• SA node
• AV node
• Bundle of His
• Bundle branches
• Purkinje fibers

Pacemaker cells have more electrical channels (Na+, Ca+, K+)

Non-Pacemaker cells have more contractile proteins

• the ion balance is returned to normal by the action of Na+/K+ ATPase
• Ca2+ is removed from the cell by the Na/Ca exchanger and the calcium ATPase

• NE
• stimulates opening of a greater number of pacemaker channels that leads to faster phase 4 depolarization

• NE
• stimulates opening of a greater number of Ca2+ channels and thereby shifts threshold potential to more negative potential

• ACh
• makes the MDP more negative by increasing the probability of K+ channel opening
• reduces the slope of phase 4
• shifts threshold potential to more positive potential

1. Coronary ischemia and tissue hypoxia
2. Electrolyte disturbances
3. Overstimulation of the sympathetic nervous system
4. General anesthetics
5. Drugs that perturb cardiac transmembrane potential

1. Phase 4 slope: sympathomimetic drugs (I), hypokalemia (I), acetylcholine (D)
2. Threshold potential: Ca2+ channel blockers (less negative, takes longer to reach  threshold)
3. Maximum diastolic potential: actylcholine (more negative)
4. Duration of action potential: K+ channel blockers (I)

Defects in impulse formation (SA node):

Drugs that cause EAD

Causes of torsades de pointes

Class IA drugs

1. quinidine
2. procainamide
3. disopyramide

Class III drugs

1. amiodarone
2. sotalol
3. dofetilide
4. ibutilide

Defects in impulse formation (SA node)

Drugs that causes DAD (atrial tachycardia with AV block)

Defects in impulse formation (SA node)

Drugs that cause DAD (ventricular tachycardia)

• increase sympathetic tone
• myocardial ischemia/reentry

1. Re-entry (ventricular tissue and AV node)
2. Conduction block
3. Accessory tract pathways

• Tissue damage by trauma, ischemia, or scarring
• Drug-induced block (digoxin, beta-blockers, verapamil)

can be manifested clinically as bradycardia

• Impulses originate at SA node and preexcite peripheral conduction system and ventricular muscle via bundle of Kent - electrical impulse arrives at ventricles much sooner than normal
• No delay at AV node
• P wave is very close to QRS (delta wave)

Defects in impulse conduction: AV re-entract tachycardia in the Wolff-Parkinson-White Syndrome

Mechanism

• An accessory atrioventricular connection is present
• Conduction through this pathway is blocked unidirectionally
• When the normal impulse is sent through the AV node and passes through the ventricular pathways, the impulse can travel back through the accessory pathway (in a retrograde manner) and re-enter the atrium
•  It then can re-enter the ventricle via the AV node and become self-sustaining

Defects in impulse conduction: AV re-entract tachycardia in the Wolff-Parkinson-White Syndrome

Treatment

• AV-nodal blocking drugs that terminate this tachycardia (with caution)

1. Ca2+ channel blockers
2. beta-blockers
3. digoxin

• Drugs that remove atrial premature beats
• Catheter ablation; removal of bundle of kent

Can increase automaticity of the SA node, AV node, or His-Purkinje fibers and thereby produce tachycardia

• Sometimes evoke delayed afterdepolarizations by increasing Ca2+ influx into cardiac cells
• They can also impair AV node conduction and cause AV block

1. Antiarrhythmic drugs (quinidine and sotalol)
2. H1 antagonists (astemizole, terfenadine)
3. Psychotropic drugs (phenothiazines)

These drugs prolong action potential by blocking K+ efflux

1. shifting threshold to more positive potentials
2. decreasing the slope of phase 4

1. decreasing conduction velocity
2. increasing the refractory period (class IA)

• Most Na+ channel blockers bind preferentially to the open and inactivated states of Na+ channel, NOT to the closed state of the channel
• ex; ischemic tissue, depolarized for a longer period of time

• Moderate block on NA channels (preferentially bind to open Na channels)
• Decrease the phase 0 upstroke velocity which decreases conduction velocity through the myocardium
• Also block K+ channels (increase refractory period)
• Prolong the repolarization of both SA nodal cells and ventricular myocytes
• All of the class IA drugs have some degree of anticholinerigc effects (significant clinically b/c it can increase conduction velocity thru the AV node)

1. Diarrhea
2. Torsade de pointes: can cause syncope secondary to a reduction in CO and BP
3. Thrombocytopenia
4. Cinchonism (higher doses): neurological symptoms including tinnitus, dizziness, and blurred vision
5. Quinidine-induced digoxin toxicity: increase serum levels of digoxin

1. Occasionally used to suppress atrial flutter, Afib, supraventricular and ventricular arrhythmias
2. IV admin. can cause considerable hypotension
3. Patients with Afib: first give digoxin (decreases AV node conduction) then give quinidine
4. Quinidine has largely been replaced by Class II agents

1. Atrial flutter, Afib, ventricular tachycardia, paroxysmal atrial tachycardia, etc
2. IV infusion, oral, IM
3. Use has declined due to concern about drug-induced arrhythmias and other adverse effects

• Administered orally to prevent life-threatening sustained ventricular tachycardia
• Sometimes effective in patients who have not responded to other drugs
• Has electrophysiological effects similar to those of quinidine
• B/c of greater negative inotropic and anticholinergic effects than other class IA drugs, it should be used with caution in patients with heart failure and in elderly patients

• I>O
• Fast dissociation from Na Channels (Na channels recover quickly from blockade)
• exhibit use-dependent block (effective for ischemic cells)

1. high serum concentration of lidocaine can cause CNS side effects such as confusion, dizziness, seizure
2. drugs that inhibit P450 enzymes (cimetidine) can precipitate lidocaine toxicity

• an analog of lidocaine metabolite
• life-threatening ventricular tachycardia

1. usually considered an antiepileptic medication
2. effective in ventricular tachycardia of young children
3. entricular tachycardia after congenital heart surgery
4. congenital prolonged QT syndrome when mon-therapy with beta-blockers has failed

an inducer of P450 3A4

• decrease automaticity by decreasing the slope of phase 4
• decreases the incidence of re-entry by slowing electrical conduction at the AV node
• the AV node is more sensitive than the SA node to the effects of beta-blockers

• Blocks K+ channels
• Prolong action potential duration
• Decrease the incidence of re-entry by increasing the effective refractory period
• Increase the likelihood of developing early afterdepolarization and torsade de pointes

• Alters the lipid membrane in which ion channels and receptors are located
• decreases re-entry by prolonging action potential duration
• decreases the rate of firing in pacemaker cells as a class I agent
• exert class II antiarrhythmic activity by noncompetitively antagonizing beta-adrenergic receptors
• can cause significant AV nodal block and bradycardia

• hypotension, AV block, various arrhythmias
• blue-gray skin discoloration
• thyroid abnormalities
• fatal pulmonary fibrosis
• corneal deposits, blurred vision, photosensitivity
• GI disturbances
• Inhibits metabolism of other drugs: digoxin, flecainide, phenytoin, procainamide, warfarin

• used orally on a long-term basis to suppress both supraventricular and ventricular arrhythmias: Afib, Aflutter, SVT, life-threatening ventricular tachycardia
• used IV to treat Vfib or sustained ventricular tachycardia

• Severe ventricular arrhythmias, especially in patients who cannot tolerate the side effects of amiodarone
• Used to prevent recurrent Afib and Aflutter

1. Fatigue
2. Bradycardia
3. Torsades de pointes

• Block cardiac Ca2+ channels
• Act preferentially on SA and AV nodal tissues
• Major therapeutic action of class IV drugs is to slow the action potential upstroke in AV nodal cells, leading to slowed conduction velocity through the AV node

• opens G protein-coupled K+ channel
• Inhibits SA nodal, atrial, and AV nodal conduction
• also inhibits the potentiation of Ca2+ channel activity by cAMP

first line agent for converting narrow-complex paroxysmal supraventricular tachycardia

1. headache
2. flushing
3. chest pain
4. excessive AV or SA nodal inhibition

• Digoxin acts indirectly to increase vagal ttone and thereby slow the AV node conduction velocity and increase the AV node refractory period
• Digoxin has been used to slow the ventricular rate in patients with Afib --> beta-blockers and CCB are usually preferred b/c of their more rapid onset of action and greater degree of AV nodal blockade

• Mg cation is the second most common intracellular cation
• Its deficiency can cause arrhythmias, congestive heart failure, and GI and renal disorders
• Administered IV to suppress drug-induced torsade de pointes, to treat digitalis-induced ventricular arrhythmias and to treat supraventricular arrhythmias associated with Mg Sulfate