Neuro: 11:00 – 12:00Scribe: Brittney Wise

Friday, April 24, 2009Proof: Laura Adams

Dr. KuPrinciples of Cardiovascular PharmacologyPage1 of 8

Abbreviated Terms:

  1. Introduction [S1]: Drugs Used in the Treatment of Arrhythmias and Sudden Coronary Death
  2. Notes on the board:
  3. Heart Rate  Electrical Properties  either Bradycardia or Tachycardia  Tachycardia can be further broken down into Supraventricular and Ventricular
  4. [S2]Key Points
  5. Arrhythmias are heart rate problems and/or electrical problems.
  6. Our electrical system that drives the heart involves specialized conducting tissues.
  7. You have SA Node (pacemaker), atrial fibers, AV Node, His bundles, left and right bundles, and then you have the Purkinje fibers.
  8. These are specialized wiring and they tell the heart to contract all at the same time.
  9. You can’t have some of the heart or heart cells contracting while the others are not contracting.
  10. When you have ventricular fibrillation, or any kind of fibrillation, and you look at the heart, you see something like a bed of worms; the cells are all contracting on their own. In order to correct this you need a defibrillator to stop all the extra movement/contractions and let the pacemaker take over and correct the heart rate.
  11. Take Home Messages:
  12. pacemaker cells
  13. include the ones in the SA node
  14. they have the fastest rhythms
  15. they are the natural pacemaker cells
  16. the AV node and the Purkinje fibers all have a so called primary and secondary pacemaker; they have intrinsic activity for the ability to self depolarize themselves
  17. the fastest ones dominate and that’s why we say that the SA node dominates
  18. when we have a problem with the sick sinus syndromes (injury to the sinus node) what happens is the other cells, Purkinje fibers or AV node or His bundle then take over as the secondary pacemakers; sometimes he calls this mutiny; when the natural pacemaker is not doing too well the other ones will then take over; this is when you start having arrhythmia problems
  19. non-pacemaker cells are the so called ventricular muscles
  20. these are really for contraction
  21. the other thing you have to remember from previous lectures are the ionic basis of action potentials
  22. know phases 0-4 (5 phases total) and what channels and/or conductance do they involve
  23. when a cell dies they are no longer able to maintain electrochemical gradients
  24. normally potassium is very high inside and low outside
  25. normally sodium is very high outside and low inside
  26. so you want to maintain that sodium/potassium ATPase pump
  27. if you poison the pump the cell is no longer able to maintain the sodium/potassium gradient, the cell will then have water come in and the cell will swell up and die
  28. you need energy to maintain electrochemical gradient
  29. you also need to understand the relationship between action potentials and EKGs; you can stick a
  30. action potentials are when you put an electrode into a single cell to determine
  31. you are not going to stick a single cell into someone’s heart so you use the EKG; know the different parts of the EKG (P, QRS, T) and their relation to depolarization and repolarization
  32. [S3]Classification of Arrhythmias
  33. There are two types of arrhythmias: tachycardia vs. bradycardia
  34. Tachycardia –fast heart rate; this constitutes most of the diagnosis
  35. Bradycardia –low heart rate;
  36. very hard to determine at what level of beats per minute is bradycardia, all we know is that it is a low heart rate
  37. a lot of time you don’t worry about a lower beat per minute until you start seeing people that are dealing with syncopy (passing out) then you have problems
  38. If you have a low heart rate and you are not passing out you shouldn’t worry about it
  39. Normal heart rate is about 60 beats per minute
  40. You can drop to about 50 beats per minute when you sleep
  41. Athletes or people who meditate can control themselves and can drop their heart rate to about 30, 20, or 15 beats per minute
  42. There are 2 major types of tachycardia:
  43. Supraventricular arrhythmias – anything above the AV node
  44. Ex// Atrial arrhythmias, paroxysmal atrial tachycardia (PAT), atrial flutter, atrial fibrillation, etc.
  45. Most of the time we don’t worry about the atrial problems because as long as you maintain ventricular rate you are ok because ventricular rate that determines your cardiac output
  46. More often now people with atrial flutter and atrial fibrillation problems it’s not because of heart rate problems, but because with atrial fibrillation for example, the blood is not moving; most of the time if you look at the structure of your atria the right atria tends to be smoother and the left atria tends to have more trabeculae where blood can get trapped and form a blood clot because the atria is not contracting; all of a sudden if the atria move and loosen these clots they can shoot into the brain and you can have a stroke
  47. So atrial fibrillation and atrial arrhythmias are mainly complications because of blood clots not because the cardiac output drops
  48. Ventricular arrhythmias –what we focus on the most
  49. With this you see right away a drop in your blood pressure or cardiac output
  50. [S4] Pathogenesis of Cardiac Arrhythmias
  51. What causes arrhythmias then? We have 2 basic mechanisms:
  52. #1 is due to abnormal generations of impulses
  53. #2 is due to the disorder of impulse conductions
  54. The 3 major parameters of electrical properties that you need to know are:
  55. automaticity
  56. conduction velocity
  57. excitability
  58. When you have problems with any of the above 3 you will have arrhythmic problems
  59. Abnormal generation of impulses due to automaticity problems increase the rhythms of secondary pacemaker cells such as the Purkinje fibers or the His bundles or you have trigger activities
  60. [S5]Mechanisms for Altering the Automaticity of pacemaker cells (SAN and AVN)
  61. There are different ways that you can alter the rate of firing. You can change the slope (how fast it is), the impulse potential, and/or the threshold potential.
  62. Class 2 and Class 4 antiarrhythmics drugs decrease the slope of phase 4 and phase 0.
  63. This is the primary mechanism to decrease the heart rate.
  64. [S6]Factors Influencing Automaticity
  65. Again, to summarize it he gave us a table.
  66. You can run up a flight of stairs really fast and run your heart rate up and that’s sympathetic activation. This will increase your rate of firing and increase the sympathetic tone. If you are really tired you just massage your adrenal gland and it will release epinephrine and this will get you going again.
  67. The parasympathetic will of course decrease heart rate. Right now as you are sitting in class the parasympathetic representation is very high and the sympathetic is very low.
  68. There are different ways that you can see different modulations with the autonomic system.
  69. Metabolic: includes cases like acidosis and hypoxia
  70. Mechanical: as it relates to stretch
  71. Drugs: this lecture will be talking about these in reference to antiarrhythmia drugs
  72. Electrolytes: includes things like calcium and potassium
  73. So this table is basically a summary that you should be familiar with.
  74. [S7] Abnormal Generation of Impulses
  75. Another mechanism is called triggered activities; you have DADs and EADs
  76. DADs – secondary depolarization occurring early in diastole and this is after a full repolarization has been achieved
  77. DAD stands for Delayed Afterdepolarizations
  78. The cells polarize, repolarize, depolarize, and then repolarize up and down in oscillations
  79. At the end of this phase 4 period, when they hit the threshold they can generate an action potential; this is a normal contraction
  80. Too much calcium can cause DADs (calcium overload in the cell)
  81. Drugs that cause this: catecholamines, cardiac glycosides, and digoxin
  82. EADs –stands for Early Afterdepolarizations
  83. Occur early after depolarization, early before (he said a phase but I couldn’t understand him)
  84. These are a secondary/slow inward Na current, most frequently related to Torsades de Pointes.
  85. By clinical definition, if you have just one depolarization then that’s ok but when you get up to 6 per minute you start classifying it as ventricular arrhythmias.
  86. Eventually this can lead to spontaneous or ventricular tachycardia because you have too calcium. We need calcium but too much is never good.
  87. These cannot initiate by themselves. What is the difference between these and auto-rhymicity? The auto-rhythmic cells can initiate by themselves (ex// SA node).
  88. These trigger activities cannot initiate by themselves; they always have to have something preceding them. But they can sustain themselves once they have been activated.
  89. [S8] Pathogenesis of Cardiac Arrhythmias
  90. We are now going to move onto impulse conduction. We are moving onto excitability and conductivity issues.
  91. Non-uniformities:
  92. The problem is that the heart must have uniform conductivity just like wiring; you cannot have one area overloaded; if you overload you can have one area that starts a fire (and that’s basically what happens in the heart)
  93. When the heart is getting big and you are about to have a heart attack (where certain cardiac muscle cells die) you can say the heart was non-uniform and that the current was no longer passing through the heart attack area uniformly.
  94. This is what reentry arrhythmias are all about. They are due to 2 things (1) the non-uniformity of excitability and (2) the non-uniformities of conductivity.
  95. When you increase the excitability what we are talking about is the ERP. ERP stands for effective refractory period. During ERP basically the heart will not respond and you need a higher voltage to get the heart excited and for the cells to fire. The longer this period you can say the less excitable this tissue is because it takes it longer before you can get it excited. If the refractory period is getting narrower then it is getting more excitable.
  96. The yellow line on the graph shows you the less excitable graph where you stretch the action potential duration.
  97. How do you increase action potential duration? How do you change the ERP? Very easily, you go back to the ionic basis and inhibit sodium or potassium channels.
  98. So again, you change the ERP by changing the potassium channels. If you activate potassium channels they will repolarize very fast. If you block them they will change the excitability of your cell.
  99. Phase 3: remember that during this phase the reason the cell repolarizes is due to potassium efflux is happening; if you block this potassium channel then you will prolong the action potential duration so that they are not repolarizing.
  100. SQ: Is the ERP the same as the absolute refractory period?
  101. Answer: During the absolute refractory period nothing can happen. Regarding the ERP, during this period the cell will respond.
  102. [S9]Major Determinants of Conduction Velocity
  103. How do we decide conduction velocity? By 2 things: (1) upstroke of velocity of phase 0, how fast is phase 0, how fast does sodium rush into the cell,and (2) the amplitude of the upstroke.
  104. If you start with -90 and then change to -95 the height is more and you can conduct faster. This is a basic principle of conduction velocity.
  105. If you look at this you can see Purkinje fibers and ventricular muscle. These can conduct very fast.
  106. However, the AV node conducts very slowly. The upstroke and the amplitude are very slow.
  107. There used to be a cable theory taught back in high school. So just like when you buy extension cords, you buy good ones that are thick. The thicker they are the faster they conduct.
  108. Purkinje fiber has a very thick cable that conducts very fast.
  109. [S10] Graphs (please note that this slide was very hard to transcribe because he was very unclear with what he was referring to on the slide)
  110. If you put excitability and conductivity together you getreentry arrhythmias. This is top left graph is showing a signal coming down from the SA node going through the atrial fibers, to the AV node, then to the His bundle, and then branching into the Purkinje branches. The signal then comes into the muscle fiber, depolarizes the cells and you get an action potential that shows up on the EKG.
  111. What happens when you have a mini heart attack or areas of ischemia? One or more of the fibers is damaged so it’s considered ½ dead. We need to define ischemia vs. infarcted.
  112. Ischemia means that you have an imbalance between supply and demand. You can salvage these cells and bring them back to normal.
  113. Infarction means that you have necrotic or dead cells that will form scar tissue and cannot regenerate.
  114. With ischemic injury the cells are very sluggish and they don’t respond very well. This is what happens after a mini heart attack. What happens is when a signal comes in the cells are just not ready and they don’t respond.
  115. (If you can picture the graph as top, middle, and bottom I think it will help you follow what he says below.)
  116. The top graph responds perfectly so they conduct very quickly.
  117. The bottom graph depolarizes and then it figures out that there is another way for it to get back to the block. So these cells are able to respond now that they have recycled back the current.
  118. Basically what you see in the bottom 2 graphs is that the front door is locked but the back door is open, so the current comes back through the back door forming a circuit. This is what allows for an extra stimulus or extra contraction.
  119. [S11] Reentry Arrhythmia (with unidirectional block)
  120. This is a cartoon illustration that is showing you a normal action potential with all the phases.
  121. Ischemic cells (decrease oxygen supply/demand) have a low ATP. When you don’t have enough ATP what happened to the sodium; potassium ATPase pumps? Answer: it becomes sluggish. When it becomes sluggish they are not pumping sodium out and potassium in so you get a lot of accumulation of sodium and calcium in the cell. What happens when you have positive charges inside the cell is that you become less negative. You need to pump the sodium out because you need the cell to become more negative and ready for the next action potential.
  122. If you become sluggish you get a lot of positive inside the cell so the cells are basically partially depolarized. They are not as good as normal cells so when a stimulus comes they will depolarize correctly the 1st time but since they are slow it will slow down the conduction. So the whole process becomes very slow. So, when the 2nd stimulus comes in, a normal cell will be able to fire, but the ischemic cell will not be able to fire. They are blocked.
  123. When the cells are blocked, if you wait for a few millisecondswhen the current comes back in the cell will be ready to depolarize and they will fire again. This is what we call reentry stimulus.
  124. So 2 things, excitability ERP problems increase ERP and conduction problems. This is a reentry arrhythmia.
  125. Once we understand this how do we treat this?
  126. You can increase your ERP further. If do this even the reentry can’t come in and you won’t respond. This is what we call creating a bi-directional block. Blocking front and back.
  127. Or you can eliminate a block and shift the ERP back to the left. This allows the cell to now respond.
  128. [S12] Conditions Required for Cardiac Reentry
  129. So this is showing you that in order to have a reentry to occur you have to have 3 things:
  130. You have to have a loop
  131. Unidirectional block
  132. Zone of slow conduction
  133. The normal myocardium has a very small heart you have very fast/rapid conduction fibers, so you don’t have this reentry problem.
  134. But when you have a hypertrophied heart, the heart is getting bigger and you are trying to supply electricity to a larger heart. Why do you have a hypertrophied heart? Answer: hypertension, congestive heart failure, any of these things will cause it.
  135. It is more likely for you to have arrhythmias with these conditions. They are all related in some way.
  136. [S13] Reentry Sites of 3 Major Arrhythmias
  137. This is just showing you the different types of arrhythmias that you can have. This is the ventricular tachycardia that he talked about (Wolf-Parkinson-White). This is very clinical so don’t worry about it.
  138. [S14] Class IA, IC, III, and IB
  139. One way we can do treatment it is through Class 1A, Class 1C, and Class 3 drugs.
  140. Basically you are converting the decreased membrane responsiveness and decreased conduction velocity to a bidirectional block.