Hi, I’m Catherine, and for my presentation I am going to talk about cardiac arrhythmias and the drug treatments that are available to treat them. There are two broad classes of arrhythmias, those based in the atrium, and that includes things like atrial flutter, atrial fibrillation, and basically any kind of abnormality in the sinus rhythm, and those that are based in the ventricles, like ventricular tachycardia, which is actually what I’m going to focus on in this talk.
OK, to get us started, here’s just a broad list of the topics that I’m going to cover today. We are going to start with the three main types of arrhythmias, or, more specifically, the actual issues that are going to cause a lot of the types of ventricular arrhythmias that we are interested in. Then I am going to go into the cardiac action potential, which is going to basically kind of provide a framework that will help us see how and where specific types of anti-arrhythmic drugs act. After that we’re going to talk about the ion channels that correspond to certain phases of the action potential, and after that the main system by which these drugs are classified. Then, we’re going to get into a few specific classes of drugs, and see an example from each, and some of the cardiac side effects that can become an issue. Finally, I am just going to briefly go over a few alternative treatments and talk a little bit about where drug research and development is focused in this area.
Triggered Arrhythmias are basically abnormal depolarizations triggered by normal depolarizations that have preceded them. They can occur in two contexts, either before the cell has recovered or after the cell has recovered. CLICK Automatic rhythms are rhythms whereby the heart normally beats. This can happen abnormally if for whatever reason some cardiac tissue develops spontaneous depolarization. It can occur abnormally, for instance, because of pH imbalances in certain parts of the cell’ Supraventricular or ventricular abnormal automatic mechanisms are produced by exposure to oatecholamines, reduced potassium concentrations, acidosis, low calcium concentrations, hypoxia, inhalation anesthetics, digitalis glycosides and trauma. Abnormal automaticity develops when one or a combination of these factors leads to impulse generation in tissues which may or may not normally exhibit automatic activity. Afterdepolarizations, for example, may become responsible for impulse generation in tissues which are normally automatic. CLICK Reentry is going to be the main issue that we are going to be concerned with since it causes most of the types of ventricular arrhythmias. Reentry is a unique mechanism which is dependent upon unidirectional conduction block and delayed conduction. Basically, a normal or abnormally generated impulse is slowed in its electrical activation of myocardium and has the opportunity to recirculate and reexcite tissues which have had time to undergo repolarization. This mechanism has been referred to as a circus movement. lschemia, hypoxia, acidosis and drug overdosage are believed to be the most common causes for reentry.
Commotio Cordis Commotio cordis is defined as sudden death or aborted sudden death secondary to a chest wall impact. This phenomenon is reported in 10–20 individuals a year. Nearly all are male and the mean age is 14 years. [32,33] Individuals in competitive sports account for nearly 60% of cases and impact always occurs over the left chest. Nearly one-third of those in competitive sports were wearing a chest protector. Resuscitation is possible with rapid cardiopulmonary resuscitation and defibrillation. An animal model has shown that the timing of the impact relative to the cardiac cycle is perhaps the most important variable of commotio cordis  followed by location of impact,  hardness of the impact object,  and energy of the impact object (Fig. 2).  Commercially available chest wall protection does not appear to be prevent commotio cordis.  (Enlarge Image) Figure 2. Variables and proposed mechanism of commotio cordis. In the animal model several variables of commotio cordis have been described and include characteristics of the impact object such as shape, hardness, diameter, velocity of the impact. Timing and location of the impact are perhaps the two most important variables accounting for the rarity of commotio cordis. In addition, cellular determinants of commotio cordis are just beginning to be understood; cell membrane stretch likely leads to ion channel activation which increases the dispersion of repolarization and providing the substrate for ventricular fibrillation to occur An appropriately timed ventricular contraction caused by the impact leads to ventricular fibrillation. Commotio cordis is thought to occur when a chest strike causes both altered dispersion of repolarization and a ventricular depolarization trigger. [32,39–41] The altered dispersion of repolarization is likely secondary to alterations in current flow. Thus far, the K ATP channel, normally closed but opened by myocardial ischemia with resultant increased K flow during repolarization, has been shown to be involved in commotio cordis.
The main types of ventricular arrhythmia that we are going to be concerned with are going to come from reentry. Re-entry is a self-perpetuating pattern of depolarization involving any cardiac tissues and does NOT depend on altered automaticity. It just depends on differences in the areas of the heart that allows for conduction in one area and block in another. This can exist in the form of functional or anatomic re-entry—I’ll just talk about re-entry in the context of the anatomic type because that’s how it is easiest to understand. Basically, anatomic re-entry is a block in conduction that is caused by a fixed structure (something like a scar) in the tissue. This re-entry causes ventricular arrhythmias such as ventricular tachycardia. These re-entry circuits are all made up of these cells whose activity is based on the cardiac action potential. If we are going to treat this with a drug, the action potential is the place we need to look to find out exactly what’s going on, and how we should proceed, so next I’m going to talk about the action potential since that is basically going to give us a sort of map of what is going to in the muscle cells at any one point in time.
There are 5 phases in the cardiac action potential Phase 4: resting membrane potential (-85 to -95 mV) Phase 0: depolarization (opening of Na + channels—Na + rushes in) Phase 1: inactivation of Na + channels Phase 2:influx of Ca 2+ coupled with the slow outflow of K+ causing plateau Phase 3: repolarization (release of K + ) Phase 4:resting membrane potential
Ok, now for each phase of the action potential there are ion channels that are coming into play. In phase 0, the fast sodium channels open. Phase 1 corresponds with the inactivation of the fast sodium channels. Now, in phase 2, there is an inward movement of calcium through L-type calcium channels that is coupled with an outward movement of potassium through slow-rectifier channels (Iks)…this coupling is what causes the plateau that is absent in the action potential of a normal muscle. In phase 3, the L-type calcium channels close, but the slow-rectifier potassium channels stay open, so the membrane potential is slowly becoming more negative, which ultimately causes more potassium channels to open (these being the rapid-delayed rectifiers).
-APD=action potential duration (repolarization)—repolarization longer -ERP=effective refractory period (prolongs phase 3)—functional ability to repolarize -IB: shortens only slightly -II: minor effect—not a big deal with the action potential -IV: minimal effect in ventricle OK, I am going to focus on classes I and III because these are the ones affecting the action potential directly so they will be most useful in these re-entry circuits
Class I antiarrhythmic drugs block sodium entry into cardiac cells. Class Il antiarrhythmic drugs are beta-adrenoceptor blocking agents. Theirantiarrhythmic membrane ionic activity is uncertain. Class lll antiarrhythmic drugs exhibit their activity by prolonging action potential duration and refractoriness. Class IV antiarrhythmic drugs inhibit calcium entry into cardiac cells. Because of the rapid and- intense development of Class I antiarrhythmic drugs, this group has been sub-categorized into groups IA, IB, and IC. Group IA antiarrhytnmic drugs are typified by quinidine, procainamide, and disopyramide and other drugs that depress phase-O of the action potential, have moderate effects upon conduction of the electrical impulse and prolong repolarizatíon. Class IB antiarrhythmic drugs are represented by lidocaine, mexíletine and tocainide and demonstrate mild effects on phase-O of the action potential and conduction velocity, but shorten repolarization. Class IC antiarrhythmíc drugs are represented by encaínide and flecaíníde and are known to profoundly depress phase-O of the action potential and conduction, but demonstrate little ori no effect on repolarization.
The class I drugs can completely block conduction through the weakened tissue. Since the weakened tissue isn’t going to block an entire pathway through the hear, just enough of one to cause some mischief, the wavefront will still be able to propogate in the surrounding normal tissue The Class III drugs prolong repolarization so the re-entry circuit will still begin to develop, but since only one side will have the issue, when the wave has circled all the way back around the cells that are slowed down still will not have recovered, so the wave front is just going to die out—it won’t just keep propogating.
Class IA drugs are of moderate strength; they also have some action at K+ channels Block the fast sodium channel This prolongs the phase 0 thereby slowing conduction This group includes drugs such as quinidine, procainamide, and disopyramide Indicated for the treatment of ventricular tachycardias and symptomatic premature ventricular beats Class IB drugs are the weakest of the class I drugs Effect sodium channels Little or no effect at slow heart rates—more effective at higher HRs Shorten the action potential and reduce refractoriness (speeds up phase 3) Include lidocaine, and mexiletine (oral lidocaine analog) Indicated for the treatment of ventricular tachycardia, symptomatic premature ventricular beats, and to prevent ventricular fibrillation Class IC drugs are the newest and the strongest of class I drugs Cause a strong depression of the slope of phase 0 of the cardiac action potential Decrease conductivity but have a minimal effect on action potential duration Includes flecainide, and propafenone Indicated for the treatment of life-threatening ventricular tachycardia or ventricular fibrillation, or symptomatic PVCs
As you can see here, it blunts the upstroke and prolongs phase 2
Analog of the local anesthetic procaine Long term oral treatment poorly tolerated (can cause lupus syndrome) Blocker of open Na+ channels only Has an cardioactive metabolyte (can also work as produg), procainamide and N-acetyl procainamide NAPA only blocks potassium channels Metabolized into NAPA in the liver
The IB drugs blunt the upstroke slightly because it is a weak sodium channel blocker, but it also has action at potassium channels which is why it shortens the action potential duration
Local anesthetic also used in the acute intravenous therapy of ventricular arrhythmias Blocks both open and inactivated cardiac Na+ channels Exerts greater effects in ischemic or rapidly driven tissues Decreases automaticity by reducing the slope of phase 4 and altering the threshold for excitability Action potential duration either unaffected or shortened
Given as flecainide acetate Can create re-entrant circuit Very long recovery from Na+ channel block which Blocks Na+ current and delayed rectifier K+ current Also blocks Ca2+ currents (K+ and Ca2+ blockage has not been demonstrated to be clinically revelent) Noncardiac side effects: Dose-related blurred vision and headache Originally marketed as Tambocor, but went off patent and is now available generically
It can create a new rhythm disturbance by facilitating the development of a new re-entrant circuit
Includes sotalol and amioderone
Given as a racemic mixture D-pure potassium channel blocker L-beta blocker and potassium channel blocker Major side effect is torsade which initiates a triggered arrhythmia (functional type) that is very dangerous and life-threat
The IA drugs can cause this too…early afterdepolarization which can cause torsades This is because of their potassium channel blocking actions Because of Q-T prolongation Prolonged phase 3 manifests as this on an EKG Started by triggered activity (caused by calcium overload) and probably is continued by functional re-entry
Ablation goes in and physically destroys the re-entrant circuit by burning out the tissue. ICD the arrhythmia can be terminated by pacing or by electrical shock
I just wanted to show you a picture of an ICD and how it is placed in the hear just to give you a better idea of how it works. Basically, it has a battery back / pacing machine that is going to go outside your ribcage and under the skin, with leads coming out of it that will be embedded into some of the tissues to the heart to give it the ability to pace it and to shock it if needed.
CARDIAC ARRHYTHMIAStacy Arvinna J,Group 3KSMU
TOPICS COVERED• Types of Arrhythmias – Ventricular• Cardiac Action Potential• Ion Channels of Interest• Classification of Anti-arrhythmic drugs• Drugs and Re-entry• Class I Drugs• Class III Drugs• Side Effects• Alternative Treatments and Future Drug Development
MECHANISMS OF CARDIAC ARRHYTHMIAS1. Enhancement or depression of impulse generationa. Enhanced or depressed normal automaticity from the SA node,b. Abnormal automaticity develop in atrial or ventricular myocardium.c. Triggered activity develop from normally quiescent cardiac tissueperi AV nodal or Purkinje system. due toI.early. afterdepolarizationsII.late"afèé1^depolarízations2. Abnormal conduction of the cardiac impulsea. Conduction blockb. Delayed conductionc. Unídirectional block and reentry or reflection
VENTRICULAR RE-ENTRY •Abnormal pattern of depolarization through the heart •Functional •Anatomic
THE VAUGHAN WILLIAMS CLASSIFICATION SYSTEM OF ANTI- ARRHYTHMIC DRUGSClass Basic MechanismI-Sodium Channel Blockade Reduce phase 0 slope and peak of action potentialIA Moderate reduction in phase 0 slope; increase APD; increase ERPIB Small reduction in phase 0 slope; reduce APD; decrease ERPIC Pronounced reduction in phase 0 slope; no effect on APD or ERPII-Beta-blockade Delay repolarization (phase 3) and thereby increase action potential duration and effective refractory period.III-potassium-channel blockade Prolongation of APD and increase ERP; no effect on phase 0IV-Calcium channel blockade Block L-type calcium-channels; most effective at SA and AV nodes; reduce rate and conduction.
HOW THESE DRUGS AFFECT RE-ENTRY • Class I: retards conduction enough so that beat still gets through normal cardiac tissue but not through any weakened tissue • Class III: prolongs refractoriness
CLASS I• IA – moderate• IB – weakest• IC – strongest
FUTURE OF DRUG DEVELOPMENT• Drugs with defibrillating effects – Sotalol – Tedisamil • Sympathomimetic-modulates cAMP • Protects Gap junctions and enhances Ca2+ uptake by SR• Drugs affecting Ion Channelopathy – hyperphosphorylation• Drugs or Devices?