A-21. Antiarrhythmic agents.

Question 1

Class I/A antiarrhythmic MOA and drugs

Answer 1

Na+ channel inhibitors; intermediate dissociation and K+ channel inhibition

a. ) quinidine
b. ) disopyramide
c. ) procainamide

Question 2

Class I/B MOA and drugs

Answer 2

Na+ channel inhibitors; fast dissociation

a. ) lidocaine
b. ) mexiletine
c. ) phenytoin

Question 3

Phase 0, depolarization/upstoke phase in cardiac action potentials

Answer 3

Sodium influx

Question 4

Phase 1, notch of cardiac action potential

Answer 4

slight repolarization as sodium channels inactivate

Question 5

Phase 2, plateau of cardiac action potential

Answer 5

Ca2+ influx

Question 6

Phase 3, repolarization of cardiac action potential

Answer 6

K+ efflux

Question 7

phase 4, pacemaker current

Answer 7

K+ influx

Question 8

Absolute refractory period

Answer 8

h gate (fast gate) closes, leaving the channel in an inactive conformation

Question 9

Relative refractory period

Answer 9

As cell repolarizes h gate open again until sufficient depolarization triggers another AP

Question 10

Class 1 antiarrhythmics bind Na+ channels in which conformation? And which confirmation does it not bind?

Answer 10

Class I antiarrhythmics bind Na+ channels in active and inactive conformations, but not in the resting state

Question 11

Types of calcium channels in cardiac myocytes? Which type are responsible for plateau phase of cardiac action potential? Which two antiarrhythmics target this channel type?

Answer 11

L and T-type calcium channels.
L-type channels are responsible for plateau phase.
Verapamil and diltiazem inhibit these L-type calcium channels.

Question 12

Which class of antiarrhythmics prolong repolarization? What are they good for treating? What risks does it cause?

Answer 12

Class III is a good class of antiarrhythmic for prolonging repolarization.
They are good at treating re-entry arrhythmias by prolonging the refractory period.
TdP tachycardia risk is increased.

Question 13

Two types of arrhythmias groupings

Answer 13

Impulse formation or impulse conduction abnormalities

Question 14

Impulse formation can be separated into?

Answer 14

Regular- only the rate is modified, as in tachy- or bradycardia
Irregular- as in triggered impulse formation abnormailites such as…
a.)Early After depolarization (EAD)
b.)Delayed After depolarization (DAD)

Question 15

Early after depolarization is

Answer 15

ion channel (Ca or Na) reactivate before repolarization has finished, triggering an extrasystole before the cell can fully repolarize.
Often the trigger of TdP tachycardia and can be caused by anything which prolongs QT interval (hypokalemia, drugs, or genetic abnormalities)

Question 16

Delayed after depolarization is

Answer 16

After repolarization is complete, an increased IC calcium level activates the Na/Ca exchanger
Such as triggering an extrasystole, due to cardiac glycoside

Question 17

Impulse conduction abnormality can be due to

Answer 17

re-entry mechanism which requires
1.) parallel pathway
2.) a unidirectional block
3.) a short enough refractory period in the ublocked path
An AP travels along the unblocked pathway, then travels retrograde back through the unidirectionally block path, restimulating the unblocked path after it’s refractory period, resulting in an extrasystole

Question 18

Re-entry arrhythmias can be treated by prolonging refractory periods of cardiac myocytes with drugs that …

Answer 18

block K+ channels (thus slowing repolarization) or blocks Na+ channels (thus leaving them inactive)

Question 19

Class I antiarrhythmic dependence effect? What does this mean?

Answer 19

Use-dependence/state-dependence
Effect depends on heart frequency will inhibit a tachycardia HR, but have less effect on normal HR.
Since class I antiarrhythmics bind inactive and active, not the resting conformation. The more rapid the heart rate the more likely it will be in active state.

Question 20

IC, IB, IA

Order from most to least use-dependence

Answer 20

IC>IA>IB

Question 21

Class 1 antiarrythmics do what to the slope of depol, conduction, and QRS?
How did it effect SA/AV nodes

Answer 21

It decreases the slope of depolarization (phase 0), slows conduction, and widens QRS
Na+ channel blockers do not affect depolarization in the SA/AV nodes

Question 22

Class I/A antiarrythmics kinetics

Answer 22

intermediate dissociation (this plus the anticholinergic effects, tends to slow physiological HR leading to bradycardia)
intermediate affinity
inhibit K channels and prolongs AP (increases risk of TdP)

Question 23

The two Class I/A antiarrhythmic drugs not used anymore

Answer 23

ajmaline (parenteral)
prajmaline (oral)
both quinidine analogs

Question 24

Quinidine
Indication?
Kinetics?
Side effects?

Answer 24

Indication: both atrial and ventricular tachyarrhythmias
Kinetics: oral admin; medium DOA
Side Effects
1.) Inhibits alpha receptors increasing reflex tachycardia
2.) Anticholinergic effect increases HR and AV conduction which can increase rate of ventricle
3.) At low doses anticholinergic effect dominates/ High doses Na+ channel blockade dominates
-Often combind with something to slow AV conduction (BB or verapamil/diltiazem)
-Note; digoxin also decreases HR and conduction, but quinidine causes an increased serum digoxin level, so the two drugs can’t be combined
4.) Negative inotropic effect- careful with admin in heart failure
5.) Chinchonism- tinnitus, headache, and dizziness
6.) Thrombocytopenia- rare

Question 25

Procainamide How does it compare to to Quinidine? Side effects?

Answer 25

Less anticholinergic and less negative inotropic effect, rarely used now due to side effects. Side effects are similar to quinidien plus Lupus-like syndrome-via long term treatment (athralgia/-itis, pericarditis, pulmonitis, etc.)

Question 26

Disopyramide How does it compare to quinidine? Side effects? Indication?

Answer 26

Similar to quinidine, with stronger anticholinergic and negative inotropic effect. Side effects 1.) Anticholinergic effects: glaucoma attack, urinary retention, constipation 2.) Strong negative inotropy- CI in HF Indication: ventricular arrhythmia associated with HCMP

Question 27

Class I/B antiarrhythmic kinetics

Answer 27

1.)Fast dissociation -Have minimal cumulative effects over multiple cardiac cycles -More specific to tissues where Sodium channels are open/inactive and APs are longer (ventricles+His/Purkinje system, rather than atria) 2.)Low binding affinity 3.)Low use dependence 4.)Modest slowing of depolarization (Blocked Na current shortens plateau/repolarization phase which shortens refractory period so there is no long QT. Also it is specific to ischemic tissue because reduced resting membrane potential delays transition from inactive to resting state of Na channels)

Question 28

Lidocaine Dosing effect? Kinetics

Answer 28

Local anesthetic a.) At low doses- inhibits cardiac Na channels b.) At high doses- neural Na channels Kinetics -Strong first pass metabolism so it is required to parenterally administer w/ DOA of 2 hours -Binds serum proteins (especially alpha acid glycoprotein which accumulates in MI, so higher doses will be needed)

Question 29

Lidocaine Indications Side effects

Answer 29

Indications a.) Used in ICU for ventricular tachyarrhythmias following MI (no effect on SVTs) b.) Cardiac glycoside intoxication- ventricular arrhythmias via DAD causes extrasystole Side effects 1.) CNS symptoms: tremor paresthesia, serizure, slurred speech 2.) Low cardiotoxicity- no anticholinergic effects so much less arrhythmogenic

Question 30

Mexiletine How does it relate to lidocaine? DOA Indication

Answer 30

Mexiletine is the oral version of lidocaine; similar effects DOA is 10 hours Indication is ventricular extrasystole and other ventricular tachycardias

Question 31

``` Phenytoin Typically used for and effect at the heart? Indications How is it given? Side effects? ```

Answer 31

Phenytoin is typically used for anti-epiletics for general tonic-clonic and partial seizures; also affects cardiac Na channels Indications include cardiac glycoside intoxication, rarely used in other arrhythmias Given parenterally Side effects 1.) Gingival hyperplasia 2.) Hematopoietics issues (anemia)- with longer use 3.) Acute neuro effect

Question 32

Class I/C antiarrhythmics kinetics

Answer 32

1.)Slow dissociation 2.) High affinity 3.) High use dependence 4.) Drastically slow depolarization 5.) Widen QRS *Contraindication: structural/ischemic heart disease since delayed conduction speeds disproportionately to the refractory period and thus have proarrhythmic increasing re-entry risk effect (Little effect on K+ channels so do not affect AP duration or repolarization significantly)

Question 33

Class I/C antiarrhythmics | MOA and drugs

Answer 33

Na+ channel inhibitors; slow to very slow dissociation 1. ) Flecainide 2. ) Propafenone

Question 34

Flecainide kinetics Effect on K channels Indications

Answer 34

Slowest dissociation kincetics (diastole lasts 500 ms; flecainide dissociates in 5-30 seconds) Weak effect on K channels Indications: supraventricular tachycardias (but has an increased risk of sudden death after MI so it is rarely used)

Question 35

Propafenone Kinetics and secondary effects Indications

Answer 35

Propafenone is safer and more typically used Orally administered with liver metabolism making for 2 active metabolites Also has B blocker effect and no K channel effects Indications are similar to group 1A (supraventricular tachyarrhythmias- especially as drug of choice in A Fib/flutter)

Question 36

Propafenone Side effects

Answer 36

1. ) GI symptoms 2. ) Visual disturbances 3. ) Impotence 4. ) Seizures 5. ) Beta blocker effects- bradycardia, decreased BP, and negative inotropy

Question 37

Class II antiarrhythmics | MOA and drugs used

Answer 37

Sympathetic tone decreasers 1. ) Propranolol 2. ) Esmolol 3. ) Metoprolol 4. ) Atenolol

Question 38

How are beta blockers used as class II antiarrhythmics

Answer 38

Sympathetic stimulation increases SA node by increasing pacemaker currents and increased conduction velocity through the AV nodes. Beta blockers exert their antiarrhythmic effect by inhibiting B-1 receptors (Gs) and decreasing cAMP closing membrane calcium channels and inhibiting nodal depolarization. Beta blockers also prolong phase 4 (pacemaker current) of the nodal AP, as well as prolong conduction time and refractory period

Question 39

Indications and disadvantages of type II antiarrhythmics

Answer 39

Indications: Generally indicated in SV tachycardias (not VTs) including atrial fibrillation with rapid ventricular response Disadvantage: Long term use upregulates the production of B1 receptors so sudden discontinuation can cause tachyarrhythmias. Overuse can cause heart block via effect on AV condution (see as long PR interval on ECG)

Question 40

``` Indications for... Propranolol Esmolol Metoprolol Atenolol ```

Answer 40

1. ) Propranolol: inhibits Na channels as well - inhibits T4 to T3 conversion; double effect in hyperthyroidism (decreasing hormone and HR) 2. ) Esmolol: short DOA (10 min) - Parenteral admin for PSVT or other tachyarrhythias in emergency settings 3. ) Metoproplol: SVT 4. ) Atenolol: SVT and ventricular extrasystole

Question 41

Class III antiarrhythmics | MOA and drugs

Answer 41

K+ channel inhibitors 1. ) Sotalol 2. ) Bretylium 3. ) Amiodarone 4. ) Dronedarone 5. ) Ibutilide 6. ) Dofetilide 7. ) Vernakalant

Question 42

Class III antiarrhythmic kinetics and indications

Answer 42

Kinetics -Exhibit reverse use dependence: at bradycardic rates, have stronger effect -Prolong plateau and repolarization phases (phases 2+3) leading to EAD and a increased risk of TdP Indications: SVTs and VTs a.) A fib. b.) Especially re-entry tachycardias- K+ channel inhibition prolongs refractory period

Question 43

``` Sotalol MOA Dose effect? Kinetics Side effects ```

Answer 43

Beta blocker with K channel inhibition effect. Normal concentration cause no Na/Ca effects Higher concentrations cause Na/Ca blockade Orally administered Side effects -bradycardia -negative inotropy -decreased blood pressure -EAD -TdP

Question 44

Bretylium MOA Kinetics Indication

Answer 44

Bretylium is an adrenergic neuron blocker MOA is that it is taken up in pre-synaptic neurons and empties the vesicles leading to decrease in BP and inhibits Na channels with RUD -Parenterally administered Indication: used as a chemical defibrillator when electrical defibrillation fails

Question 45

Amiodarone Has properties of which antiarrhythmic classes? MOA?

Answer 45

Amiodarone has properties of class 1-4 antiarrhythmics MOA -Inhibits Na channels like I/B (fast dissociation) -Inhibits L type Ca channels (this leads to peripheral and coronary vasodilation and pacemaker effects) -Inhibits alpha and beta receptors -Dominant effect is K+ channel inhibition (w/out RUD making it non-arrhytmogenic and with low TdP risk)

Question 46

Amiodarone kinetics

Answer 46

Amiodarone kinetics - Oral, IM, or IV administration - Binds serum proteins; accumulates in tissues - Due to protein binding and tissue accumulation, requires loading period (i.e. 800 mg/day for 2 weeks, then 400 mg, then 200)

Question 47

Amiodarone side effects

Answer 47

1. ) Hypo or hyperthyroidism - Via iodine content of drug; test T function before and during treatment 2. ) Corneal microdeposits- grey; can be asymptomatic or cause halos/blindness 3. ) Skin symptoms due to skin deposits causing photosensitivity and grey discoloration 4. ) Pulmonary fibrosis - restrictive lung disease; bi-yearly radiologic control, fatal in 1% 5. ) Heart block via beta blocker and CCB effects 6. ) Heart Failure, especially when given IV 7. ) Hepatitis due to a hypersensitivity mechanism (do regular liver function tests) 8. ) Neuro effects- tremor, ataxia, peripheral neuropathy, sleep disturbances 9. ) CYP450 inhibition

Question 48

Indications of amiodarone

Answer 48

All types of atrial and ventricular arrhythmias

Question 49

Dronedarone Similarities/Differences to amiodarone? Which patients does it lower mortality and which does it increase mortality?

Answer 49

Amiodarone analog w/o iodine so no thyroid dysfunction. Also no pulmonary toxicity but has stronger liver side effects and may cause fatal liver toxicity. Decreases mortality in A. fib patients but increases mortality in HF (only use when no HF in anamnesis or when EF is higher than 40%)

Question 50

Ibutilide and dofetilide | MOA and indication

Answer 50

MOA: inhibit rapid delayed rectifier K channels Indication: pharmacological cardioversion of A. Fib

Question 51

Vernakalant Indication Kinetics Side effects

Answer 51

Indication: pharmacardioversion of A. Fib Kinetics: Parenteral administration Side Effects: decrease in BP and bradycardia

Question 52

Class 4 antiarrhythmics | MOA and drugs

Answer 52

Calcium channel blockers 1. ) dihydropyridines 2. ) verapamil 3. ) diltiazem

Question 53

What effect do the L-type calcium channel blocker have on the heart? (type 4 antiarrhythmics)

Answer 53

Negative chrono/dromo/inotropy (so should not be combined with BBs) *Remember that SA/AV nodal APs rely on Calcium influx for depolarization so CCBs mainly affect arrhythmias via effects on nodes (decreasing pacemaker activity, prolonging conduction time/refractory period)

Question 54

Indication of type 4 antiarrhythmics

Answer 54

Mainly SVTs | -Atrial fibrillation- CCBs slow ventricular response via negative dromotropy (decreased conduction speeds)

Question 55

Side effects of type 4 antiarrhythmics

Answer 55

1. ) Cardiac Depression- bradycardia, AV block (w/ PR prolongation), cardiac arrest 2. ) smooth muscle effects causing constipation and nausea 3. ) Vasodilatory side effects cause flushing, dizziness, peripheral edema

Question 56

Class 5 antiarrhythmic drugs

Answer 56

1. ) adenosine 2. ) digoxin 3. ) atropine 4. ) magnesium 5. ) ivabradine

Question 57

Adenosine | MOA

Answer 57

MOA: activates the inhibitory A1 receptors on cardiomyocytes and nodes which increases K+ efflux and decreases Ca2+ influx. This leads to hyperpolarization and decreased automaticity. 1. ) Decreased AV node conduction with transient high grade AV block 2. ) A2 receptor effects increase coronary vasodilation (used during stress tests to meaure flow in CAD patient)

Question 58

Adenosine kinetics and indications

Answer 58

Adenosine Kinetics: short DOA (10 second half-life); administered as IV bolus Indications: first-line for PSVT treatment in emergency settings

Question 59

Adenosine side effects and interactions

Answer 59

Side effects of adenosine 1.) Asystole- can cause cardiac arrest, so only administer with defibrillator available (patient may experience dyspnea, chest pain, and sense of doom 2.) Hypotension effects- including headache and fainting Interactions: Thyeophylline/Caffeine (adenosine receptor blockers which can decrease adenosine effects

Question 60

Digoxin MOA and indication

Answer 60

Digoxin MOA: Vagal stimulation which decreases HR and AV conduction Indication: SVTs associated with heart failure (including atrial fibrillation)

Question 61

When is atropine used?

Answer 61

Used in any condition when increased vagal activation causes severe bradycardia/AV block (ex. digoxin intoxication or post-MI cardiac arrest via overactive vagal stimulation)

Question 62

Magnesium | MOA and 1st line treatment for what?

Answer 62

MOA: various effects on ion channels, including Na+ and K+ channels, and Na/K-ATPase 1st line for tx of TdP, used parenterally

Question 63

Ivabradine | Used off-label for? Treats? Official indication?

Answer 63

Used off-label to inhibit funny current and decrease pacemaker activity to treat SVTs. Official indication is for HF and angina (IHD)