A21. Antiarrhytmic agents

Question 1

List the different drugs used in cardiac arrhythmias.

Answer 1

• Group 1: Sodium channel blockers (procainamide)
• Group 2: Beta blockers (esmolol)
• Group 3: Potassium channel blockers (amidarone, dofetilide)
• Group 4: Calcium channel blockers (Verapamil)
• Group 5: Miscellaneous group (Adenosine, K+, Mg2+)

Question 2

Classify the Arrhythmias.

Answer 2

1. Brady versus tachyarrhythmias: bradyarrhythmias normally can’t be treated with pharmacology. Can only give atropine in sinus brady from high parasympathetic tone. most drugs are for tachycardias.
2. Supraventricular versus ventricular
3. Impulse generation versus conduction problems

Question 3

Physiology: What happens during phase 4 of a SA nodal action potential?**

Answer 3

In Phase 4, there is a rising membrane potential due to the inward Na+ current from the funny channels. Sympathetic tone influences more Na influx via cAMP (β1 action). Reaching the threshold sooner can result in a tachycardia. Beta blockers inhibit here on this phase**.

Question 4

Physiology: What happens during phase 4 in a ventricular action potential?

Answer 4

In phase 4: mostly K+ efflux and Na/K ATPase. Na etc are all in resting state (-85 mV). Reach threshold from other cells depolarizing, around -55 mV.

Question 5

List the Vaughan-Williams Classification of Antiarrhythmics?

Answer 5

• Class I: Sodium channel blockers
• Class II: β blockers (Only some of them, and all are older drugs)
• Class III: Potassium channel blockers
• Class IV: L-type Calcium channel blockers
• Others: Adenosine, Mg2+, Atropine and digoxin

Question 6

Adenosine

Answer 6

• A1 receptors → outward K+ current ↑ → hyperpolarization + less Ca2+ influx in nodes - In heart, adenosine acts on nodal cells similar to Ach. results in hyperpolarization (more potassium current). dramatic overshoot of membrane potential slows down frequency for about 20 seconds and interrupt the reentry.

Question 7

What are the indications for the use of Mg2+?

Answer 7

Only indicated in Torsade de pointes: - Torsade is a “pro-arrhythmia”, it can start or stop spontaneously. If it doesn’t stop, then it turns to “real” arrhythmia, ventricular tachycardia. - Not really understood why, seems to be a calcium antagonist.

Question 8

What are the indications of Atropine use as an antiarrhythmic?

Answer 8

• Rarely used now. current protocols say atropine can be used for SA or AV block if it’s because of high parasympathetic tone. - Has been removed from resuscitation protocol and 3rd grade AV block

Question 9

What are the indications for Digoxin use?

Answer 9

• Can be used in A-fib or A-flutter as rate control - Parasympathomimetic effect: similar indications to B blockers and CCB ( treat rapid ventricular response in SVTs)

Question 10

Name the drugs in group IV in the vaughan-williams classification?

Answer 10

L-type Calcium channel blockers drugs: 1. Verapamil 2. Diltiazem (not really used for arrhythmias)

Question 11

What is Verapamil MOA?

Answer 11

1. Most strong effect seen in nodal cells. can widen AP duration, slowing the rate 2. AV node seems more sensitive than SA node. so usually indicated in nodal reentry-based tachyarrhythmias, used in a-fib and a-flutter as rate control.

Question 12

Name the drugs in group III of Vaughan-Williams classification.

Answer 12

Postassium channel blockers: 1. Amiodarone 2. Dronedarone 3. Vernakalant 4. Sotalol 5. Ibutilide and Dofetilide 6. Bretylium

Question 13

What is the MOA of Amidarone?

Answer 13

Amiodarone is the most popular and most important drug out of group III. It binds to all kinds of things, all types of anti-arrhythmics, sodium channels, non-selective beta blocking, non-competitive, binds to potassium, inhibits L-type calcium channels, most efficient. may even reverse v-fib alone.

Question 14

What is the MOA and Indications for Dronedarone?

Answer 14

MOA: similar but doesn’t come w/ iodine. no thyroid dysfunction. mechanisms are similar tho, can bind most. not as good as amiodarone against ventricular arrhythmias. Indications: mostly indicated w/ atrial fibrillation.. can be used if resistant a-fib. but not actually better for a-fib more negative inotropic than amiodarone. drug is old but re-licensed recently for a-fib.

Question 15

What is the MOA of Vernakalant?

Answer 15

MOA: inhibits transient outward K current (phase 1 inhibition) → ideally prolonged action potential w/o slowing down repolarization. but this is not what occurs bc also inhibits Na channels.

Question 16

What is the MOA and indication for Sotalol?

Answer 16

MOA: non-selective β blocker and potassium channel blocker. usually given in racemic mixture (L-sotalol and D-sotalol. one is the β blocker and the other is the K blocker). believed that maybe β blockers can protect against torsade. Indications: in lower dose indicated for SVTs. when you exceed this dose limit, it becomes indicated for inhibition of ventricular tachyarrhythmias (marked widening of action potential, but torsade risk jumps over this dose)

Question 17

What is the MOA and indications of Ibutilide and Dofetilide ?

Answer 17

Ibutilide and Dofetilide: - MOA: pure potassium channel blockers. induce torsade with high rate. - Indicated in a-fib in countries where they are licensed. more rare.

Question 18

What is the MOA of Bretylium?

Answer 18

Bretylium: K+ blocker, Na+ blocker, and also inhibits NE release (mentioned in one of the earlier adrenergic topics).

Question 19

What is the MOA of β blockers in group II Vaughan-Williams Classifications?

Answer 19

MOA: cAMP ↓ → phase 4 slope ↓ + longer repolarization. Risk of heart block.

Question 20

Name the Sodium channel blockers in group I/A?

Answer 20

I/A - not popular anymore. Moderate Na+ channel binding. Widens action potential duration. 1. Quinidine 2. Procainamide 3. Disopyramide 4. Prajmaline

Question 21

What is the indication for the use of Verapamil?

Answer 21

Indicated in nodal reentry-based tachy-arrhythmias, used in a-fib and a-flutter as rate control. others indications: • chronic stable angina • prinzmetal angina • hypertension

Question 22

What are the side effects of taking Verapamil?

Answer 22

side effects include: 1. Bradycardia 2. Constipation 3. Hypotension 4. Gingival hyperplasia *avoid combination of IV verapamil with beta blockers. causes heart block! (not absolutely contraindicated if oral beta blockers, but must be cautious)

Question 23

Pharmacokinetics of Verapamil?

Answer 23

Elimination: high first pass metabolism in liver Administration: oral dose is much higher than IV dose.

Question 24

What are the side effects of taking Adenosine?

Answer 24

Side effects include: 1. patients feel like they’re going to die for a short time, can’t breathe (bronchospasm). but doesn’t last long. 2. hot flush, vasodilation, hypotension 3. doesn’t prevent arrhythmias. organic reasons for PSVT can cause it to return. NOTE: that xanthine drugs block adenosine receptors

Question 25

What are the indications for the use of Adensine?

Answer 25

Indicated in PSVT. maybe can differentiate a-fib with RVR versus PSVT

Question 26

Physiology: What occurs during phase 0 of the SA nodal action potential?

Answer 26

In Phase 0, depolarization starts with T-type Ca2+ and then L-type afterwards. No K+ conductance. Calcium channel blockers inhibit some here.

Question 27

Physiology: What happens in phase 3 of the SA nodal action potential?

Answer 27

In phase 3, eventually calcium channels have stopped and fast repolarization occurs. Membrane potential drops well below threshold and cycle starts over again. potassium channel blockers inhibit here

Question 28

Physiology: What happens in phase 1-2 of the SA nodal action potential?

Answer 28

In phase 1-2 which is the peak of the action potential, potassium channels open (inward depolarizing), and outward current initially balance each other causing a slow infliction in membrane potential.

Question 29

Physiology: what happens to the parasympathetic tone during SA nodal action potential?

Answer 29

Parasympathetic tone: M2 (Gi) - Gi α inhibits cAMP production but also adds an additional potassium current to repolarization. Accelerates repolarization + overshoots in repolarization phase more. Threshold is reached later causing bradycardia. (atropine inhibits here)

Question 30

What effects does sodium channel blockers have on SA nodal action potential?

Answer 30

Sodium channel blockers do not inhibit nodal function! Doesn’t affect HR like the others.

Question 31

Physiology: what happens in phase 0 of ventricular action potential?

Answer 31

In phase 0, VG-Na channels open → sodium conducted inwardly (ONLY sodium). reached to +30 mV, then Na channels quickly inactivate/close (no chance to re-depolarize the cell). some Na channel blockers can make the slope of this less steep (groups I/A and I/C). sodium channels show different affinity for different types of Na channels at different states - they don’t bind to resting channels but opening ones like here.

Question 32

Physiology: What happens in phase 3 of ventricular action potential?

Answer 32

In phase 3, more calcium channels reach resting state.

Question 33

Physiology: What happens in phase 2 of ventricular action potential?

Answer 33

In phase 2, plateau phase until L-type Ca channels inactivate and close (absolute refractory period).

Question 34

Physiology: What happens during phase 1 of ventricular action potential?

Answer 34

In phase 1, there is a rapid drop in membrane potential from transient outward K. but L-type calcium channels slowly begin to open and plateau begins. Calcium channel blockers, dramatically shorten the AP here. It can lead to desynchronization of the cells which could then lead to v-fib. Can also block K+ channels to slow down repolarization, lengthen it. Can even eliminate ventricular fibrillation! but can also cause long QT → base for triggered activity → early after depolarization → torsades de pointes. Any drug that inhibits K channels / causes QT prolongation (ziprasidone, some macrolides..).

Question 35

What are the indications for the use of Propranolol?

Answer 35

• Propranolol is a non-selective to β1 or β2 blocker. It has some sodium channel blocking activity too and inhibits T3 formation (some). - Propranolol is useful in hyperthyroidism - very important here: thyrotoxicosis can cause tachycardias; high-output heart failure can occur with high O2 demands and tachycardias

Question 36

What is the MOA of Esmolol?

Answer 36

• Esmolol is a short-acting cardioselective beta blocker - It’s only given as infusion - After ending the infusion, duration of action is about 9 minutes.

Question 37

What are the indications for the use of Atenolol?

Answer 37

• Atenolol is also mainly used in supraventricular tachyarrhythmias. - In some countries, also Ventricular extrasystole (VES). - Beta blockers decrease calcium current, they may be protective against torsade.

Question 38

What are the indications for the use of Metoprolol?

Answer 38

Metoprolol exists in oral or parenteral form. 1. Used in supraventricular tachyarrhythmias

Question 39

Name the sodium channel blockers in I/B?

Answer 39

I/B: very fast acting. Least Na+ channel binding – blocks only during AP, rapid binding/unbinding 1. Lidocaine 2. Phenytoin 3. Oral lidocaine drugs: mexiletin, tocainide

Question 40

Name the sodium channel blockers in I/C?

Answer 40

I/C: strongest Na+ channel binding. QRS is widened (rate-dependent effect), but AP duration is the same. 1. Propafenone 2. Encainide, Flecainide.

Question 41

Encainide, Flecainide?

Answer 41

• Slow dissociation, very long QRS, strong use dependence. - more typical I/C. slow. inhibit higher fraction of Na drugs, so ventricular AP slope is even steeper. action is the same as any sodium channel blocker effect. • efficient for A-fib, but increase mortality after MI. don’t use much - mainly indicated for supraventricular tachycardias.

Question 42

Propafenone:

Answer 42

more popular. Used for SVTs (a-fib, a-flutter) • intermediate between I/A and I/C. slower than quinidine in terms of its dissociation time, but faster than real I/C drugs. • also a β blocker (propranolol) - decrease chance of triggered activity • very efficient with supraventricular tachyarrhythmias • CI if ischemic / structural disease - pro-arrhythmic in this case (opposite to lidocaine) • side effects are mainly similar to β blockers • just sometimes observed torsades

Question 43

oral lidocaine drugs?

Answer 43

“Oral lidocaine drugs” - • mexiletin: prevent ventricular extrasystoles or tachycardia o can cause all Na channel blocking side effects. N/V/D, ataxia, tremor, double vision etc • tocainide

Question 44

What is Diltiazem’s indication in Arrhytmias?

Answer 44

Diltiazem is not really used for arrhythmias

Question 45

Phenytoin

Answer 45

• Phenytoin: • depends on country if its licensed. not used in hungary, but some countries it is the main drug for digitalis intoxication. • also indicated to shorten QT interval if someone has long QT syndrome.

Question 46

Lidocaine

Answer 46

• Lidocaine: shortens AP duration / refractory period. No risk of torsade. • not used orally bc first pass metabolism is too high. parenteral, IV o usually 100 mg IV first and then to prolong action need infusion (6mg/minute rate) • only VG Na channel blocking effect, nothing else! o won’t affect nodal function at all • no affect on SVT reentry-based. main indication is ventricular tachyarrhythmia • if you give it to normally-functioning heart, it won’t make a difference. jumps on open channels then jumps off before the next AP o however, if you have high ventricular rate, lidocaine stays on and can prevent extrasystoles/ ventricular tachycardia o Selective to His/Purkinje/Ventricles. More selective when the tissue is ischemic. • not as popular anymore. used to be routine after AMI, but no benefit. • may be considered for digitalis intoxication • or to maybe help after electric shock for v-fib, prevents relapse • side effects are minimal if not used at very high dose. Neurological side effects.

Question 47

What is the MOA and indications for Prajmaline?

Answer 47

MOA: Prajmaline is a pure Na and K channel blocker. not anticholinergic or ganglion blocker. atrial and nodal cells are more sensitive than ventricular cells. Indications: Maybe indicated for PSVT like in WPW or LGL

Question 48

What are the side effects of Vernakalant?

Answer 48

1. Bradycardia 2. Hypotension 3. Probably Torsade de pointes

Question 49

What are the indications for Amidarone use?

Answer 49

Indications: - both supraventricular and ventricular arrhythmias, both acute and chronically.. pharm cardioversion. protective: doesn’t provoke torsades.

Question 50

What is the MOA and the indications for Disopyramide?

Answer 50

• like a boosted quinidine. anticholinergic action as strong as atropine (causes all those side effects). stronger negative inotropic too. - good in hypertrophic cardiomyopathy, bc HCM has 2 problems: bad LV emptying from septum partially closing aorta (lower inotropy can help here) and hypoxia based arrhythmias reduced

Question 51

What is the SE of Amidarone?

Answer 51

SE: 1. negative inotropic effect. may decompensate patients with heart failure. 2. As pacemaker is slower, may cause bradycardia and AV block. 3. Contains iodine (amiodarone) – can → hyper or hypothyroidism. must check thyroid function regularly. 4. long-run → pulmonary fibrosis. need regular lung check. 5. Can be hepatotoxic, may cause liver adenomas. Inhibits CYP450s 6. may form corneal deposits / spots (gray deposits → halos, rarely blindness) 7. half-life varies individually. between 2 weeks and 100 days (!) - not plasma concentration but terminal half-life. if you use amiodarone for a long time, it accumulates in SubQ and when you stop it takes a long time to be eliminated. subQ deposits → bluish-grayish colors, photodermatitis in sun-exposed areas. 8. much better to use this drug acutely than chronically. normally cardiology depts just use amiodarone, and if it’s not able to be used then propafenone. ***

Question 52

Quinidine?

Answer 52

Quinidine: main one [Sorry about this description in particular, was just writing down whatever Riba was saying and it’s probably hard to follow] • dissociation time is 1-2 seconds (quite long) • doesn’t bind to resting channel, but has affinity for open or inactivated channel and inhibits. Means the time while sodium channels are in an inactivated state is longer. when channel comes back to the other stage, it recovers from block. AP comes, quinidine binds to inactivated channel, remains there even during diastole, and channels are recovering but chances are by next AP, some channels are still inactivated. if you decrease the resting channel pool, current will be lower. decrease slope in depolarization, inhibit ventricular phase 0 • importance can be seen in between 2 action potentials o more efficient when the frequency is high - “use dependent effect”. higher the frequency, the greater the inhibition • all sodium channel blockers can inhibit w/ high ventricular rate: VES, ventricular tachycardia. block future action potentials. • More things about quinidine: o also K+ channel blocker - slows down pacemaker, prolongs QT interval o atrial fibrillation, flutter, AV nodal reentry could even be reversed or prevented. WPW o has some anti-malaria activity similar to quinine. quinine can cause severe bradycardia, but quinidine doesn’t bc it has parasympatholytic activity (antimuscarinic). can even cause tachycardia. o Causes cinchonism: tinnitus, headache, dizziness o negative inotropic action, not good for CHF patients (even though they’re susceptible to arrhythmia) –probably contraindicated with heart failure o may have some alpha blocking effect, vasodilatory action o may cause thrombocytopenia • can be indicated acutely for tx or chronically for prevention • cheap

Question 53

What is the MOA and the indications for Procainamide?

Answer 53

• Procainamide is an ester like local anesthetics, but only used as an antiarrhythmic. (not used much anymore) - can be used acutely for SVT, but don’t use chronically.

Question 54

What is the MOA of Quinidine?

Answer 54

Quinidine: main one (dissociation time is 1-2 seconds, quite long) MOA: doesn’t bind to resting channel, but has affinity for openor inactivated channel and inhibits. Means the time while sodium channels are in an inactivated state is longer. when channel comes back to the other stage, it recovers from block. AP comes, quinidine binds to inactivated channel, remains there even during diastole, and channels are recovering but chances are by next AP, some channels are still inactivated. if you decrease the resting channel pool, current will be lower. decrease slope in depolarization, inhibit ventricular phase 0. importance can be seen in between 2 action potentials. more efficient when the frequency is high - “use dependent effect”. higher the frequency, the greater the inhibition. all sodium channel blockers can inhibit w/ high ventricular rate: VES, ventricular tachycardia. block future action potentials. also K+ channel blocker - slows down pacemaker, prolongs QT interval.

Question 55

What are the contraindications of Dronedarone?

Answer 55

• Absolutely contraindicated in CHF! - Severe hepatic impairment was observed.

Question 56

What are the indications for quinidine?

Answer 56

Quinidine is a cheap option and can be indicated in: - atrial fibrillation, flutter, AV nodal reentry could even be reversed or prevented. WPW - has some anti-malaria activity similar to quinine. quinine can cause severe bradycardia, but quinidine doesn’t bc it has parasympatholytic activity (antimuscarinic). can even cause tachycardia. - can be indicated acutely for tx or chronically for prevention.

Question 57

What are the side effects of Quinidine?

Answer 57

1. Causes cinchonism: tinnitus, headache, dizziness
2. Negative inotropic action, not good for CHF patients (even though they’re susceptible to arrhythmia) –probably contraindicated with heart failure
3. May have some alpha blocking effect, vasodilatory action.
4. May cause thrombocytopenia