Lesson 9

Question 1

What is the afterpolarization

Answer 1

We have seen how the heart automaticity can be altered, this altered automaticity can be induced for example by an afterdepolarization, in this case ****we have a normal action potential but at a certain point there is an extra depolarization before the occurrence of the following action potential. There are two different types of afterdepolarization:

• early afterdepolarization: It occurs during the inciting action potential or during the plateau phase, and in this graph we see an action potential and then we have the start of a repolarization but immediately after there is an early afterdepolarization with a new peak of depolarization, then there finally the repolarization. In the example the early afterdepolarization happens during phase 3 and it is caused by voltage gated sodium channels which are responsible for the upstroke and depolarization, when they open it immediately cause the depolarization, then they enter desensitization and after a while they recover the resting state so they have the possibility to open again, that is why we have a sort repolarization and then a new depolarization. If the early afterdepolarization happens repeatedly it can cause arrhythmia. As we said, sometimes an early afterdepolarization can happen during the plateau phase, in this case sodium channels are inactive and the afterdepolarization is caused by calcium channels. The early afterdepolarization is quite dangerous; when this phenomena is observed in an electrocardiogram, it is called “torsades de pointes” since it looks like a classical dancer jumping. When a patient experiences this condition, the heart chambers do not have the time to be filled with blood before the afterdepolarization so this condition might be fatal.
• delayed afterdepolarization: it happens after the end of the repolarization phase, it this case we have a slow depolarization, whose mechanism is not well understood yet, probably calcium channels are involved; most likely, there is an abnormally high Ca2+ concentration, which triggers an inward current and hence a train of abnormal action potentials, this is only an hypotesis. In this case as well arrhythmias can be developed.

Question 2

Speak about the defects in impulse conduction and the accessory tract pathway

Answer 2

The heart pacemaker cells are not the only ones which can undergo pathological conditions, infact we might also have defects in the conduction of the impulse which affects all other heart cells, this happens even when the pacemaker cells are working correctly. There are 3 main events of this type:

• re-entry: in a normal situation we have that impulse goes from SA node, to the AV node, then to the bundle of His, then Purkinje system, and finally to the myocardium. The cellular refractory period ensures that stimulated regions of the myocardium depolarize only once during the propagation of an impulse. The re-entry of an electrical impulse occurs when a self-sustaining electrical circuit stimulates an area of the myocardium repeatedly and rapidly. Two conditions must be present for a re-entrant electrical circuit to occur: a unidirectional block, meaning that forward conduction is prohibited, but retrograde conduction is permitted, and a slowed retrograde conduction velocity. So, if we look at the picture will will see that in a normal conduction, the stimulus arrives at a junction and stimulates both branches which then undergo the the refractory period and will not be stimulated anymore. In the re-entry condition, we see that the stimulus arrives at the junction and stimulates both branches but in one of the two there is a unidirectional block due to damage in that area, so here the cells are only partially in the refractory period. Then from point B, the stimulus will renter said branch with a slow retrograde conduction and then this branch can send the stimulus again to the healthy branch causing a re-entrant conduction. This leads to so we have a tachyarrhythmia which is characterized by a faster rhythm of our heart.
• Conduction block: It occurs when an impulse fails to propagate because of the presence of an area of unexcitable cardiac tissue, physiologically this happens when an healthy tissue is still refractory, pathologically it happens when the tissue has been damaged by trauma, ischemia, or scarring. So the impulse is blocked, and in this situation, the cells with spontaneous stimulation, thus the cardiac myocytes are free to beat, but they have an intrinsically slower frequency and we will have a lower rhythm called bradycardia.

THE ACCESSORY TRACT PATHWAY

In a normal cardiac cycle we have that the SA node initiates an impulse that travels quickly through the atrial myocardium and arrives at the AV node where it slows down to allow sufficient time for filling of the ventricles with blood before ventricular contraction is initiated. Then, it again propagates quickly throughout the ventricles to trigger ventricular contraction.
Now, some individuals possess accessory electrical pathways that bypass the AV node called bundle of Kent, this is due to congenital problems. An, impulse conduction through this accessory tract is more rapid than the conduction through the AV node, setting up the conditions for re-entrant tachyarrhythmias as we have previously seen. Infact in the ventricles there will be a more intense impulse and an increased rhythm causing tachyarrhythmia.

Question 3

What are the antiarrhythmics? speak about class I

Answer 3

THE ANTIARRHYTHMICS

We have seen how defects in impulse formation and altered impulse conduction can lead to disturbances in cardiac rhythm. **To solve these problems it is possible to use antiarrhythmic agents which are able to restore the normal cardiac rhythm by targeting proarrhythmic regions of the heart.

Where do these drugs work? they can work in the SA node, infact there are compounds which naturally increase the heart rhythm, such as noradrenalin, which can be used in case of bradycardia. On the other hand, if we have to slow down the heart we can use beta-antagonists, ****also we can slow down the depolarisation phase by blocking the sodium channels or we might work on phase 2 by blocking the plateau phase or even block the repolarisation. So we have 4 classes of drugs:

• Class I: they are able to block phase 0. It is divided in multiple subclasses. Class Ia is composed by drugs like disopyramide which cause the blockage of sodium channels, so they are capable to block phase 0 but also phase 3. classes Ib (lidocaine) and Ic also block sodium channels but in a different way and the only act on phase 0.
• Class II: these drugs are beta adrenoreceptors antagonists, such as propranolol and they can intervene on phase 4 and phase 2
• Class III: is the class of the potassium channel blockers which intervene on phase 3, blocking it.
• Class IV: compounds which block calcium channels thus blocking phase 2

Anyway, antiarrhythmic drugs act mainly on four targets: the diastolic potential in pacemaker cells, the rate of phase 4 depolarization, the threshold of the potential and the duration of the action potential.

They are capable of causing a state dependent channel block, we saw something similar with local anesthetics because they also work on sodium voltage gated ion channels.

CLASS I ANTIARRYTHMICS

We said that class I antiarrhythmics are sodium channel blockers, their action targets the SA cells. This can happen in two ways: they can shift the potential threshold causing a more positive potential or they can decrease the slope of phase 4 depolarization. They are very good to treat tachyarrhythmia.

We know that in phase 4, the SA node action potential is due to the opening of calcium channels, but the spontaneous depolarization is due to the IF current which depends on the cationic channels of both calcium and sodium; thus sodium channels are important to determine the threshold in the sinoatrial node, and if they are blocked it means that we delayed the occurrence of the action potential, decreasing the hear rate.

But these channels are mainly important during phase 0. Na+ channel blockers act on ventricular myocytes to decrease the re-entry by decreasing the upstroke velocity of phase 0 and thus conduction velocity, and by prolonging repolarization. And for class one drugs we also have a prolonged repolarization; this is because these drugs can also increase the refractory period.

Depending on the subclass there are different ways of changing the conduction velocity. This depends on the ability of the compound to dissociate from the channel: the slower they are and the more intense the blockade is going to be. There are mild, moderate and marked sodium channels blocking activities.

• Class Ia is composed by quinidine, disopyramide and procainamide and is characterized by less selectivity for these channels, in fact they can also block potassium channels and thus decrease the action velocity while also increasing the refractory period.
• Class Ib drugs like lidocaine have a very mild blockade effect of sodium channels and cause a mild decrease in the upstroke velocity and a shorter repolarization.
• Class Ic drugs cause a marked blockade of sodium channels and a decrease in upstroke velocity and no alteration in the repolarization phase. class Ic are the most potent of the these compounds and are very useful for tachyarrhythmias since they are slowing the action potential in the ventricular and creating a more normal rhythm in the heart. The ability of this class to block the Na channels is called “use dependent”, infact this alteration is a feature of a damaged area of the heart, these compounds only work when the channels are in the open or inactive state, they are not able to block channels in the resting state and prolong the refractory period. This means that the more they are used, the more they are blocked and this happens when they are hyper-stimulated in a damaged tissue. In other words they work better in a damaged tissue and work less in the normal conductive tissue of the heart, blocking the high frequency excitation without preventing the normal frequency one.

Question 4

Speak about class II antiarrhythmics

Answer 4

CLASS II ANTIARRYTHMICS

Class II antiarrhythmics are able to work on the physiological modulation of the heartbeat produced by beta adrenergic receptors, in this case we are talking about Beta1, since it is the most abundant beta receptor in the heart. These receptors can be found in the SA node, where this compound class acts the most.

These drugs can work by: increasing the pacemaker current, increasing in the rate of phase 4 depolarization and by causing a more frequent firing of the SA node.

in the AV node we have b1 receptors which are able to increase calcium and potassium currents causing, at the end of the day, an increase in the rhythm of the heart. In a pathological situation we want to block these receptors so we use antagonists. There are 3 different generations of antagonists:

1. The first generation is represented by propranolol, which is a non selective compound and is able to work on beta1, 2 and 3 receptors, but since in the heart we mainly have beat1 it would be better to block only beta1, infact, if we block beta2, we are also blocking the relaxation of the bronchi, causing bronchoconstriction. This is why the fist generation of compounds is not ideal.
2. the second generation is represented by metoprolol which, only at low dosage, selectivly blocks beta 1 receptors and slows the heart rate, while also causing a prolonged repolarization in the AV node.
3. the third generation drugs are characterized by compounds which can have activity towards both beta1 and alpha1 receptors, the latter are found in the vascular smooth muscle and when they are antagonized we have vasodilation, helping the heart. In the third generation we find drug such as labetalol and carvedilol. These drugs have a wide spectrum of clinical applications and are safe and most useful antiarrhythmics on the market, that is why they are the first choice drugs to cure these issues. On top of everything they are also cheap.

Question 5

Speak about Class III antiarrhythmics

Answer 5

Class III antiarrhythmics agents block potassium channels thus they block the repolarization phase. But we know that these channels are also involved in balancing calcium during the plateau phase, so if they are blocked we have a prolonged plateau and repolarization phase. This is useful to control arrhythmias, for example, by interrupting re-entrant currents because cells are not able to repolarize, and also by interrupting tachycardias and suppressing ectopic activity.

As side effects of these compounds we have an increasing risk of causing an early afterdepolarization. so all classes of antiarrhythmics are useful but if not properly dosed they can themselves cause arrhythmias.

This class of compounds are less selective among the ones we have seen, that is because a part from acting on K channels, which is their main target, they also act on other structures. For example the drug amiodarone can also work as a beta adrenergic antagonist and thus it has more then one mechanism of action.

Question 6

Speak about class IV antiarrhythmics and other types of antiarrhythmics. what are the future perspectives?

Answer 6

Class IV antiarrhythmics work on calcium channels, which play an important role in the depolarization in the SA and AV node, since they heavily depend on calcium for the depolarization phase.

If we block both transient and long-lasting calcium channels, we are slowing the occurrence of the depolarization which is going to take longer to cause the action potential and thus the SA node activity is going to slow down together with the heartbeats. The consequence of this is that we are also going to have a slower conduction in the AV node. Because of this action, the compounds in this class can be used for arrythmias that involve re-entry through the AV node, but high dosages of calcium channel blockers can prolong AV nodal conduction and cause heart block.

Now, the thing is that different tissues express different subtypes of calcium channels, and different subclasses of calcium channel blockers interact preferentially with different calcium channel subtypes meaning that the various calcium channel blockers have differential effects in different tissues. If we were able to only hit a specific calcium channels we would have the perfect drug, but unfortunately this it is not the case, instead there are 3 different classes of calcium channels blockers.

verapamil and diltiazem which is a benzothiazepine (WITH A T NOT D ), are class IV drugs which happen to be relatively more selective for cardiac tissues and target L-type calcium channels. These drugs are the most used for the blockade of arrhythmias, infact they have a relatively greater effect on the Ca2+ current in vascular smooth muscle and are more selective for vascular smooth muscle calcium channels.

OTHER AGENTS THAT MODULATE CARIDIAC RHYTHM

Another important agent which is able to control the heartbeat is adenosine. The nucleoside adenosine is naturally present throughout the body; by stimulating the A1 class of purinergic receptors, adenosine opens a G protein-coupled K channel and inhibits the SA nodal, atrial, and AV nodal conduction. We only use adenosine when patients are not responding to the other classes.

The most important new directions that pharmacologists are taking is to create more selective drugs with less side effects. So, they are trying to identify specific genes or ion channels in the human heart in order to create these specific drugs. For example we have no drugs for the T type calcium channels. One of the goals of recent research is to create a drug which is able to block HERG channel, a K channels involved in the prolongation of the QT interval. The research is still going on because the drugs used nowadays, like beta antagonists, sometimes have important side effects, for example beta antagonists might cause impotence.

Question 7

Speak about cardiac contraction. what are its feature and how does it happen?

Answer 7

There might also be other problems to the heart, like for example we have heart failure, commonly caused by systolic dysfunction of the left ventricle. In the left ventricle we have a weaker wall that is not able to inject the blood properly in all our body, so the symptoms might be shortness of breath and coughing since there is not proper oxygenation, and we can also have tiredness. Another symptom is edema causing ankles and legs to swollen and also causing weight gain.

To understand how these problems are generated we need to know that the heart receives non oxygenated blood into the right atrium, this blood then goes into the right ventricle and then in the lungs where it is oxygenated. From here the blood moves to the left atrium and ventricle and then to the rest of the body. The heavier work is done by the left ventricle since it pumps blood for the entire body and needs to go against the impedance of the blood circulation.

The relationship between the tension generated during the systolic phase of the cardiac cycle and the extent of the left ventricle (LV) filling during diastole is referred to as the contractile state of the myocardium. This state together with the preload, which is the **amount of blood that can be present in the left ventricle (intraventricular blood volume), and heart rate, myocardial contractility is a primary determinant of cardiac output.

So in a normal cardiac cycle the SA node initiates an impulse that travels quickly through the atrial myocardium and arrives at the AV node where it slows down to allow sufficient time for filling of the ventricles with blood before the ventricular. Then, the impulse propagates quickly throughout the ventricles to trigger ventricular contraction.

We have to pay attention to how cardiac muscle are able to contract, the first event is the action potential of the ventricle, then we have the plateau where we have the importance of the calcium ion gated channels, they open so calcium enters the cell, and this triggers the opening of the internal storage of calcium. So this allows the increase of calcium activates contractile elements like actin and myosin, which interact with each other. There are also tropomyosin and troponin complex composed by troponin I, C and T. These are the steps for the contraction of the myocites

1. Everything begins with the hydrolysis of ATP to ADP by myosin; this reaction energizes the myosin head
2. the Ca2+ released from the sarcoplasmic reticulum binds to Troponin-C and **this reaction causes a conformational change in tropomyosin which allows myosin to form an active complex with actin
3. The Dissociation of ADP from myosin allows the myosin head to bend; this bending pulls the Z lines of the muscle closer together and thus it shortens the I band. This contracted state is often referred to as a rigor complex because the muscle remains in the contracted state until there is sufficient ATP available to displace the myosin heads from actin.
4. Then we have the binding of a new ATP molecule to the myosin which **allows the actin–myosin complex to dissociate. Ca2+ is also dissociates from TN-C complex, and the contraction cycle is repeated

this cycle generates a movement which allows contraction by pulling Z lines closer together. As we have seen, in the contracted form there is no ATP, that is why we have the rigor mortis, since without ATP there can be no relaxation: we need ATP to dissociate actin and myosin.