Pharmacology- Drugs for Cardiac Arrhythmias

Arrhythmias -alteration of cardiac rhythm -abnormality in impulse ___ ( ) (3) -abnormality in impulse ___( ) (2)

*Abnormality in impulse generator (automaticity)* -chemicals (meds) -hypoxemia -electrolyte abnormalities -Na & K, K even more so -K EC [ ] is lower--> doesn't take much to exert a more prominent physiologic effect -tends to be more damaging w/ changes -Class I & Class III themselves may induce their own arrhythmias *Abnormality in impulse conduction (reentrant)* -ischemia or hypoxic damage of myocardium

Overall Arrhythmia Types *Atrial fibrillation* *Atrial Flutter* *Paroxysmal supraventricular tachycardia* *Ventricular tachycardia*(3) *Vfib* (2)

*Atrial fibrillation* -extremely rapid & irregular atrial rhythm (200-240 bpm) *Atrial Flutter* -heart upper chambers beat to quickly *Paroxysmal supraventricular tachycardia* -episodic tachy originating from atria *Ventricular tachycardia* -tachycardia originates from ventricles -*torsade de pointes*--> prolonged QT, often drug induced *Vfib* -irregular & chaotic ventricular rhythm -often results in no CO & CV collapse

*Look at the graph* -KNOW Class 1a Class 1b Class 1c

*Class 1a* (red) -blocks Na influx & K efflux, slows rate of depolarization, extend repolarization *Class 1b* (blue) -blocks open & closed Na channels, promote K efflux & shorten repolarization *Class 1c* (green) -Na channel blockers, don't effect K channels, slow rate of depolarization , no effect on repolarization

Vaughan Williams Classification of Agents

*Class I* (Ia, Ib, Ic) (Na+ channel blocker) -Ic pure Na blocker *Class II* (Beta blockers) *Class III* (K channel blockers) *Class IV* (Ca channel blockers)

Class 1a Class 1b Class 1c Drugs we need to know (3)

*Double quarter pounder w/ lecttuce and mayo, more fries please* Disopyramide *Quinidine* (class 1a) Procainamide *Lidocaine* (class 1b) Mexilitine Moricizine *Flecainide* (class 1c) Propafenone

*Class III* Mechanism Examples (3 KNOW)

*Mechanism* -blockade of K efflux -increase refractory period -Prolong QT Examples: *Dofetilide* -purest of the K channel blockers *Sotalol (betapace)* -also a beta-blocker at lower doses -renal excretion -requires dose adjustments *Amiodarone* Also: Dronedarone- similar to amiodarone but doesn't work as well -no iodine in it -when they modified the drug, they took away a lot of its efficacy but fewer SEs Ibutilide- -used for cardioverting -more so this one Bretylium -used for cardioverting

Look at Cardiac Rhythm *P wave* (4) *QRS wave* (2) *T wave* (1) *QT interval*

*P wave*- atrial depolarization -atria contracting -in btw P & QRS, blood flowing from atria to ventricles-->pause -this distance tells you how long its taking to do this -*drugs can SLOW this down, widen the PR interval* (beta-blockers, Ca+ channel blockers (non-dihyropyridines) -propanol, verapamil) - slow HR down *QRS wave*- ventricular depolarization -Na influx into cell *T wave* -ventricular repolarization *QT interval* -distance btw the Q wave & end of T wave -K leaving the cell

Action Potential of Cardiac Cells *Phase 0* *Phase 1* *Phase 2*

*Phase 0*- rapid depolarization -activation of Na+ channels & rapid influx of NA+ -membrane potential depolarizes to (+) values *Phase 1* -Partial repolarization -inactivation of Na+ channels w/ some K+ efflux *Phase 2*-Plateau Phase -activation of Ca+ channels & slow influx of Ca+ -membrane potential remains depolarized

Action Potential of Cardiac Cells *Phase 3* *Phase 4* Two biggest components pharmacologically are phases ___ & ___: ____ & ____

*Phase 3*- End of repolarization -inactivation of Ca+ channels & rapid efflux of K+ -membrane potential repolarizes to resting potential *Phase 4* -Rest membrane potential -activation of Na+-K+ pump to maintain RMP -Two biggest components pharmacologically are phases 0 & 3 : depolarization & repolarization

*Sotalol (betapace)* -very commonly used to treat What would it do to the EKG? Adverse effects (4) Use

-arrhythmias -fairly well-tolerated -good place to start What would it do to the EKG? -slow HR -wider PR interval -lengthening of QT interval Adverse effects: -arrhythmias (bradycardia, torsades de pointes) -fatigue -dizziness -dyspnea Use: atrial & ventricular arrhythmias -especially good for atrial arrhythmias bc its a beta-blocker -also can be useful for ventricular arrhymias bc its chemically modifying K channel outflow, and thus can affect the heart wherever that's happening -if you can't tolerate sotalol or you have a life-threatening arrhythmia, you would use amiodarone

*Class II* ___- blockers -e.g. 3 Mechanism Adverse effects: (4) Use:

-beta- blockers -metoprolol, atenolol, esmolol (given by continuous IV infusion, cleared almost as fast as administered) *Mechanism* -beta-1 selective antagonists -reduce conduction velocity -increase PR interval *Adverse effects* -bradycardia -fatigue -dyspnea, bronchospasm (may happen at higher doses) *Use* -atrial arrhythmias

Why do we care about treating arrhythmias?

-depending on severity & type--> there could be hemodynamic compromise & imminent death (want to prevent death) -trying to prevent some of the complications that result from chronic hemodynamic changes/compromises -improve quality of life (improve sxs & help ppl feel better)

Class III Agents *Amiodarone (cordarone, pacerone) 3 1/2 life ? VD?

-exhibits properties of all 4 classes -blocks Na channels, K channels, Ca channels, and beta receptors -blocks more K than other things -most effective anti-arrhythmic, but also the most toxic -long 1/2-life & large volume distribution (T1/2= 13-130 days)-->1/2 life gets longer the longer you've been on the med (Vd=10,000 liters- highly lipophilic) -highly protein bound -extensive hepatic metabolism (CYP450) ---> can be a substrate or inhibitor of these enzymes -can persist for months after you've stopped taking it bc of the super long half-life

Class III Agents *Dofetilide (Tikosyn)* clearance: contraindications: (4) adverse effects: use:

-pure class III antiarrhythmic (pure K channel blocker) -best tolerated! clearance: 2/3 renal, 1/3 hepatic -check kidney & liver fx contraindications: -congenital or acquired long QT syndrome -QT > 440 msce -CrCl <20 ml/mm -Drug interactions (ex/ verapamil, cimetidine, certain azole antifungals) adverse effects: -arrhythmias -torsades de points (up tp 3%) -->very high risk for QT prolongation in the pop we would want to use these in (studies done on pts that could tolerate these) -headache -CP -dizziness use: atrial arrhythmias

Why do we care about treating arrhythmias? When we use drug therapy to do this, what are the goals of these drugs? (3)

-take an abnormal rhythm & turn it into a normal one (acutely abort the abnormality) -prevent one from happening in the 1st place -may also induce its own arrhythmia (cause induce abnormal rhythms in the heart, some inherent risk when using these) (class 1 or class 3) *** now-a-days moving more towards procedures & devices

*QT interval* -distance btw the Q wave & end of T wave -K leaving the cell Why do we care about this? (6) Ideally, Qt interval should be no more than ___% of R-R interval.

-the longer this is, the greater the chances that someone might have an early depolarization -*refractory period*-some other AP might be triggered again & give you a premature depolarization -the longer that *refractory period (QT interval)* is, the greater chance of that to occur, greater you risk of having an abnormal ventricular beat (potentially a vfib) -ideally, QT interval should be no more than 50% of R-R interval -when it starts to consume more than that, we start to get really concerned -greater risk for early after depolarizations

Antiarrhythmic Therapy (3)

1-Medications 2-Radiofrequency catheter ablation 3-Implantable cardiac defibrillator (ICD)

*Amiodarone (cordarone, pacerone) 4 things you need to monitor

1-PFTs 2-thyroid functioning test 3-LFTs 4-Regular eye exams

Class II Agents *Amiodarone (cordarone, pacerone) Adverse Effects: (8) Use:

1-Tosades de pointes (lowest risk, ~0.5%) -least likely of class III drugs to prolong QT segment 2-Pulmonary fibrosis (PFTs -*most concerning* -10% of ppl get this & 10% die as a result of this -can progress to something life-threatening -*PFTs to monitor this* 3-Corneal microdeposits (eye exams) -abnormalities in vision -can lower dose or stop if seeing occulded vision -*regular eye exams* 4-Skin pigmentation -skin can change color (bluish) 5-Photosensitivity -more sensitive to UV light specifically --> this will change the skin color - only happens on parts exposed to the sun 6-Hepatic dysfunction (LFTs) -can be a stress on the liver to the pt of hepatotoxicity -*check LFTs* 7-Hypo/hyperthyroidism (TFTs) -amiodarone looks like iodine -what do we produce that looks like iodine? -thyroid hormone -body might think it is thyroid hormone, stop producing it--> drop in thyroid activity --> hypothyroidism or can induce hyperthyroidism -*monitor thyroid function* 8-Neuropathies Use: atrial & ventricular arrhythmias -severe hx of vent arrhythmias

*Dofetilide (Tikosyn)* If we want to start someone on this drug what do we do?

1-monitor organ fx 2-baseline EKG 3-admit to hospital to take drug initially and monitor EKG over the next few days to see if they are tolerating it well -if goes well, can send them home on the drug

A-fib & rate vs rhythm control (look at chart)

A-fib MC type of arrhythmia -will encounter this over and over again -approach is 3-fold: -not sig enough for me to do anything: watch & wait approach -more common: severe enough that it needs tx (correct underlying arrhythmia or don't correct but prevent complications that occur w/ it) -can use chronic meds to keep ppl in normal rhythm (or just reduce rate & prevent complications like coag)

Class IV What are they? ex/ 2 KNOW Mechanism: Adverse effects: (4) Use:

Ca channel blockers (non-dihydropyridine) -*verapamil* -*diltiazem* Mechanism: -inhibit influx of Ca through channels -decreased conduction velocity -increased PR interval Adverse effects: 1-bradycardia 2-hypotension 3-constipation 4-drug interactions Use: atrial arrhythmias

What Class of drugs may induce there own arrhythmia's?

Class I & Class III

Vaughen Williams Classification of Agents

Class I (Ia, Ib, Ic) -Na channel blockers Class II -beta-blockers Class III -K channel blockers Class IV -Ca channel blockers

*Class Ib* Mechanism: (2) Examples: (4) Adverse effects: (2) Use: (1)

Mechanism: -*little blockade of Na influx* - no/minimal effect on depolarization -*shortened repolarization* --->shortening of refractory period ---->net effect promoting K efflux --->shorten QT interval (for someone who presents w/ treatable QT prolongation) Examples: *lidocaine*- local anesthetic, w/in cardiac AP can have a pronounced effect Mexilitine (Tocainide, Phenytoin-->dilantin/anticonvulsant) Adverse effects: -mainly CNS (confusion, dizziness, ataxia, tremor) -OD or take them away abruptly may induce seizure activity -Also GI (nausea) Use: *ventricular arrhythmias* -used more emergently -arrhythmias that are life-threatening like torsade de pointes

*Class Ia* Mechanism: 1-(2) 2-(2) examples (3- KNOW THESE!) Adverse effects: (4) Use: (2)

Mechanism: 1-*Blockade of Na influx* -decrease rate of depolarization (phase 0) -prolong QRS (wider) 2-*Blockade of K efflux* -increase refractory period -prolong QT examples: *Disopryamide*, *Quinidine*, *Procainamide* Adverse effects: -arrhythmia (torsades de pointes) -GI -Anticholingeric effects (disopyramide, quinidine) -dry mouth, constipation, urinary retention, confusion -Lupus like syndrome (procainamide) -person does not actually have lupus--> makes them feel like they have it (many of the serologies that we use to test for lupus come back positive) Use: *atrial & ventricular arrhythmias* -could be used for both -affecting ion flow -cause effects regardless of where you are in this cycle of events

*Class Ic* Mechanism: 1- (2) 2 Examples: (3) Adverse effects: (5) Use: (2)

Mechanism: 1-*blockade of NA influx* -reduce rate of depolarization -prolong QRS 2-*little/no effect on repolairzation* Examples: Moricizine *Flecainide* Propafenone Adverse effects: -arrhythmias (re: CAST) -blurred vision -dizziness -GI -bronchospasm - (w/propafenone) -some have beta-blocking effects, impair ability of smooth muscle to relax (beta-2 receptors) Use: *atrial & ventricular arrhythmias* -often used for pts that would have vent. arrhythmias that were not life-threatening but rather symptomatic -CAST study trials

Cardiac Arrhythmia Suppression Trials I & II Population Intervention Conclusion

Population- Post MI, asymptomatic or mildly symptomatic ventricular arrhythmias Interventions -Cast-I: encainide or flecainide +/- moricizine vs placebo Conclusion -drug therapy increase risk for mortality from arrhythmia -evidence that lead to seldom use of these drugs

Other agents Adenosine -mechanism: -features: -admin? -onset/ duration? -use: -dose: Adverse effects: (3)

mechanism: -slows conduction through AV node (directly suppress this) - acutely stops the heart from beating ex/ caffeine is an adenosine receptor antagonist (speeds up the heart, constricts blood vessels) -giving adenosine--> expect to do the opposite (dilate blood vessels, decrease HR) features: -IV only -fast onset, very short acting (1/2 life around 10 secs) use: PSVT dose: 6 mg IV push, if ineffective then repeat w/ 12 mg IV push Adverse effects: -CP -flushing -dyspnea (lungs fill up w/ blood)