1. Na+ enters cell through fast Na+ channels
2. Fast Na+ channels close
3. Ca²⁺ and additional Na⁺ enter the cell through slow channels
4. K⁺ exits cell and resting membrane potential is reestablished
5. equilibration of Na⁺ and K⁺ occurs

• ions not distributed equally across cell memb.
• Transporter pumps drive K⁺ into cells while pumping Na⁺ and Ca²⁺ out , giving rise to electrical gradients across membranes
• final membrane potential depends on:
  • # of channels of each ion
  • conductance (channel ability to pass ions)
  • Duration channel remains open
• Cardiac AP are long (up to 1/2 a second) allowing sustained cardiac contraction

• each ion channel conceptually has 2 gate types: activation and inactivation gates
• Activation gate opens during depolarization to allow ion current to enter/exit cell
• inactivation gate later closes to stop ion movement
• at resting state, the activation gates are closed and inactivation gates are open
• cell cylces between 3 states: resting, activated (open), inactivated (closed)

1. altered automaticity 
2. triggered activity
3. impulse conduction defects

• sympathetic (↑ HR)
• parasympathetic (slows SA node)
• pathologic conditions may alter automaticity or impair conduction of SA impulse

1. Reentry
   • sustained pattern of rapid depolarizations that trigger tachyarrhythmias
2. conduction block
   • impulse fails to propagate and lead to bradycardia
3. accessory tract pathways
   • pathways that bypass AV node
   • predispose to tachyarrhythmias

use of anti-arrhythmic drugs has ↓in last 2 decades, due to:

1. drug toxicity and proarrhythmia
2. tech. advances and development of extremely effective non-drug therapies (e.g. catheter ablation, refined internal cardioventer-defibrilators), which have better outcomes

1. Termination of symptomatic arrhythmia: e.g. atrial fibrillation (AF) is most widely accepted. Pts are usually closely monitored and drug exposure is brief. 
2. chronic therapy may be beneficial initially, but efficacy may be lost
3. serious adverse effects appear to ↑ over time

• 3 subclasses (IA, IB, and IC)
• all decrease conduction velocity
• similar effects on SA node AP
• different effects on ventricular AP (repolarization)
• classes differ in length of action b/c affinity to the Na+ channel

• moderate Na+ channel block
• bind to open channels ("moderate on-off")
• have anticholinergic actions that can lead to both an ↑ in SA rate and AV conduction (undesirable), b/c they are extensively innervated by vagal (cholinergic) efferent nerves. This can offset the direct effects of the drugs on these tissues 
• qiunidine and disopyramide have most anticholinergic activity

• mild Na+ Channel block
• rapid binding to and dissociation from Na+ channel ("fast on-off")
• bind to both open and closed channels

• marked Na+ channel block
• bind to open channels ("slow on-off")

• in ischemic myocardium (e.g post MI), Na+ channel inactivation is longer. Class IB offer greater activity (b/c bind both active/open and inactive/closed channels)
• B/C atrial repolarization if faster compared to ventricles, class IB play little role in atrial arrhythmias

• torsades de pointes (life threatening ventricular arrhythmia)
• hypotension, dirrhea, lupus-like syndrome (procainamide)
• Have a pro-arrhythmic effect therefore not used

• Class IA ↓ conduction velocity and prolong AP duration (APD)
  • also affects K+ channels, so shift in repolarization (unfavorable)
• Class IB ↓ conduction velocity slightly and shorten APD slightly 
• Class IC ↓ conduction velocity, no effect on APD

• class IB antiarrhythmic agent
• Is weakest among Na channel blockers
• blockade of Na+ channel allows very quick binding and dissociation form Na+ channel
• Exhibit "use-dependent" block in diseased (ischemic) myocardium (cells fire more frequently)
• Used in ventricular arrhythmias associated with MI
• Blocks nerve Na+ channels & nerve impulses
• not effective for atrial arrhythmias (brief inactivated phase)

• Neurological side effects including dizziness, nausea, drowsiness, confusion, etc (dose related)
• serious toxicity: seizures, psychosis, respiratory depression 

• ventricular arrhythmias (MI or cardiac surgery)
• local anesthetic

• loading dose = 50-100 mg IV followed by infusion of 1-4 mg/min
• t_1/2 = 1.5-2 hrs, 90% liver metabolism

• inhibition of transmembrane influx of extracellular sodium ions via fast Na+ channels
• classified as IC, but also has weak β-adrenergic blocking activity (non-selective) and is structurally similar to propranolol
• considered a "broad-spectrum" antiarrhythmics agent

• slow onset and offset kinetics
• eliminated by CYP2D6 (polymorphism leads to poor metabolizers)
• t_1/2 = 5-7 hours 
• fecal excretion

• metallic or bitter taste(15-20%), nausea, constipation
• worsening asthma (b/c of β blocking activity)
• proarrhythmia (e.g. ventricular tachycardia) is possible, but than other agents
• negative inotropic effects (avoid in CHF)

• ↑ digoixn levels by 40-60%
• ↑ warfarin levels

clinical uses of propafenone

• Supraventricular tachyarrhythmias for maintenance of sinus rhythm in pts with symptomatic atrial fibrillation (AF) 
• Ventricular arrhythmias
  • reserved for situations where arrhythmia may be life-threatening
  • avoid in pts with poor LV fxn or structural heart disease

• Pill in the pocket approach uses self-administration of a single dose shortly after start of palpitations
• Goal is to terminate an episode and prevent recurrence while ↓ need for ER visits, hospitalizations, and cardioversions
• this approach studied in pts who do not have structural heart disease
• effect is usually seen in 3-4 hrs

• Class II antiarrhythmics
• sympathetic and parasympathetic fibers innervate the SA and AV nodes
• Sympathetic stimulation leads to ↑ HR and conduction velocity
• β blockers block β₁ receptors in SA and AV nodes. AV node is more sensitive to this
• ↓ automaticity causes ↓ myocardial O₂ demand
• by ↓ AV conduction, β blockers slow ventricular response rates in atrial flutter/fib
• selective β₁ blockers are most frequently used for supraventricular and ventricular arrhythmias precipitated by sympathetic stimulation

• prevent recurrent infarction and sudden death in pts recovering from acute MI
• all MI patients get a β blocker (standard)

• multifactorial rational for it use 
• used prophylactively even for non-cardiac surgeries

• bradycardia (neg chronotropic effects)
• CNS: mild sedation, vivid dreams
• worsening of asthma
• may initially worsen symptoms of HF (neg. inotropic effects) 
  • do not start pt with acute HF on β blockers
  • start in early signs of HF for protective effect
• worsening of glycemic control

• predominantly class III antiarrhythmic that blocks K+ channels
• Exhibits activity in each of the 4 Vaughn-Williams antiarrhythmic classes
  • binds preferentially to inactivated Na+ channels
  • some α and β blocking activity
  • blocks K+ channels
  • Ca²⁺ channel blocking activity

• prolongs AP duration and effective refractory period (ERP) of atrial and ventricular tissue
• broad spectrum of actions may account for its relatively high efficacy and less severe side effect profile: lower incidence of torsade de pointed despite significant QT interval prolongation

• supraventricular arrhythmias (e.g. Atrial Fib.)
• ventricular arrhythmias

• Hypotension
• Thyroid effects
• Pulmonary fibrosis (less common)
• Other Rare effects:
  • Corneal microdeposits (often asymptomatic)
  • Hepatic dysfunction (asymptomatic transient elevation of hepatic enzymes)
  • Neuromuscular symptoms (most commonly peripheral neuropathy or proximal muscle weakness)
  • Photosensitivity (blue-gray skin discoloration, with chronic use. Use sun block to prevent)
  • Optic neuritic (very few cases caused blindness)
  • Proarrhythmia

• relaxes cardiac and vascular smooth m. thereby dilating both systemic and coronary arteries
• seen with IV dose, may be due in part to solvent 

• Amiodarone is structurally similar to thyroxine, and contains 37% iodine
• Thyroid effects are complex:
  • ↓ peripheral deiodinases that convert T₄ to T₃ (see ↑ in T₄ and ↓ in T₃)
  • blocks T₄ entry into cells
  • blocks T₃ receptor binding
• Causes Hypothyroidism (8%)
• Hyperthyroidism (2%) occurs mostly in areas with iodine-deficient diets

• can be rapidly progressive and fatal
• Risk factors include underlying lung disease, doses of 400 mg/day or more, and recent pulmonary insults such as pneumonia
• may be caused by drug-induced phospholipodosis or immune-mediated hypersensitivity rxn
• manifests as cough and progressive dyspnea

• Bioavailability = 50%
• Protein binding = 96%
• extensive liver metabolism
• biliary route of excretion
• Highly lipophilic (high tissue penetration)
• t_1/2 = 53 days
• eliminated extremely slowly; so drug interactions and adverse effects may resolve very slowly

• effective for both ventricular and supraventricular arrhythmias. However, its toxicity limits its use
• life-threatening drug-refractory atrial fib
• in pts with CHF or history of recent MI amiodarone is effective for suppressing ventricular arrhythmias and does not depress ventricular function

• noniodinated derivative of amiodarone (better for thyroid)
• antiarrhythmic properties of all 4 Vaughan-williams classes, but contribution of each activity clinically is unknown
• Like amiodarone, inhibits K, Na, and Ca currents in myocytes and exhibits antiadrenergic (α and β adrenergic receptor antagonist) properties

• may exhibit a negative inotropic effect
• only slightly blocks T₃ receptor binding to its thyroid hormone receptor
• does not affect plasma thyroid hormones
• its chemical structure makes it less lipophilic, resulting in a shorter t_1/2 and lower tissue accumulation (less side effects)

• Steady state serum levels achieved within 4-8 days
• absolute bioavailability is around 4% b/c of hepatic 1st pass metabolism by CYP4A3
• t_1/2 = 20 hours
• 1º metabolite is debutyldronedarone which is 3-10 times less potent
• around 6 of administered does is excreted in urine as metabolites (no unchanged drug)

• Concomitant use of CYP3A4 inducers (e.g. rifampin, phenobarbital, ...) and grapefriut juice can ↓ dronedarone levels
• CYP3A4 inhibitors (e.g itraconazole, cyclosporine, ...) can ↑ dronedarone levels
• Digoxin levels can ↑ by 1.7 fold (lower digoxin dose before initiating dronedarone)

To reduce risk of cardiovascular hospitilization in:

• Atrial fib., Paroxysmal of Persistent
• Atrial flutter, Paroxysmal or persistent

Adverse effects of Dronedarone

• Diarrhea, nausea, abd pain, vomiting, and asthenia
• QTc prolongation reported in 28% of dronedarone treated pts compared with 19% placebo recipients
• for most part better side effect profile than amiodarone (except GI effects)

• Severe HF (class D)
• Bradycardia
• Severe hepatic impairment

• Based on limited comparative data with amiodarone, not as effective as amiodarone for maintenance of sinus rhythm in pts with atrial fibrillation
• generally better tolerated
• GI side effects may occur more 
• not recommended in moderate to severe LV dysfunction (EF < 35%)

Sotalol mechanism of action and pharmacology

• Racemic mixture: both isomers contribute to its antiarrhythmic actions
• Both isomers exhibit K+ channel blocking activity 
• L-isomer shows more non-selective β blocking activity (Class III and II)
• prolongs atrial and ventricular AP and refractory period. Also, slows AV node conduction
• highly dependent on renal elimination

• ventricular tachycardia and fibrillation (especially if intolerant to amiodarone)
• Supraventricular tachycardias (e.g. prevents recurrent AF and maintains sinus rhythm)

• Fatigue
• bradycardia
• Pro-arrhythmia (dose related), to observe for this effect should preferably be initiated and dose increased in hospital
• risk of torsade de pointes, especially at low ventricular rate
  • risk greatly ↑ with renal dysfunction (dose must be adj to renal fxn)

1. Sotalol
2. Ibtilide (corvert)
3. Dofetilide (Tikosyn)

• Class III antiarrhythmic 
• used for rabid conversion of atrial fib or flutter of recent onset to sinus rhythm
• may have other effects beyond class III (e.g. enhances slow inward Na+ channels)
• Prolongs atrial and ventricular AP duration and refractoriness
• Incidence of fatal arrhythmia (torsades de pointes) = 2%. so not often used

Dofetilide (Tikosyn)

• Class III antiarrhythmic 
• used orally for maintenance of normal sinus rhythm in pts with AF. also effective in restoring normal sinus rhythm in these pts
• New pts placed for a min of 3 days in facility that provides Crcl calculations, continuous ECG monitoring and cardiac resuscitation

major side effects of Dofetilide (Tikosyn)

• Bioavailability - 100%
• high renal excretion (80% of dose eliminated unchanged in urine)
• dose based on renal fxn and QTc

Mech of action and pharacology of Miscellaneous antiarrhythmic agents: Adenosine

• a naturally occurring nucleoside present throughout the body
• fxns to regulate blood flow in many vascular beds, including the myocardium
• Stimulates the P₁ class of purinergic receptors and activates inward rectifier K+ current
• inhibits Ca₂₊ channel
• directly inhibits AV nodal conduction but has lesser effects on SA node

• qiuckly cleared by cellular metabolism
• t_1/2 = 10 seconds
• onset of action = within 1 minute

• drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm
• adenosine stress test: the direct coronary artery vasodilation induced by adenosine is attenuated in diseased coronary arteries

• adenosine receptor blockers (e.g. theophylline or caffeine) ↓ effects of adenosine
• adenosine effects are potentiated by adenosine uptake inhibitors such as dipyridamole (prevents degradation of adenosine)

• flushing (20%), headache, chest pain, bronchospasm (especially in asthmatics)

• act preferentially on SA and AV node b/c these tissues depend on Ca²⁺ currents
• major effect is to slow AV conduction
• little effect on Na+ channel dependent tissues (atrial, ventricular tissues, Purkinjie fibers)
• Dihydorpyridine Ca²⁺ channel blockers have greater effect on Ca²⁺ in vascular smooth m
• Verapamil and diltiazem most affect cardiac tissues

• constipation, nervousness, and peripheral edema
• negative inotropic effects (use with caution in pts receiving β blockers and other inotropic drugs)

• similar in efficacy to verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation
• given as IV bolus then infusion, then convert to oral agent

• Cardiovascular: Atrioventricular block, Bradyarrhythmia, CHF, Exacerbation (rare), peripheral edema, Syncope
• GI: drug induced gingival hyperplasia
• neurological: Dizziness, headache

• 1st derived form foxglove plant 1785
• limited role in pharmacotherapy of HF, since newer therapies can alleviate symptoms and improve survival
• only digoxin is in widespread clinical use

• Tablets
• pediatric elixir
• injection (adult and pediatric strengths)

• Inhibits Na/K ATPase, an enzyme that regulates the quantity of Na and K inside cells
• Inhibition of the enzyme leads to and ↑ in intracellular [Na+], and thus (by stimulation of the Na-Ca exchange) an ↑ in the intracellular [Ca²⁺]
• ↑ in Ca²⁺ interacts with contractile proteins and leads to ↑ force of contraction (positive inotropic effects)

Cardiac Glycosides (Digoxin) mechanism of electrophysiologic effect

(independent of effects on Na/K ATPase)

• binds to Na+ pumps in neurons in central and peripheral nervous systems
  • ↑ in vagal (parasympathetic) tone
  • ↓ in sympathetic nervous system activity
• ↓ AV nodal automaticity and conduction velocity (direct action)
• These aggregate effects may cause sinus bradycardia or arrest and /or prolongation of AV conduction or higher grade AV block
• no longer used for this purpose (AF)

• oral bioavailability = 75%
• peak effect (IV): 1-5 hours
• t_1/2 = 36 hours
• elimination: 90% renal excretion, proportional to GFR (or Creatine clearance)
• volume of distribution: large (640 L/70 kg):
• binds to skeletal muscle
• for rate control in AF, β blockers, diltiazem, or verapamil are preferred over digoxin b/c of their quicker onset

• Pharmacodynamic:
  • β blockers, CCBs (can lead to ↓ AV nodal conduction and AV block)
• Pharmacokinetic
  • erythromycin, clarithromycin, verapamil, and amiodarone ↑ digoixn levels
  • Cholestyramine, colestipol, levothyroxine, ↓ digoxin levels
• Hypokalemia ↑ the myocardial localization of digoxin (check K+ before prescribing)

• Heart block
• visual disturbances (Blurred yellow vision)
• nausea, vomiting, dirrhea

• rapid digitalization of 0.75-1.5 mg (for adults) given in divided doses q 6 hrs
• maintenance dose = 1.125 to 0.25 mg/day
• adjust dose in renal dysfunction

• brand names: Digibind, Digifab
• antigen binding fragments (Fab) derived from specific antidigoxin Ab produced in sheep
• binds molecules of digoxin, making them unavailable for binding at their site of action.
•  The Fab fragment-digoxin complexes accumulate in blood and are excreted by kidneys
• net effect is to shift equilibrium away from binding of digoxin to its receptors in the body, reversing its effects
• indicated for the treatment of life threatening digoxin toxicity or overdose
• not for milder cases of digoxin toxicity

• onset of action: improvement in 2-30 minutes
• elimination: renal (excreted bound to digoxin)
• t_1/2 = 15-20 hours in pts with normal renal fxn. t_1/2 ↑ up to 10-fold in pts with renal impairment

• based on amount of digoxin ingested and/or degoxin levels, body weight, ..etc. 
• Given IV over 30 minutes

• digoxin Immune Fab will interfere with digoxin immunoassay measurements
• digoxin levels can be clinically misleading until the Fab fragment is eliminated from body
• obtain digoxin level before digoxin immune Fab administration. Levels drawn within 8 hrs after dose are misleading due to drug's long distribution phase (equilibrium between digoxin levels in serum and tissue)
• total serum [digoxin] may rise precipitously following administration, but will mostly be bound to the Fab fragment