Phase 0 occurs once a threshold level of depolarization is reached.  It is caused by an 'all-or-none' response in which voltage gated Na+ channels open.

Phase 1 involves the inactivation of Na+ channels and a transient opening of K+ channels.

Phase 2 (plateau phase) occurs because of the opening of Ca++ channels causing an influx of calcium.  This balances the ongoing eflux of K+.

Phase 3 (rapid repolarization) occurs once the Ca++ channels have inactivated and the K+ channel permeability increases.

Phase 4, the spontaneous depolarization of pacemaker cells, involves a gradual increase in Na+ and Ca++ permeability with a simultaneous decrease in K+ permeability.  This phase brings the pacemaker cells closer and closer to the threshold membrane potential until the action potential is restarted.

Extrasystoles, supraventricular and ventricular tachycardias all have a disturbance in the normal impulse formation.

Abnormal impulse formation can occur when a depolarization event interrupts phase 3 or 4 of the normal action potential.

Class 1a antiarrhythmics are Quinidine and Procainamide. 
(Amiodarone also has a class 1a effect)

All class 1 antiarrhythmics cause a Na+ channel blockade.

1a drugs moderately decrease the phase 0 slope (slow down depolarization).  This is because they block mainly the activated Na+ channels. 

They also prolong the repolarization phase.  This is because they also cause a weak blockade of K+ and Ca++ channels.

Class 1b antiarrhythmics are Lidocaine, Mexiletine, and Phenytoin.

All class 1 (a, b, c) antiarrhythmics block Na+ channels.

Class 1b drugs cause a minimal reduction in phase 0 slope (minimal reduction in conduction velocity).  This is because they preferentially block inactivated Na+ channels.  They also shorten the repolarization phase.

The class Ic antiarrhythmic is Flecainide.

All class I antiarrhythmics block Na+ channels.

Class Ic drugs cause a marked decrease in phase 0 slope (marked decrease in conduction velocity) and have little effect on the repolarization phase.  They only block activated Na+ channels, and the effect is strong and long-lived.

Class IV antiarrhythmics are Ca++ channel blockers!  They are the non-dihydropyridines Verapamil and Diltiazem.  (Amiodarone also exhibits class IV effects)

Class IV drugs block Ca++ channels, causing a decrease to the slope of phase 0 in slow fibers.

(Recall: slow fibers utilize Ca++ for phase 0, fast fibers utilize Na+)

Quinidine is a class 1a antiarrhythmic, and therefore acts mainly by blockade of Na+ channels.  It mainly acts on activated Na+ channels.  However, it does cause some blockade of inactivated Na+ channels as well as K+ and Ca++ channels.

These blockades result in a decreased conduction velocity (longer phase 0 - Na+), an increased refractoriness (phase 2 and 3 prolonged - K+) and a decreased automaticity (phase 4 prolonged - Ca++).  In other words, quinidine prolongs all phases of the cardiac action potential.

Quinidine also exerts an antimuscarinic effect on the SA and AV nodes.  This is matched by a direct depressive effect of quinidine and the HR is therefore relatively unaffected.

Quinidine is a dangerous drug because it can cause arrhythmias and even polymorphic ventricular tachycardia.  This may result in torsade de pointes and lead to sudden death.  (this can occur in up to 8% of patients!)  This risk is increased if the patient already has a prolonged QT interval, such as patients taking Macrolides, TCADs or neuroleptics.

Quinidine may cause cinchonism = systemic effects due to muscarinic and alpha blockade.

Diarrhea, allergic reactions, and thrombocytopenia are also common. 

What is cinchonism?

How do you treat it?

Cinchonism refers to a syndrome with the following symptoms:

blurred vision, vertigo, tinnitus, photophobia, confusion, tremor, delerium.

It can be precipitated by an overdose of Quinidine (which is obtained from cinchona bark)

Treatment of Quinidine overdose is with sodium-lactate. 

Quinidine should not be used in patients with a long QT because this increases the risk of polymorphic ventricular tachycardias (torsade de pointes)!  remember: class Ia and class III antiarrhythmics are contraindicated in patients with long QT risks

Do not use in patients with complete or bundle branch block.

Do not give to patients with diarrhea, as quinidine will only worsen this.

If a patient has digoxin-induced arrhythmias, quinidine is contraindicated because it increases the digoxin plasma concentration by displacing it from proteins.  This will worsen the arrhythmia.

Procainamide is a class 1a antiarrhythmic (the other one is quinidine).  It's main mechanism is the blockade of activated Na+ channels, though it also blocks K+ channels.  This causes a decrease in conduction velocity (decreased slope of phase 0)

Unlike Quinidine, it does not have as many systemic effects through M and Alpha receptors

Procainamide can cause a lupoid syndrome after prolonged treatment. (up to 30% of patients!)  It can cause arrhythmias and tachycardias in the heart.  While it doesn't cause cinchonism, it can produce dizziness and delerium.

"Lupoid is like lupus (wolf), and shepards carry a cane around to ward off wolves"  (to connect procainamide with lupoid syndrome; and also that it is DOC for Wolf-Parkinson-White syndrome)

Use Procainamide in Wolf-Parkinson-White syndrome. 

The accessory bundle of Kent is made up of normal heart muscle fiber (non-nodal) so class II and IV drugs are inneffective and even contraindicated. It is also non-ischemic, so class Ib drugs like lidocaine that preferentially act on ischemic/damaged tissue don't have any advantage.

 It is also used in the prevention of ventricular and supraventricular arrhythmias.

Remember: in V-Tach, the drugs amiodarone and lidocaine are preferred, and procainamide acts as a 'back-up' drug.

Wolf-Parkinson-White Syndrome involves an accessory conduction bundle in the heart (bundle of Kent), which connects the atria and ventricles.  This allows electrical communication between the ventricles and atria by a path other than the AV node. As the ventricles depolarize, the signal can reenter the atria, causing another action potential to propagate prematurely and speeding up heart rate.  Additionally, the ventricles can cantract prematurely because there is no pause in the accessory pathway, as there is in the AV node.  This is called pre-exitation.  So someone with a fast atrial beat can have an equally fast ventricular beat, leading to decreased CO (because impaired diastolic filling).  This also promotes arrhythmias like the ever-feared ventricular fibrillation.

Procainamide (or Amiodarone) is often used to treat WPW syndrome.  Never give a Ca++ channel blocker or digoxin because they can worsen the condition by shunting all of the current through the bundle of Kent.

The accessory bundle is composed of normal heart muscle rather than nodal tissue.  SO it is blocked by class I and III drugs and not II or IV.

Lidocaine blocks inactivated Na+ and to a lesser extent, activated channels.  This equates to a slight decrease in conduction. It also causes a lengthened refractory period in ischemic/arrhythmic cells because it slows the return of inactivated Na+ channels to their repolarized/resting state. 

Ion channels in ischemic tissue spend more time in the inactivated state than channels in normal tissue.  Therefore, Lidocaine has its largest effect on ischemic, arrhythmic myocardial tissue.  It is used in acute ischemic ventricular arrhythmias following MI.  It has little effect on atrial tissue or AV/SA nodal tissue.
Lidocaine is also used to treat digitalis toxicity

Lidocaine, a class 1b antiarrhythmic (alongside phenytoin and mexiletine), is contraindicated in patients with heart block, cardiac failure, and atrial fibrillation. 

It is used mainly to treat ventricular arrhythmias, especially after an MI or during open-heart surgery.

Flecainide is a class 1c antiarrythmic.  It blocks activated Na+ channels and causes a marked decrease in conduction.  It has little effect on refractoriness.

Use it to control atrial flutter or fibrillation.  Do not use it in patients with a structural cardiac disease, as it has a chance of increasing the likelihood of arrhythmias and also of worsening congestive heart failure.

Use beta-blockers for arrhythmias caused by adrenergic activity, such as in hyperthyroidism or pheochromocytoma.  Also use them in arrhythmias associated with hypertrophic cardiomyopathy because they have the benefit of increasing the diastolic filling period for these patients. 

Beta blockers are good drugs for the chronic control of atrial fibrillation and reentry arrhythmias.  They also help prevent fatal ventricular arrhythmias in patients that have had a heart attack.

Not contra'd in pregnancy

Amiodarone is a class III antiarrhythmic.  It works by blocking K+ channels and therefore prolongs the refractory (repolarization) period.  This increases the overall action potential duration.  Amiodarone also blocks inactivated Na+ channels and Ca++ channels, giving it class I and class IV properties.

Amiodarone also inhibits the CYP450 system.

Because amiodarone has a large iodine content, it affects thyroid finction, most commonly inhibiting it.

Quinidine is a class 1a antiarrhythmic that blocks activated Na+ channels, causing a decreased phase 0 slope.  It also prolongs phase 3 because it has K+ blocking effect too.

Amiodarone mainly prolongs phase 3 because of its K+ channel inhibition.

Amiodarone may cause hypotension, Torsade de pointes (b/c prolongs QT interval), constipation, headache, dizziness, pneumonitis and pulmonary fibrosis.  This last effect is dose-related and may be fatal!  (Amiodarone has an incredibly long half life (80days!) and sticks around, bound to proteins = hapten... which triggers inflammatory cells and results in situations like pulmonary fibrosis!)

Amiodarone may be deposited in the cornea and may also cause hypothyroidism (because it has a high iodine content)

Amiodarone inhibits the CYP450 system, so you must titrate the dose of other drugs!

What drug contains all of these contraindications:

long QT syndrome, torsade de pointes, pulmonary disease, iodine hypersensitivity or thyroid condition, pregnancy?

Amiodarone! 

Recall amiodarone has a high iodine content so thyroid problems may manifest after administration.  It also may cause pulmonary fibrosis of pneumonitis.  Finally, amiodarone is a category D drug and should be avoided in pregnancy!

TCADs increase the risk of torsade de pointes.  Class III antiarrhythmics (amiodarone, sotalol) and class Ia antiarrhythmics (quinidine, procainamide) also increase the TDP risk by increasing the QT interval.  Therefore, class III and Ia antiarrhythmics should not be given to patients on TCADs.

In patients with Wolf-Parkinson-White syndrome or long QRS complexes, Ca++ channel blockers cannot be used.  Treatment of a tachycardic WPW is different than treating patients with normal conduction tachycardia. If you close down the normal AV node pathway, or try to slow it down with Ca++ blockers, you will be rerouting any normal conduction right to that extra pathway, whic his normal heart muscle and unlike nodal tissue, not affected by Ca++ blockers. 

Drugs like Verapamil and Diltiazem work by slowing calcium influx in the cardiac cells, particularly the SA and AV node. But they also work in the vascular smooth muscle. What happens when you block or slow the calcium influx in the smooth muscle?  Vasodilation! How does the autonomic nervous system respond? By stimulating the sympathetic branch. Those impulses will bypass the regular SA-AV nodal system and proceed through the accessory pathways (Kent Bundles), thereby worsening the tachycardia.

Adenosine is a drug of choice for attacks of supraventricular tachycardia (SVT).  It acts by blocking the conduction through the SA and AV nodes due to its opening of K+ channels. 

If the patient were a pregnant female, metoprolol would be a drug of choice.  But remember, the onset of beta blockers is slower.

Beta-blockers and Ca++ channel blockers are the drugs of choice for atrial fibrillation patients.

These are also the DOC for chronic control of these problems.

Digoxin can be used in patients with atrial fibrillation and heart failure.

For both acute and chronic control of ventricular tachycardia, amiodarone is the top choice.  It is a class III antiarrhythmic that blocks K+ channels, prolonging the repolarization phase of the cardiac cycle, increasing the refractoriness, and causing an overall lengthening of the cardiac action potential.

Lidocaine is another DOC for the acute treatment of v-tach.

Beta-blockers!

Recall, you want the Beta-2 action for bronchodilation.

You also want the Beta-2 action because it increases insulin release.  Also Beta-blockers will mask the symptoms of hypoglycemia (brought about by sympathetic activation), which can lead to a hypoglycemic coma!

The class Ia and class III antiarrhythmics are contraindicated in long QT situations.  The class III drugs are amiodarone, sotalol, and ibutilide.

Class Ia drugs are quinidine and procainamide.

Risk of torsade de pointes is increased with a prolonged QT interval.  A long QT interval corresponds to a lengthened refractory phase of the action potential.  Drugs that block the K+ channels during phase 3 of the action potential increase the refractoriness and therefore carry an increased risk of TDP.  These K+ blocking drugs are class Ia and class III drugs.

Drug names: quinidine, procainamide, amiodarone, sotalol, ibutilide

TCADs, neuroleptics, macrolides, and quinolones also lengthen the QT interval.

Cardioversion is the return of a heart with cardiac arrhythmia to a normally functioning heart.  It can be accomplished either pharmacologically or with the use of direct current.  Often, the pharmacological approach is tried first. 

Ibutilide is the first choice drug for pharmacological cardioversion.  It is a class III antiarrhythmic.

other drug possibilities include quinidine, procainamide, and flecainide, but they are generally not as effective.

(Note that all of these except flecainide are class Ia and class III antiarrhythmics, the same two groups of drugs that are contraindicated in long-QT situations because of the risk of torsade de pointes.)

Any drug that can protect the ventricles from the atrial fibrillation by inhibiting transmission through the AV node are useful here.  These include:
Beta-blockers

Ca++ Channel Blockers

Digoxin (only if there is also cardiac failure)

contraindications will help determine which one to use.  Ex: in an asthmatic don't use a beta-blocker.

Amiodarone, Lidocaine, and Procainamide.

Amiodarone is often considered more effective than lidocaine, but lidocaine has a lower incidence of adverse effects.  Procainamide is a back-up drug if the first two are ineffective.

1) Beta blockers decrease HR, SV, thereby decreasing the CO.  This protects the myocardium because it lowers its oxygen demand

2) Beta-blockers prevent cardiac remodeling (angiotensin II and norepinephrine are the systems involved in cardiac remodeling).  Remodeling (ex: hypertrophic heart) is bad, unless in athletes, because a hypertrophic heart is an ischemic heart (capillary growth does not normally match myocardial growth)

3) Beta-blockers result in an up-regulation of B-receptors.