
- K+ higher inside cell than outside
Maintenance by ion selective channels, active pumps and exchangers (can be passive, ligand-gated or voltage-gated)
Describe the four phases of the fast cardiac action potential
Phase 0: rapid Na+ influx through open fast Na+ channels
Phase 1: Transient K+ channels open and K+ efflux returns transmembrane potential to 0mV
Phase 2: Influx of Ca2+ through L-type Ca2+ channels is extremely balanced by K+ efflux through delayed rectifier K+ channels
Phase 3: Ca2+ channels close but delayed rectifier K+ channels remain open and return transmembrane potential to -90mV
Phase 4: Na+, Ca2+ channels closed, open K+ rectifier channels keep trans membrane potential stable at -90mV
What are the effects of blocking Na+ channels?
Marked slowing conduction in tissue (phase 0) – slope is shifted to the right
Minor effects on action potential duration
Sodium Channel Blockers: They will bind to the sodium channels (same as local anaesthetics) and inhibit the action potential propagation in the cardiac myocytes, thus affecting myocytes in the phase 0 of depolarisation. They can be further further classified into 1a, 1b and 1c depending upon their rate dissociation from the channels (intermediate, fast and slow respectively)
What are the effects of beta-blockers?
Diminish Phase 4 depolarisation and automaticity
Minor effect on Phase 2
What are the effects of blocking K+ channels?
Increase action potential duration – extension of Phase 3
Class III agents: Amiodarone, Sotalol, ibutilide, dofetilide
They block outward K+ channels thus affect phase 3 of the cardiac action potential, increasing the action potential periods and thus suppressing re-entry circuits by closing excitable gaps (rhythm control)
What are the effects of blocking Ca2+ channels?
Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarisation
Effect plateau phase of action potential
Not a big change in AP duration
Also slow down conduction velocity
Describe the effect of Ca2+ channel on the pacemaker action potential
What are the drugs that affect automaticity?
Arrythmia Mechanisms: what could abnormal impulse generations be due to?
Abnormal impulse generation: could be due to
Automatic rhythms (could be due to)
- Enhanced normal automaticity (increased Action Potential from SA node) OR
- Ectopic focus (AP arises from sites other than SA node e.g. abnormal electrical conduction due to ventricular ectopic foci)
Triggered rhythms (could be due to)
Explain about afterdepolarisations
Delayed afterdepolarisation (arises from the resting potential) occur in late phase 3 or early phase 4 when the AP is nearly or fully repolarised. The mechanism is poorly understood however is associated high intracellular Ca2+ concentrations. The triggered impulse can lead to a series of rapid depolarisation e.g. a tachyarrhythmia.
Early aftepolarisation (arises from the plateau)- occur during late phase 2 or phase 3 and can lead to a salvo of several rapid action potentials or a prolonged series of APs.
NB: afterdepolarisations are triggered by a preceding action potential and can result in either atrial or ventricular tachycardia. They occur either during phase 3 or phase 4. Triggered activity is more likely to occur when the AP duration is abnormally long such as in long Q-T syndrome and drugs that prolong the AP duration e.g. potassium-channel blockers can sometimes precipitate triggered activity.
Arrythmia Mechanisms: what could abnormal conduction be due to?
. Abnormal conduction could be due to Conduction block (this is when the impulse is not conducted from the atria to the ventricles) or due to Reentry
Conduction block (could be due to)
- 1st degree
- 2nd degree
- 3rd degree
Reentry (most common arrhythmia mechanism)
- Circus movement
- Reflection (2 pathways for rhythm to go down; slow and fast). First pathway is blocked so the impulse from this pathway travels in a retrograde fashion (backward) (2.). 3. The cells here will be re-excited (first by the original pathway and the other from the retrograde)
- The blockage could be due to an area of infarct leading to a re-entry loop developing.
What happens in Wolff-Parkinson-White Syndrome?
Abnormal Anatomic Conduction
Present only in small populations
Leads to excitation => Wolf-Parkinson-White Syndrome (WPW)
The accessory pathway here is called the bundle of Kent (abnormal accessory electrical conduction pathway between the atria and the ventricles). Electrical impulses stimulate the ventricles to contract prematurely, resulting in a unique type of supraventricular tachycardia referred to as an atrioventricular reciprocating tachycardia
Describe the pharmacological rationale behind antiarrhythmic drugs
Action of Drugs
- In case of abnormal generation: affect automatacity by affecting the slow action potential so decrease phase 4 slope (in pacemaker cells) and raise the threshold (so action potential is higher)
- In case of abnormal conduction: decrease conduction velocity (affect Phase 0) and increase effective refractory period (so the cell won’t be excited again)
Pharmacologic Rationale and Goals
- Restore normal sinus rhythm and conduction
- Prevent more serious and possibly lethal arrhythmias from occurring
- Antiarrhythmic drugs are used to:
- Decrease conduction velocity
- Change the duration of the effective refractory period (to try and stop extra beats)
- Suppress normal automaticity
Describe Sodium Channel Blockers: Class Ia
Absorption and elimination (oral or IV)
Effects on cardiac activity: intermediate binding offset kinetics
- Decrease conduction (decrease phase 0 of the action potential)
- Increase refractory period (increased action potential duration (K+) and increased Na inactivation)
- Decrease automaticity (decrease slow of phase 4, fast potentials)
- Increase threshold (Na+)
Quinidine has anticholinergic (atropine like action) to speed AV conduction used with digitalis, Beta-blocker or Ca2+ channel blocker. Quinidine is also an alpha receptor antagonist (need to be careful in people with hypertension or renal disease).
Effects on ECG: increased QRS, +/- PR, increased QT
Uses: wide spectrum
- Quinidine: maintain sinus rhythms in AF and flutter and to prevent recurrent tachycardia and fibrillation
- Procainamide: acute treatment of supraventricular and ventricular arrhythmias
Side effects: hypotension, reduced cardiac output, proarrhythmia (generation of a new arrhythmia e.g. Torsades de Points – increased QT interval), dizziness, confusion, insomnia, seizure (high dose), gastrointestinal effects (common), lupus-like syndrome (especially procainamide).
Describe Class Ib:
Lidocaine, mexiletine, phenytoin – no change in phase 0
Absorption and elimination
- Lidocaine: IV only
- Mexiletine: oral
Effects on cardiac activity: fast binding offset kinetics
- No change in phase 0 in normal tissue (no tonic block)
- AP duration slightly decreased (normal tissue)
- Increased threshold (Na+)
- Decreased phase 0 conduction in fast beating or ischaemic tissue
Effects on ECG: non in normal, in fast beating or ischaemic increased QRS
- Acute: ventricular tachycardia (especially during ischaemia)
- Not used in atrial arrhythmias or AV junctional arrhythmias
Side effects: less proarrhythmic than Class Ia (less QT effect) but CNS effects include dizziness and drowsiness. Lidocaine is rarely used due to significant adverse effects (contra-indications to HF, nystagmus and seizures)
Describe Class Ic
Flecainide, propafenone – marked phase 0
Absorption and elimination: oral or IV. Flecainide is well-absorbed orally, metabolised by CYP 2D6 ad eliminated renally (half life of 10-18 hours)
Effects on cardiac activity: very slow binding offset kinetics (>10s)
- Substantially decreases phase 0 (Na+) in normal)
- Decreased automaticity (increased threshold)
- Increased AP duration (K+) and increased refractory period, especially in rapidly depolarizing atrial tissue.
Effects on ECG: include increased PR, increased QRS and increased QT
Wide spectrum – Flecainide is the most commonly used class I anti-arrhythmic.
- Used for supraventricular arrhythmias (fibrillation and flutter). It contraindicated in history of IHD and fibrillation but used as treatment and prophylaxis against paroxysmal AF.
- Premature ventricular contractions (caused problems)
- Wolff-Parkinson-White Syndrome
- Proarrhythmia and sudden death especially with chronic use (CAST study)
- Increased ventricular response to supraventricular arrhythmias (flutter)
- CNS and gastrointestinal effects like other local anaesthetics
Describe the effects of Class II:
Beta-blockers e.g. Propranolol, acebutolol and Esmolol (very common, normally first line therapy?)
Will act as negative chronotrophic and inotrophic agents by reducing the autonomaticity to the heart. They can be non-selective (e.g. propranolol), Beta1-selective (e.g. atenolol and bisoprolol) or mixed Beta1alpha1-agonist (e.g. carvedilol)
Absorption and elimination
- Propranolol: oral, IV
- Esmolol: IV only (very short acting half life, 9 minutes)
- Increase action potential duration and refractory period in AV node to slow AV conduction velocity
- Decrease phase 4 depolarisation (Catecholamine dependent)
ECG: Increased PR, decreased HR
Describe the uses and side effects of Beta-blockers
- Treating sinus and catecholamine dependent tachy arrhythmias (prolonged PR interval)
- Converting reentrant arrhythmias in AV (prevent AF/atrial flutter)
- Protecting the ventricles from high atrial rates (slow AV conduction)
- They are used as rate control in AF, secondary prevention of VT or VF and heart failure
- Hypotension (effect on peripheral vasculature)
- Don’t use in partial AV block or ventricular failure or asthma. Caution in COPD and acute heart failure.
Describe the action of Amiodarone
Absorption and elimination: oral or IV (half life about 3 months). It is very lipid soluble so has a very large volume of distribution and as a consequence requires a large loading dose and has a half life of 10-100 days. It is metabolised by CYP450 yet due to its volume of distribution, dose adjustments are not required for renal, hepatic or cardiac dysfunction.
- Increased refractory period and increased action potential duration (K+)
- Decreased phase 0 and conduction (Na+)
- Increased threshold
- Decreased phase 4 (Beta-blockers and Ca2+ blocker effect)
- Decreased speed of AV conduction
Effects on ECG: increased PR, increased QRS, Increased QT and decreased HR
Uses: very wide spectrum – effective for most arrhythmias. Amiodarone can be used in stable VT and SVT, and the rate control of AF when other anti-arrhythmics are contra-indicated.
Describe the side effects of Amiodarone
Side effects: many serious that increase with time (long time use)
- Pulmonary fibrosis
- Hepatic injury
- Increased LDL cholesterol
- Thyroid disease
- Proximal myopathy
- Peripheral neuropathy
May need to reduce the dose of digoxin and monitor warfarin more closely (due to CYP450 enzymes)
May still be present in body 6-12 months after termination
Describe the side effects of Sotalol
- Increased action potential duration and refractory period in atrial and ventricular tissue
- Slow phase 4 (similar to Beta-blocker(
- Slow AV conduction
- ECG effects: increased QT, decreased HR (class II-like activity)
Uses: wide spectrum – supraventricular and ventricular tachycardia
Side effects: proarrhythmia (due to prolongating QT interval), fatigue, insomnia
Describe Class IV
Class IV: Verapamil and Diltiazem
- Verapamil: oral or IV
- Diltiazem: oral
- Slow conduction through AV (block the inward Ca2+ channels on the SAN and AVN)
- Increased refractory period in AV node
- Increased slope of phase 4 in SA to slow HR (very good at affecting slow action potentials) (negative chronotrophic and inotrophic effect)
ECG: increased PR, increases or decreases HR (depending on blood pressure response and baroreflex)
Describe the uses and side effects of Calcium channel blockers
- Control ventricles during supraventricular tachycardia
- Convert supraventricular tachycardia (re-entry around AV)
- Main clinical uses are for hypertension, angina, rate-controlled AF but only when beta-blockers are contra-indicated. Contra-indications for their use include heart failure, bradycardia and AV node block.
- Caution when partial AV block is present. Can get asystole if Beta-blocker is on board.
- Caution when hypotension, decreased CO or sick sinus
- Some gastrointestinal problems
Additional Antiarrhythmic agents: describe Adenosine
Administration: rapid IV bolus, very short half life (seconds)
Mechanism: natural nucleoside that binds A1 receptors and activates K+ currents in AV and SA node – leading to decreased APD, hyperpolarization => decreased HR (transient temporary heart block). Then normal rhythms start again from the SA.
- Decreased Ca2+ currents – increased refractory period in AV node
Cardiac effects: slows AV conduction (used for termination of natural arrhythmias)
Uses: convert re-entrant supraventricular arrhythmias. It can be used to distinguish SVT as if given as the tachycardia continues, then the re-entry loop is likely to occur between the atrium and the ventricles, and not at the AVN. Also used for hypotension during surgery, diagnosis of Coronary Artery Disease, but can cause bronchospasm in asthmatics
Additional Antiarrhythmic agents: describe Digoxin
- Enhances vagal activity (increased K+ currents, decreased Ca2= currents, increased refractory period)
- Slows AV conduction and slows HR
- It also inhibits the action of Na+-K+-ATPase thus leading to a reversion sodium-calcium exchanger => increased store of Ca2+ in sarcoplasmic reticulum => positive inotrophic effect.
Uses: treatment of rapid AF and atrial flutter
Normally requires a loading dose (given in 2 doses) for rapid onset and is quite lipid soluble so has a large volume of distribution, reflecting in its half life of 36-48 hours. As it is excreted renally, any renal impairment should result in altered dosing in the patient. Main adverse effects are with cardiac toxicity, yet any severe digoxin toxicity can be treated with Digiband.
Additional antiarrhythmic agents: describe Atropine and Magnesium
Atropine: normally given whilst waiting to put a pacemaker as an emergency
- Mechanism: selective muscarinic antagonist
- Cardiac effects: block vagal activity to speed AV conduction and increase HR
- Uses: treat vagal bradycardia
Magnesium: treatment for tachycardia resulting from long QT
Which drugs oculd be used for AF?
Either rate control (slow action potential) or rhythm control (slow AV conduction => then SA wakes up and starts generating normal rhythms)
Consider Beta-blocker (slows AV node), Calcium Channel Blockers, Flecainide, Digoxin, Amiodarone or Sotalol (the latter two would also affect conduction and slow HR)
Which IV drug first for VT? Should Flecainide be used alone for atrial flutter? Best drug for WPW?
Which IV drug first for VT
Should flecainide be used alone for atrial flutter?
- Flecainide slows down conduction but creates flecainide flutter (‘organises’ AF into atrial flutter with 1:1 conduction)
- The first response would be give Beta-blocker or (possible calcium channel blocker or digoxin) – target AV node conduction
Best drug for WPW?
- Flecainide - Slows conduction (bundle of Kent) (slows AV conduction)