The heart contains five distinct types of excitable tissue.

    The SA node (sinus or pacemaker) is the first of these to fire, setting in motion one complete cardiac cycle.  It has the greatest degree of automaticity (ability to fire independently of external stimuli) of any of the five types.  This automaticity is due to the large number of Na leak channels that are present in SA nodal tissue.  Under normal circumstances this tissue will spontaneously depolarise and fire, generating an electrical impulse that spreads through the rest of the heart.  However, it receives neural input from both the sympathetic system (to increase the firing rate) and the parasympathetic system (to decrease the firing rate) as needed.  Because of this automaticity, the SA node does not have a true resting membrane potential, but begins to depolarise once repolarisation has occurred.  The influx of sodium will generate the action potential (AP) that, once generated, will cause T-type calcium channels to open and close relatively quickly, allowing calcium influx.  Potassium channels then open, allowing potassium efflux and repolarisation.
    The impulse is then disseminated throughout the atrium causing atrial contraction.  The atrial action potential is very similar to that of the ventricle (discussed below), differing only in that calcium channels do not stay open as long as in the ventricle.  However, they do stay open long enough to produce a short plateau.  Note that atrial tissue may spontaneously depolarise and produce an action potential independent of the SA node.  This is not the normal situation and results in an ectopic impulse, a precursor to one type of atrial arrhythmia.
    The impulse from the SA node also travels via a specific conductive pathway to the AV node.  The AP of the AV node is similar to that of the SA node EXCEPT there is a true resting membrane potential.  This is due to the relatively few numbers of Na leak channels.  Note that there is no plateau in the AP of the AV node, again due to the relatively rapid opening and closure of T-type channels.  Note also that in the absence of atrial (pacemaker) input, the AV node will fire spontaneously to generate a ventricular beat.The AV node also receives input from sympathetic and parasympathetic fibres, thus controlling AV firing, if needed.
    The impulse then spreads through the purkinje system and the ventricles.  The AP generated within these tissues is very similar.  The plateau that is created is due to the opening and relatively slow closing of L-type calcium channels.  Similar to the AV node, if no impulse is received, the purkinje system may spontaneously generate an AP, producing a ventricular contraction.  Also, similar to atrial tissue, the ventricle may be a sight of ectopic generation of impulses.  Additionally, beta-1 adrenergic stimulation may directly cause an AP in ventricular myocardium and cause a contraction without an impulse being received from the normal pathways.

The normal generation of these AP are the result of specific ionic movement across the cellular membranes, and may be divided into specific phases.
        Depolarisation occurs with Na influx and the actual generation of the AP. (Phase 0)
        Overshoot occurs when Na influx exceeds that necessary to cause the AP and the interior of the cell actually achieves a positive membrane potential (Phase 1).
        The plateau results from prolonged Ca influx seen with the L-type of calcium channel (Phase 2).
        Repolarisation is the return to the resting membrane potential and results from K efflux (Phase 3).  Phase 4 is the time that is spent at the resting membrane potential, when initial ionic concentrations are returned to normal. 
The sequence of these events may be recorded as an overall electrical event of the heart.  As may be observed below, each specific AP results in either atrial or ventricular contraction.  When these impulses are summed, they produce the familiar electrocardiographic tracing pictured below.  Be aware that the ECG may look different, depending upon the placement of specific leads (electrodes that collect the impulse).  The one pictured below is that of Lead II electrode placement.  Regardless of the placement, the wave generated will represent specific cardiac events. The P wave occurs with atrial depolarisation.  The QRS complex of waves represents atrial repolarisation and ventricular depolarisation.  The T wave represents ventricular repolarisation.

Note that damage to the myocardium may disrupt the normal flow of electrical impulses.  Many times, structural damage (for example, following a myocardial infarction) will impede the conduction of the impulse.  This may result in the non-propagation of the impulse and incomplete ventricular contraction OR it may result in a circus or re-entry impulse in which the impulse travels "backwards" through the conductive pathway and initiates a "circus" circuit (circular impulse) that continuously feeds itself.  Note that re-entry may be so extensive as to spread the impulse from the ventricle back to the atrium and re-enter the ventricle through the AV node, initiating a second ventricular beat that was NOT initiated by the SA node.  The re-entry of the impulse by this accessory pathway is common in Wolf-Parkinson-White arrhythmias.  Note also that structural damage may cause a hypersensitised area of myocardium that may begin to spontaneously generate impulses (an ectopic focus).

 
 

Drugs that treat improper conduction through the heart may be classified by their mechanism of action and cardiac effects.  The classic classification scheme is as follows:

Class I -- Blocks Na Channels -- This class may be further divided by the effects on the AP.
    Class IA -- Lengthens the AP duration.  These drugs often have an intermediate time of interaction with Na channels.  Drugs include quinidine, procainamide, and disopyramide.
    Class IB -- Shortens the AP duration.  These drugs often interact rapidly with the Na channel, and include lidocaine, phenytoin, tocainide, and mexiletine.
    Class IC -- Little effect on AP duration, these drugs interact slowly with Na channels.  Flecainide, encainide, and propafenone are examples.
Class II -- Sympatholytic -- These agents block adrenergic activity to the conductive pathways.  Drugs include propranolol, esmolol, and acebutolol.

Class III -- These drugs prolong the AP duration by mechanisms other than Na channel blockade.  One characteristic Class III drugs share is their ability to block K channels.  Examples are sotalol, bretylium, and amiodarone.

Class IV -- Block Ca channels.  These agents include verapamil and diltiazem.

Miscellaneous -- Anti-arrhythmics which do not meet one of the above classification schemes, include digoxin and adenosine.

Note that as these agents are discussed, the classification scheme noted above is imperfect.  Many of these drugs share characteristics with drugs in other classes (for instance sotalol is a beta antagonist as is propafenone, however the latter is classified as a IC and the former has similar characteristics of the III type of anti-arrhythmics).

Although bradycardia may be considered an arrhythmia, most therapeutic anti-arrhythmics are intended to treat either abnormally fast cardiac beats or beats of abnormal origin that result in extra beats.  Any drug that inhibits the generation of an AP or the spread of an impulse along the conductive pathway, either by preventing the generation of an action potential (blocking sodium channels, preventing sympathetic induced AP) or by prolonging the time required to generate a second AP by increasing the duration of the AP (Na blockade) or the refractory period (K blockade) will be beneficial in the treatment of arrhythmias.  NOTE that in all instances, the medication is creating an abnormal conduction, therefore any drug that may treat arrhythmias, may also cause arrhythmias.
    Arrhythmias may arise from the SA node, atrium, AV node, purkinje system, or within the ventricle itself.  In most cases of arrhythmia, the ultimate goal is to prevent involvement of the whole heart.  Note that arrhythmias arising in the atrium are atrial arrhythmias,  those arising in the ventricles are ventricular arrhythmias.  Arrhythmias that arise in the atrium and spread to the ventricles are called supraventricular arrhythmias (or less commonly, re-entry arrhythmias, because re-entry may be within the same chamber).  While atrial arrhythmias may be potentially dangerous, enough blood will generally enter the ventricles for delivery to the body.  Ventricular arrhythmias, however, may actually reduce cardiac output to the point of decreased blood flow to the kidneys, liver, or brain so that hepatic failure, renal failure, or cerebral ischaemia follow.  Again, the primary goal of therapy is to prevent this decrease in CO by preventing ventricular arrhythmia, regardless of the origin of the impulse.

Quinidine -- a naturally occurring alkaloid derived from Cinchona bark.

Mechanism -- Quinidine blocks activated Na channels.  Additionally, it possesses alpha adrenergic antagonist actions and anti-muscarinic actions.

Pharmacodynamics -- Quinidine reduces pacemaker rate (especially ectopic pacemakers), reduces conduction velocity and excitability (especially in cells that are already depolarised), lengthens the refractory period (the time required before a cell may fire again, or achieve another AP), and lengthens AP duration (NOTE, this effect increases the risk of torsade de pointes, a specific type of arrhythmia that is characterised by a prolonged QT interval).

Adverse Effects -- Quinidine Syncope -- lightheadedness, fainting, secondary to torsade de pointes -- torsade de pointes may occur in 2-8% of patients taking quinidine.  Quinidine syncope may occur in 1-5% of patients taking the drug.  Cinchonism -- quinidine is a stereoisomer of quinine.  Classic signs of quinine toxicity may be seen with quinidine and include nausea, anorexia, dizziness, and tinnitus.  GI upset -- 1/3 to ½ of patients taking quinidine will experience diarrhoea, nausea, and vomiting.  Reflex tachycardia may also be seen with quinidine.  Through its alpha-blocking ability, quinidine may cause a decrease in blood pressure with a reflex increase in heart rate.  This is augmented by its anti-muscarinic effects (blockade of vagal inhibition of the SA node).  However, this reflex tachycardia may be off-set by the direct sinus inhibition of quinidine.

Therapeutic uses for quinidine include atrial fibrillation, atrial flutter, and ventricular tachycardia.

Mechanism -- Procainamide blocks activated Na channels.  It has better Na channel blockade activity and less anti-cholinergic activity than quinidine.  Procainamide also blocks sympathetic ganglionic transmission (which may decrease blood pressure).

Pharmacodynamics -- Similar to quinidine.

Adverse Effects -- Similar to quinidine.  Note however, that cinchonism would not occur with this drug.  An additional adverse reaction to procainamide is a lupus-like syndrome of arthralgia and arthritis.

Procainamide is used for most atrial and ventricular arrhythmias.  It is also the 2nd drug of choice (after lidocaine) for ventricular arrhythmias following a myocardial infarction.

Mechanism -- Disopyramide blocks activated Na channels.  It has more anti-muscarinic activity than quinidine.  It also has negative inotropic effects (which may cause heart failure, even in patients without pre-existing cardiomyopathy).

Pharmacodynamics -- Similar to quinidine

Adverse Effects -- Disopyramide generally produces typical anti-cholinergic side effects (dry mouth, constipation, urinary retention, decreased sweating).

Disopyramide is used primarily for ventricular arrhythmias.  It is not a first line agent and should be used only when patients do not respond to other agents.

Mechanism -- Lidocaine blocks both activated and inactivated Na channels.  It is typically more effective in depolarised cells (more time with inactivated Na channels).  Lidocaine also has mild negative inotropic effects (may precipitate failure in patients with pre-existing conditions).

Pharmacodynamics -- Lidocaine shortens the AP duration but lengthens the refractory period by blocking the activated Na channels (preventing full repolarisation).

Adverse Effects -- Lidocaine produces relatively few cardiac effects, however it may produce ventricular arrhythmias.  Neurologic effects (by blockade of Na channels on nerve cells) include paraesthesias, tremor, nausea (of central origin), lightheadedness, hearing disturbances, slurred speech, and convulsions.

Therapeutic Use -- Lidocaine is the drug of choice for the treatment of ventricular tachycardia, ventricular fibrillation after cardioversion, post-MI V-tach and digoxin-induced arrhythmias.  (NOTE -- lidocaine should not be used to prevent V-tach post-MI due to the risk of asystole or total cessation of cardiac activity).  It is only available (and effective) with parental administration.  Therefore, lidocaine is only used in ER/cardiac care situations.

Mechanism -- Similar to lidocaine, but with preferential activity at (open) activated channels.

Pharmacodynamics -- Similar to lidocaine

Adverse Effects -- Similar to lidocaine plus nausea due to the drug in the stomach.

Therapeutic Use -- Similar to lidocaine.  These agents are simply oral versions of lidocaine.  Mexiletine is also used for the treatment of chronic pain associated with diabetic neuropathy and nerve injury.

Mechanism -- Phenytoin blocks inactivated sodium channels.

Pharmacodynamics -- Similar to lidocaine

Adverse Effects -- Phenytoin has a wide range of side effects, toxic effects, and teratogenic effects that are independent of its anti-arrhythmic activity.  Refer to previous semesters notes on anti-convulsant therapy for a full description of potential effects.

Therapeutic Use -- Similar to lidocaine.  Phenytoin is the second drug of choice for digoxin-induced arrhythmias.

Mechanism -- Flecainide and encainide block both activated Na and K channels.  They differ from the previous drugs in the duration of their action, blocking the Na channel longer that Class IA or IB drugs.

Pharmacodynamics -- Similar to lidocaine, with a longer delay of the refractory period.

Adverse Effects -- Similar to lidocaine.

Therapeutic Use -- Primarily used in supraventricular arrhythmias and to suppress premature ventricular contractions (PVCs).

Mechanism -- Propafenone blocks activated and inactivated  Na channels similarly to quinidine (activated channels) but with a duration similar to flecainide (long duration).  Additionally, propafenone blocks calcium channels, potassium channels, and is a weak beta antagonist.

Pharmacodynamics -- Similar to flecainide, with some beta-antagonistic (negative chronotropy and inotropy) and calcium antagonistic (decreased blood pressure) effects.  Its anti-arrhythmic activity is similar to flecainide.

Adverse Effects -- Similar to lidocaine.

Therapeutic Use -- Similar to flecainide.

Mechanism -- Moricizine is a phenothiazine derivative that blocks activated and inactivated Na channels and is devoid of dopaminergic activity.

Pharmacodynamics -- Moricizine reduces conduction velocity in the AV node (similar to Class IA drugs, in which it is often classified) but does not prolong nor shorten AP duration (similar to Class IC drugs).

Adverse Effects -- Increased potential for arrhythmias, as with other drugs.  No additional side effects of high incidence.

Therapeutic Use -- Moricizine is used primarily in the treatment of V-tach and PVCs.

Mechanism -- The anti-arrhythmic activity of these drugs is most likely due to beta-1 blockade at the SA, AV nodes, and ectopic foci in myocardial tissue, decreasing the frequency of AP generation.

Pharmacodynamics -- These agents produce negative inotropic (decreased force of contraction) and negative chronotropic (decrease rate of contraction) effects.  They may decrease CO, cause bradycardia, and decrease peripheral resistance.

Adverse Effects -- Depending upon the lipophilicity of the specific agent, these drugs may also produce CNS depression, including sedation, drowsiness, and confusion.  They may also produce sexual dysfunction in males.  For further information on their side effect profile, refer to notes from the previous semester.  Since congenital Wolf-Parkinson-White syndrome is dependent upon a slow-firing AV node, beta blockers should not be used in those patients (they would worsen the condition and the arrhythmia).

Therapeutic Uses -- Beta blockers may be used to treat atrial flutter or fibrillation, with the primary goal of therapy to reduce the spread of the arrhythmia to the ventricles.  They may also be used to treat ectopic ventricular tachycardia.  Esmolol is a parenteral agent that has a relatively short duration of action (due to rapid plasma hydrolysis) making it a valuable emergency drug without risk of prolonged block.

Mechanism -- In addition to its blockade of beta receptors, sotalol blocks potassium channels.

Pharmacodynamics -- Similar to beta antagonists.  It may be more effective in conductive tissues that in myocardial tissues.

Adverse Effects -- Similar to beta antagonists.  Unlike the other beta antagonists, sotalol may cause torsade de pointes.

Therapeutic Uses -- V-tach, atrial fibrillation.

Mechanism -- Bretylium blocks K channels, interferes with noradrenaline re-uptake and also inhibits noradrenaline release.

Pharmacodynamics -- Bretylium will prolong ventricular AP duration.  Following bolus injection, bretylium may produce initial positive ino- and chrono-tropic effects and elevated blood pressure (due to the inhibition of NA uptake) followed by a drop in pressure (inhibition of NA release).

Adverse Effects -- Primarily those described above that affect cardiovascular function.

Therapeutic Uses -- V-tach that is not corrected by cardioversion or lidocaine.  Bretylium should NOT be used in digoxin-induced arrhythmias or in arrhythmias that are dependent upon beta-activity (i.e. increased ectopic automaticity).

Mechanism -- These drugs block both K channels and Na channels.

Pharmacodynamics -- Prolong the AP, effectively by lengthening the refractory period.  Although the characteristics of these drugs are more similar to the Class III (potassium blockers) drugs, much of their effect may be due to sodium blockade.  These drugs do lengthen the QT interval and therefore may precipitate torsade de pointes.

Adverse Effects --  Nausea, headache, hypotension (associated with prolonged QT interval).

Therapeutic Uses -- Atrial fibrillation and atrial flutter.  Dosage is based upon the pre-existing QT interval.  (If QT intervals are > 500 msec, these drugs should not be used.  If, during therapy the interval exceeds this amount, the drug should be discontinued.)  Patients with renal impairment should not be given these drugs nor should the drug be administered with an inhibitor of the CYP 3A4 system (either situation will result in an increased half-life and risk of torsade de pointes).

Mechanism -- Amiodarone blocks inactivated Na channels, K channels, and Ca channels.  It is also a non-competitive anti-adrenergic.  Additionally, amiodarone is a structural analogue of thyroid hormone.  (Recall that thyroid hormone exerts effects on the heart that are mediated by/very similar to beta receptor activation).

Pharmacodynamics -- Similar to bretylium.  Some of its activity may be due in part to an antagonist action at thyroid hormone receptors.

Adverse Effects -- Amiodarone may produce pulmonary fibrosis (5-15% of patients) that may be of rapid onset and progress to fatality.  The drug may deposit in the cornea (causing "halos" around bright lights) and in the skin (causing photodermatitis, 25% of patients).  It may also cause constipation (20%), thyroid dysfunction (5%), and hepatic dysfunction.

Therapeutic Uses -- V-tach and V-fib resistant to other drugs, atrial fibrillation, and acute treatment of ventricular and supraventricular arrhythmias.

Mechanism -- Block both activated and inactivated Ca channels.

Pharmacodynamics -- These agents prevent the expression of an AP (it may be generated by Na influx, but Ca influx is not permitted) thus reducing the firing of excitable and contractile tissues.  Majority of effect is seen at SA, AV nodes, and purkinje fibres.  They may also decrease CO (by negative inotropic effects in the myocardium) and blood pressure (by vasodilatation).

Adverse Effects -- Primarily an extension of their cardiovascular effects, bradycardia, fatigue, orthostatic hypotension.  For a full discussion of the adverse effects of calcium antagonists, refer to notes of the previous semester.

Therapeutic Use -- Re-entrant supraventricular tachyrhythmia and atrial flutter and fibrillation (primary goal is to prevent the spread of the arrhythmia to the ventricles).  Bepridil appears to have better effect in atrial arrhythmias than the other agents of the class.  Calcium channel blockers should NOT be used in ventricular arrhythmias of ectopic origin (origin within the ventricle) due to severe hypotension and potential cardiogenic shock.

Mechanism -- Adenosine acts as an agonist at endogenous adenosine receptors.  Agonist activity at the receptor activates a G-coupled protein which opens acetylcholine-dependent potassium channels.  This in turn results in potassium efflux and hyperpolarisation of the cell, effectively lengthening the refractory period.

Pharmacodynamics -- This potassium efflux will shorten AP duration in cells that have already fired and the hyperpolarisation will reduce automaticity in resting cells.  Adenosine is especially effective in atrial, SA, and AV nodal tissues, slowing the sinus rate and AV nodal conduction.  Block of conduction may be so complete as to produce asystole (total cessation of cardiac activity).  This effect generally lasts approximately 5 sec.  Following the asystole, the sinus rhythm will be re-established, preferably without the arrhythmia, producing a chemical cardioversion.

Adverse Effects -- Adenosine produces very few side effects, primarily because of its short (10 sec) half-life.

Therapeutic Use -- Adenosine is used primarily to treat re-entrant supraventricular arrhythmias but may also be used in V-tach.  It must be given by rapid IV bolus, due to the short half-life.  The actions of adenosine may be augmented by dipyridamole (which blocks adenosine re-uptake) or diminished by methylated xanthines (caffeine, theophylline -- which are adenosine antagonists) that the patient may have taken prior to admission.

Adenosine is also used to conduct chemical (pharmacological) stress tests in those individuals physically unable to withstand an actual stress test.  The drug is slowly infused, causing peripheral vasodilatation with subsequent reflex tachycardia.

Mechanism -- The primary anti-arrhythmic effects of digoxin are due to its vagomimetic actions, acting as an agonist at SA and AV node muscarinic receptors to inhibit sinus rate.

Pharmacodynamics -- The results of the anti-arrhythmic actions of digoxin are slowed impulse propagation and conduction velocity in the SA and AV nodes.  This is generally expressed as bradycardia.  For additional cardiac effects, refer to the section on heart failure and its treatment.

Adverse Effects -- Please refer to the section on heart failure and its treatment.

Therapeutic Uses -- Atrial fibrillation and flutter, atrial tachycardia, supraventricular (re-entry) arrhythmias.  The primary goal of therapy is to prevent the spread of the arrhythmia to the ventricles.

Potassium -- Potassium is used primarily in either hypokalaemia-induced arrhythmias or digoxin-induced arrhythmias associated with hypokalaemia.

Non-Pharmacologic Intervention

        Cardioversion -- In emergency situations, electrical charges (DC or direct current) are applied to the patient (either whole body or directly on the heart in cases of surgery).  This sudden charge will cause asystole, or complete cessation of cardiac activity.  The hope is that when the SA node re-establishes itself, the arrhythmia will not accompany the impulse.  If this does not work, the current may be increased up to a point, but drugs may have to be given.
        Pacemakers -- These devices are implanted in patients and provide a constant stimulation to the SA node to maintain a normal sinus rhythm.  These are often used with severe, chronic bradycardia or other arrhythmias that are unpredictable and characterised by prolonged intervals between beats.
        Implanted Cardioverter/Defibrillator (ICD) -- These devices are "smart" pacemakers that can detect an area of fibrillation/flutter or tachycardia.  When (and not until when) these areas are detected, a small charge is applied, causing cardioversion and pacing until a normal rhythm is established.
        Ablation -- In cases where specific sensitive areas of ectopic focus or accessory pathways that allow re-entry (as with congenital Wolf-Parkinson-White syndrome) of impulses are found, the physician may physically ablate the area, eliminating the cause of the arrhythmia.
 

Summary
In all cases of arrhythmias, pre-treatment evaluation should include
    Recognition and Correction of Complicating or Etiologic Factors, such as hypoxia, electrolyte imbalance (hypokalaemia, et c.), drug therapy (drug-induced arrhythmias), hyperthyroidism
    Correct Diagnosis of the Specific Arrhythmia (Recall that beta or calcium blockade is a preferred therapy in V-tach without structural damage but may be life threatening in re-entry V-tach.)
    Establish Baseline Function (ECG)
    Determine if Therapy is Warranted, and if so the most appropriate therapy considering pre-existing conditions.

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