ANTIARRHYTHMICS

Ia - Quinidine, Procainamide, Disopyramide
Slows Upstroke, Increases AP Duration
Increase refractory periods and slow conduction velocity in atrial and ventricular myocardium and in bypass tracts but not in AVN
Quinidine: alpha blocker (hypotension), inhibits CYP3A4, 2D6 and P-GP, blocks Ito in Brugada Sd
Procainamide: active metabolite NAPA eliminated renally, lupus, agranulocytosis, efficacy in WPW
Disopyramide: vagolytic, efficacy in HCM, saturable protein binding

Ib - Lidocaine, Phenytoin, Mexiletine, Tocainide
Shorten AP duration
Increase refractory periods and slow conduction velocity in ventricular myocardium and in bypass tracts only
Mexiletine: CNS toxicity, agranulocytosis, LQT3 Rx by blocking INa


Ic - Flecainide, Propafenone
Slows +++ AP duration
Increase refractory periods and slow conduction velocity in all cardiac tissue including the AVN
Side effects: use dependence, PFN active metabolite, proarrhythmia (SVT and VT), increase pacing and DFTs, used for diagnosis of Brugada Sd
(Miyazaki, JACC 1996, Borgreffe 2005), used for pill-in-pocket Rx
Flecainide dosing 50 mg PO TID. Flecainide significantly increased both acute and chronic thresholds and the most marked rise (greater than
200%) occurred during chronic oral therapy

III - Sotalol, Amiodarone, Dofetilide, Dronedarone
Increases AP Duration
reverse use dependence, TDP
Sotalol: use with ICDs, renal dosing, BB vs. Ikr
Dofetilide: use in CHF (DIAMOND)
Ibutilide: facilitation of DC CV, CI with low EF
Amiodarone: increase INR, increase Digoxin, lower DFTs, pulmonary, thyroid, ocular, hepatic, neurologic toxicity
Dronedarone: deiodinated, no effect on INR, increases digoxin

All AAD are Class C for pregnancy except for Sotalol (B) and Amiodarone (D)
Amiodarone, Propafenone and Flecainide will significantly reduce VT CL
AAD
Loading dose may hasten time to therapeutic range but does not change time to steady state

CYP2D6 and CYP3A4 are most important for EP
CYP2D6
-7% of caucasians and african-americans are deficient in CYP2D6. Deficiency is rare in Asians.
CYP2D6 metabolizes metoprolol, carvedilol, timolol, flecainide Ic, propafenone Ic
CYP2D6 is strongly inhibited by Quinidine which increases the concentrations of the above
CYP3A4
CYP3A4 metabolizes Quinidine Ia, dofetilide III (30%), amiodarone III, dronedarone, Verapamil, diltiazem, some statins (simva, atorva, lova), cyclosporine,
cisapride and terfenadine.
CYP3A4 is inhibited by macrolides, azole antifungals, diltiazem, cimetidine, amiodarone and grapefruit juice.
CYP3A4 is induced by phenytoin, phenobarbital, carbamazepine, St John's wort and rifampin

Propafenone (Ic) interactions
Metabolized by CYP2D6, parent drug has beta-blocker effect. Has CNS side effects.

Quinidine (Ia) Interactions quinidine
is most potent CYP2D6 inhibitor (increases BB and Ia drug concentrations) but metabolized primarily by CYP3A4

Dofetilide (III) Interactions dofetilide


Amiodarone (III) Interactions amiodarone


Dronedarone (III) Interactions dronedarone - dronedarone


Adenosine Interactions adenosine


AAD Selected Interactions AAD

Herbal Interactions herbal



Warfarin
racemic mixture of S and R anantiomers (R are 3x more potent). Metabolized by CYP2C9
VKORC1 is the gene for Vitamin K epoxide reductase the warfarin target
Recent trials have shown benefit of warfarin genotyping and it is endorsed by the FDA

Terfenadine and Ketoconazole interaction causes TDP
Acetylator phenotypes
Whites and Blacks are ~50%
Asians are 90% rapid acetylators
Procainamide major metabolite is NAPA which has class III
AA properties and is renally cleared
Procainamide induced lupus is less common in rapid
acetylators

P-Glycoprotein
found in gut, liver, BBB, renal tubules.
Inhibited by quinidine, verapamil, cyclosporine, amiodarone,
dronedarone
Probably mechanism for digoxin-quinidine interaction
PHARMACOKINETICS AAD
DOSE RANGES AAD
AAD effect on DFT
Fuster et al JACC 2006; 48: 854-906
2006 ACC/AHA AF Guidelines
-Both amiodarone and dronedarone will block organic cation transport iin the renal tubules. Creatinine
will increase but that does not reflect a decrease in GFR. Recheck Creat in 4 weeks
-Dronedarone increases mortality in acute decompensated HF
-
Amiodarone hypothyroidism:  is 37.5% organic iodine. It blocks T4 5'-deiodination to T3 lading to
accumulation of rT3. Incidence is
6-13% (6% in USA high iodine intake countries)
-Amiodarone usually unmasks disease in people who are iodine deficient. Thyrotoxicosis occurs in 2-12%.
Type I amiodarone thyrotoxicosis
is unmasking of prior thyroid abnormality usually prolonged course
Diffuse Thyroid enlargement
Type II amiodarone thyrotoxicosis is follicle toxicity with inflammation. Usually transient and responsive to
steroids. IL-6 levels and CRP are elevated
Remote history of thyroiditis
High serum IL-6
Favorable response to steroids
-Amiodarone pulmonary toxicity 0.5-2% first year; 0.5-1% / year afterwards
acute (first few days)- subacute (first few weeks)-chronic (insidious dyspnea)
Phospholipoidosis, alveolitis, foamy macrophages, inflammatory cell infiltrate, fibrosis
PFTs: low DLCO, low PO2
Do a high resolution CT, BAL
Differential: Bronchoalveolitis obliterans organizing pneumonia BOOP, CHF, infection, ARDS
-Amiodarone Ocular toxicity: halo vision, reversible, bilateral loss with gradual onset due to optic neuritis,
due slit lamp exam and acuity testing, if both eyes=> amiodarone. NAION (non arteritic ischemic optic
neuritis), disk edema can lead to optic neuropathy
-Amiodarone Neurotoxicity: tremor, gait disturbance (can't get up from chair, walking distances, climbing
up stairs), peripheral neuropathy, accumulation in myoelinated and unmyelinated axons with inclusions.
Tests: EMG.
Responds well to dosage reduction
-IV Amiodarone:
earliest effects, leads to increase in SCL, AH and AVNERP. Increases VF thresholds (Ca
channel blockade +/- BB effect). Use dependent Na channel blockade
Toxicity: bradycardia, hypotension, phlebitis
IB amiodarone only increases percentage ofpatients survivng to admission after cardiac arrest not to
discharge (same mortality)
Class IV AAD: Verapamil, Diltiazem
Interaction with: Dofetilide, digoxin, cyclosporine, CYP3A4, PGP substrates
Avoid use in CHF -
Atrial remodeling concept

Adenosine:
Direct effect: inhibits IK(Ach-ADO) which is not present in the ventricles
Indirect effect: antiadrenergic due to a decrease in cAMP
Biphasic response due to chemoreceptor activation. Ultrashort half life
Interactions: Dipyridamole, theophylline
Proarrhythmia: torsades, faster AF, new AF (by lowering atrial ERP)
Diagnostic uses (WPW, AVNRT, SND)

Quinidine:
beneficial in Brugada by blockade of the Ito inward current

Ranolazine:
beneficial in LQT3

Flecainide
side effects (especially 300 mg pill in the pocket) => Pro-arrhythmia: VT. Rx: IV metoprolol

Methadone blocks IKr and prolongs QT

Dronaderone contraindicated with simvastatin/atorvastatin. Give pravastatin

Digoxin levels increase after starting amiodarone or quinidine by effect of Blocking of renal P-GP activity

Rifampin
contraindicated with Quinidine

If you are starting Amiodarone 400 mg on somebody already on Warfarin you should cut the warfarin dose by half

Disopyramide
is a good AAD for PAF and HCM

Dofetilide
increases monophasic Action Potential. It has no effects on Na+ channels, adrenergic alpha receptors, or adrenergic Beta
receptors.

If somebody fails AF CV 3x (100, 200, 300 J), you can administer Ibutilide and reattempt CV same session

Following an anterior MI, you would expect decreased
Central volume of distribution

Cardiac transplant
on cyclosporine presents with SVT, dose of adenosine to give is 1 mg

Adenosine leads to preexcited AF in WPW by shortening atrial AP duration (Increased outward K+ current)

In RVOT VT, Adenosine
suppresses the arrhythmia by suppression of DADs (due to Ca++ overload)