- Email: [email protected]
Discussion I
DiscussionI Dr. Marcus: I noticed in the reports on electrophysiology that there was a decrease in the diastolic excitability when moricizine HCl was given. I wonder whether this has any clinical relevance, particularly in patients with either defibrillator or pacemaker implants, or both. Professor Smetnev: We have some patients with arrhythmias of different types who have pacemaker implants. We have been able to stop the various kinds of arrhythmia without any trouble by injecting moricizine HCl or Ethacizine. Although we have checked these results by 24-hour Holter monitoring, no special electrophysiologic study was conducted. Dr. Somberg: Professor Smetnev, perhaps you can comment on the effects of moricizine HCl in patients with atria1 flutter and atria1 fibrillation. Some of the electrophysiologic findings suggest that the drug has no effect in controlling ventricular response in atria1 fibrillation. Would you agree with these results? Professor Smetnev: It has been our experience that moricizine HCl works in 36% of patients with atria1 fibrillation. Dr. Lown: Does that mean that if the patient has chronic atria1 fibrillation, he will be reverted, or are you speaking about those patients with paroxysmal atria1 fibrillation? Professor Smetnev: Only those with paroxysmal atria1 fibrillation; there is no effect on stable atria1 fibrillation. Dr. Somberg: My question also refers to the ventricular response in atria1 fibrillation. We had a patient who was undergoing programmed stimulation with moricizine HCl, and he had atria1 fibrillation with some acceleration. We do not know whether the acceleration was due to the sympathetic tone or due to drug, but on the basis of this clinical experience, would you say that the drug controls ventricular response or has no effect? Professor Smetnev: In atria1 fibrillation, ventricular response is not controlled by drug. Moricizine HCl is not the drug of choice in the treatment of such patients. Dr. Woosley: Have intravenous and oral modes of administration been Compared? Professor Smetnev: This is a very complicated question. Sometimes after intravenous use of drug, the tachycardia is controlled. However, during the course of certain long-term parallel studies, it was found that moricizine HCl may have an arrhythmogenic effect. Dr. Vaughan-Williams: I am curious about the autonomic effects: does moricizine HCl have any direct or indirect antisympathetic effects on the central nervous system? Also, what is the distribution in the central nervous system? Presumably, the drug does not cross the blood-brain barrier and enter the central nervous system. One wonders, then, whether the drug has a direct antisympathetic effect. 45F
Dr. Rosenshtraukh: During my last visit to the US some years ago, I conducted a study [with Dr. James and co-workers] on a dog model. This was a comparison of the different effects of moricizine HCl and Ethacizine when administered in the sinus node and atrioventricular node arteries. It was found that Ethacizine had transient vagolytic effects. Moricizine HCl had significantly less vagolytic action. It was also found that moricizine HCl had adrenolytic action, but that Ethacizine did not. Dr. Vaughan-Williams: One of the interesting points is the prolongation of AH conduction time, although there is little negative inotropic effect. In other words, I believe that this effect is independent of any direct action on calcium currents. Therefore, it must be attributed to either an antisympathetic effect or to the lead-in and lead-out delay in conduction, without any specific effect on calcium channels in the atrioventricular node. Dr. Rosenshtraukh: This is a difficult point, but we do know that moricizine HCl has practically no interaction at all with the slow calcium channel. It sometimes can increase the slow calcium channel current, and we now understand the mechanism for this. On the other hand, Ethacizine can depress the slow inward calcium current. It should also be noted that these 2 drugs have opposite effects on the different receptor systems. Dr. Woosley: Like most phenothiazines, moricizine HCl does accumulate in the central nervous system, but I don’t think that the significance of this is well understood. Dr. Rosenshtraukh: We have studied serotonin receptor binding of both moricizine HCl and Ethacizine. We discovered that the rate of binding with these receptors was rather infrequent with both these drugs. Dr. Harrison: Dr. Woosley, while working with the radiolabeled compound, it seems that metabolites accumulate, building to steady-state plasma levels at 4 to 6 days of testing. Since this correlates somewhat with time of drug effect, does this suggest the presence of an active metabolite? Dr. Woosley: Yes, I think your observation is astute. The correlation is better between the accumulation of radioactivity and pharmacologic effect than between the parent compound and pharmacologic effect. Yet, the findings are not exact: we must assume that there are also many inactive metabolites. This is as expected, since many are conjugated metabolites-most probably the inactive ones. Dr. Antman: Dr. Woosley, is there any evidence that there is saturable hepatic metabolism with long-term administration? I imagine that would affect the maintenance dose you would use. Dr. Woosley: There is actually evidence to the contrary; saturation does not seem to occur. Indeed, hepatic metabolism seems even more active with long-term dosing, which
46F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
again seems to imply induction of metabolism or changes in protein binding, with more free fraction of the parent compound in long-term administration, thereby increasing clearance. Dr. Antman: Isn’t this unusual? Wouldn’t this situation warrant higher doses during long-term therapy? Dr. Woosley: That would be what you would expect if moricizine HCl were the only active compound; however, I think the evidence is overwhelming that this is not the case. Dr. Somberg: I am confused about the pharmacokinetics of moricizine HCl in terms of a very basic consideration: what is the appropriate dosing interval of the drug? We have discussed the various half-lives involved, and of course this is basic to any observations on pharmacokinetics and efficacy. If we look, for example, at fi blockers as a class, biologic effects and pharmacokinetics are often disparate, and dosing interval is generally based on when ventricular premature complex curves indicate that drug levels start to attenuate. Is this an apt example of what occurs, or is there an appropriate dosing interval that pharmacokinetics predict? Dr. Woosley: I think it is very clear at this point in the research that you cannot rely on measurements of the parent compound to guide clinical investigation or dosing. I think the next step is to find out which compounds are active and then try to establish correlations between their presence and changes in electrocardiographic intervals or ventricular premature complex counts. These analyses are probably easier to tackle than those of the more life-threatening arrhythmias, which show too many variations in the clinical endpoint. However, duration of pharmacologic action is probably the missing element. If, for example, we find that the halflife for the change in QRS is, say, 6 hours, as it is with encainide, this helps ascertain when pharmacologic effect will reach steady state and enables us to say something about dosing interval. To my knowledge, there are very few data available as to just how frequently one can administer the drug. I would suspect that once pharmacologic effect is ascertained, dosing interval could be scaled to 2 times daily, or even longer in some patients. Dr. Kennedy: When studies began in the US in the late 167Os,we followed ventricular arrhythmias in patients at dosage titrations of 5,7,10,X2 or 15 mg/kg and watched for levels at which efficacy, side effects or both were apparent. The majority of patients responded at the 10 to 12 mg/kg range, and we began to see the side effects of central nervous system toxicity-nystagmus or certain central nervous system paresthesias-at the 15 mg/kg point. In these older studies, side effects data in terms of proarrhythmic effect were apparent before the fourth day. In the present series, however, we’ve been following half-life for 4 to 7 days. Is it clear, then, on the strength of approximately 8 years of clinical experience, that what we are seeing is a disparity in plasma levels of the parent compound versus clinical and proarrhythmic effects? And another thought: is the active compound of Ethacizine actually a metabolite? So far, classic pharmacokinetic studies have not helped in our clinical management. Dr. Lown: In using the drug as we do in short-term testing, with 600 mg/kg of moricizine HCl, Dr. Podrid noted that the drug was ineffective at the outset. That is to say, 36 hours or
AGENT
longer were required before any antiarrhythmic effect was seen. This, then, raised the question of whether it was some phenothiazine property in blood-brain transit, a metabolite, or some other factor accounting for efficacy. It is interesting to note, however, that an almost immediate effect with moricizine HCl is seen in 10% of patients. Dr. Kennedy: Both Dr. Morganroth and I started with higher initial doses. When one starts with a higher single dose, some effect is seen within 24 hours, In fact, whether it was a pro- or an antiarrhythmic effect, it would be seen within 24 hours. So, although a metabolite may be the active compound in the long run, something happens in the first 24 hours if a high enough dose is given. What is the significance of this observation? Dr. Woosley: I think that when you are dealing with a compound as variable in terms of pharmacokinetics as this is, it’s going to be difficult to know when steady state is achieved for any one of a number of metabolites, which probably have many different pharmacologic actions. For example, the pharmacologic potencies of encainide are very different from those of procainamide. And N-acetyl procainamide has very different pharmacologic actions as well. So the minor structural changes that the liver produces make for tremendous differences in pharmacologic profiles, It is entirely possible, then, for certain people to produce an early accumulating, arrhythmogenic metabolite, and for others to produce something totally different. An example is encainide, which produces N-dimethyl encainide, a metabolite with very different pharmacologic actions. It’s very difficult to predict the presumed activity of metabolites, especially in the case of moricizine HCl, which has a multitude of them. What is more important to establish is the spectrum of effect at each dose of moricizine HCl, and the minimum effective dose at steady state. This of course is going to be variable in each population. Dr. Bigger: Dr. Woosley, don’t you think that it’s more a liability than an advantage to have so many metabolites that are potentially active? Dr. Woosley: I agree; but this is not a liability that is exclusive to moricizine HCl, and is common with almost all of our drugs. These factors have been present for years, and the mystery is gradually unraveled as we continue to identify and measure these compounds. Let us take the example of Thorazine. This is a very wellknown and frequently used drug, even though it has all the problems we discussed. And encainide is one of the most complicated drugs around, but this does not change the fact that the effective dose is the same for the slow metabolizers as for the rapid metabolizers. So having multiple metabolites is not a liability for the final efficacy of a drug: it just makes clinical evaluation that much more difficult by taking away therapeutic blood level monitoring as a useful clinical tool. Dr. Roberts: Dr. Woosley, in your slide showing blood levels of moricizine HCl in patients on day 11, could you comment on why blood levels increased for more than half the patients? Dr. Woosley: You may be right, but it was my impression that blood levels decreased for more patients. What we are seeing here is a question of interpatient variability. Liver metabolism induction is something that isvariable, and some
October 16, 1987
patients may not be induced. Another possibility is the variability of protein-binding saturation playing a contributory role. Comment: On the slides shown by Dr. Woosley on pharmacokinetics, there was a very clear intercept on the x axis, indicating that there must be some threshold effect. As the dose increases, as plotted against the area under the curve, the curve does not pass through the origin. An inference may be drawn that a dose may be given that is so low that none of
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
47F
the drug enters the systemic circulation. So there must be some threshold effect, and perhaps some saturation, at least at low levels. This for me suggests tremendous interpatient variability. Dr. Woosley: Yes, this is yet another instance of the variable things that can happen. For example, a 10 mg dose may never reach the systemic circulation in one patient, whereas a 100 mg dose may never reach the systemic circulation in another.
Dr. Rosenshtraukh: During my last visit to the US some years ago, I conducted a study [with Dr. James and co-workers] on a dog model. This was a comparison of the different effects of moricizine HCl and Ethacizine when administered in the sinus node and atrioventricular node arteries. It was found that Ethacizine had transient vagolytic effects. Moricizine HCl had significantly less vagolytic action. It was also found that moricizine HCl had adrenolytic action, but that Ethacizine did not. Dr. Vaughan-Williams: One of the interesting points is the prolongation of AH conduction time, although there is little negative inotropic effect. In other words, I believe that this effect is independent of any direct action on calcium currents. Therefore, it must be attributed to either an antisympathetic effect or to the lead-in and lead-out delay in conduction, without any specific effect on calcium channels in the atrioventricular node. Dr. Rosenshtraukh: This is a difficult point, but we do know that moricizine HCl has practically no interaction at all with the slow calcium channel. It sometimes can increase the slow calcium channel current, and we now understand the mechanism for this. On the other hand, Ethacizine can depress the slow inward calcium current. It should also be noted that these 2 drugs have opposite effects on the different receptor systems. Dr. Woosley: Like most phenothiazines, moricizine HCl does accumulate in the central nervous system, but I don’t think that the significance of this is well understood. Dr. Rosenshtraukh: We have studied serotonin receptor binding of both moricizine HCl and Ethacizine. We discovered that the rate of binding with these receptors was rather infrequent with both these drugs. Dr. Harrison: Dr. Woosley, while working with the radiolabeled compound, it seems that metabolites accumulate, building to steady-state plasma levels at 4 to 6 days of testing. Since this correlates somewhat with time of drug effect, does this suggest the presence of an active metabolite? Dr. Woosley: Yes, I think your observation is astute. The correlation is better between the accumulation of radioactivity and pharmacologic effect than between the parent compound and pharmacologic effect. Yet, the findings are not exact: we must assume that there are also many inactive metabolites. This is as expected, since many are conjugated metabolites-most probably the inactive ones. Dr. Antman: Dr. Woosley, is there any evidence that there is saturable hepatic metabolism with long-term administration? I imagine that would affect the maintenance dose you would use. Dr. Woosley: There is actually evidence to the contrary; saturation does not seem to occur. Indeed, hepatic metabolism seems even more active with long-term dosing, which
46F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
again seems to imply induction of metabolism or changes in protein binding, with more free fraction of the parent compound in long-term administration, thereby increasing clearance. Dr. Antman: Isn’t this unusual? Wouldn’t this situation warrant higher doses during long-term therapy? Dr. Woosley: That would be what you would expect if moricizine HCl were the only active compound; however, I think the evidence is overwhelming that this is not the case. Dr. Somberg: I am confused about the pharmacokinetics of moricizine HCl in terms of a very basic consideration: what is the appropriate dosing interval of the drug? We have discussed the various half-lives involved, and of course this is basic to any observations on pharmacokinetics and efficacy. If we look, for example, at fi blockers as a class, biologic effects and pharmacokinetics are often disparate, and dosing interval is generally based on when ventricular premature complex curves indicate that drug levels start to attenuate. Is this an apt example of what occurs, or is there an appropriate dosing interval that pharmacokinetics predict? Dr. Woosley: I think it is very clear at this point in the research that you cannot rely on measurements of the parent compound to guide clinical investigation or dosing. I think the next step is to find out which compounds are active and then try to establish correlations between their presence and changes in electrocardiographic intervals or ventricular premature complex counts. These analyses are probably easier to tackle than those of the more life-threatening arrhythmias, which show too many variations in the clinical endpoint. However, duration of pharmacologic action is probably the missing element. If, for example, we find that the halflife for the change in QRS is, say, 6 hours, as it is with encainide, this helps ascertain when pharmacologic effect will reach steady state and enables us to say something about dosing interval. To my knowledge, there are very few data available as to just how frequently one can administer the drug. I would suspect that once pharmacologic effect is ascertained, dosing interval could be scaled to 2 times daily, or even longer in some patients. Dr. Kennedy: When studies began in the US in the late 167Os,we followed ventricular arrhythmias in patients at dosage titrations of 5,7,10,X2 or 15 mg/kg and watched for levels at which efficacy, side effects or both were apparent. The majority of patients responded at the 10 to 12 mg/kg range, and we began to see the side effects of central nervous system toxicity-nystagmus or certain central nervous system paresthesias-at the 15 mg/kg point. In these older studies, side effects data in terms of proarrhythmic effect were apparent before the fourth day. In the present series, however, we’ve been following half-life for 4 to 7 days. Is it clear, then, on the strength of approximately 8 years of clinical experience, that what we are seeing is a disparity in plasma levels of the parent compound versus clinical and proarrhythmic effects? And another thought: is the active compound of Ethacizine actually a metabolite? So far, classic pharmacokinetic studies have not helped in our clinical management. Dr. Lown: In using the drug as we do in short-term testing, with 600 mg/kg of moricizine HCl, Dr. Podrid noted that the drug was ineffective at the outset. That is to say, 36 hours or
AGENT
longer were required before any antiarrhythmic effect was seen. This, then, raised the question of whether it was some phenothiazine property in blood-brain transit, a metabolite, or some other factor accounting for efficacy. It is interesting to note, however, that an almost immediate effect with moricizine HCl is seen in 10% of patients. Dr. Kennedy: Both Dr. Morganroth and I started with higher initial doses. When one starts with a higher single dose, some effect is seen within 24 hours, In fact, whether it was a pro- or an antiarrhythmic effect, it would be seen within 24 hours. So, although a metabolite may be the active compound in the long run, something happens in the first 24 hours if a high enough dose is given. What is the significance of this observation? Dr. Woosley: I think that when you are dealing with a compound as variable in terms of pharmacokinetics as this is, it’s going to be difficult to know when steady state is achieved for any one of a number of metabolites, which probably have many different pharmacologic actions. For example, the pharmacologic potencies of encainide are very different from those of procainamide. And N-acetyl procainamide has very different pharmacologic actions as well. So the minor structural changes that the liver produces make for tremendous differences in pharmacologic profiles, It is entirely possible, then, for certain people to produce an early accumulating, arrhythmogenic metabolite, and for others to produce something totally different. An example is encainide, which produces N-dimethyl encainide, a metabolite with very different pharmacologic actions. It’s very difficult to predict the presumed activity of metabolites, especially in the case of moricizine HCl, which has a multitude of them. What is more important to establish is the spectrum of effect at each dose of moricizine HCl, and the minimum effective dose at steady state. This of course is going to be variable in each population. Dr. Bigger: Dr. Woosley, don’t you think that it’s more a liability than an advantage to have so many metabolites that are potentially active? Dr. Woosley: I agree; but this is not a liability that is exclusive to moricizine HCl, and is common with almost all of our drugs. These factors have been present for years, and the mystery is gradually unraveled as we continue to identify and measure these compounds. Let us take the example of Thorazine. This is a very wellknown and frequently used drug, even though it has all the problems we discussed. And encainide is one of the most complicated drugs around, but this does not change the fact that the effective dose is the same for the slow metabolizers as for the rapid metabolizers. So having multiple metabolites is not a liability for the final efficacy of a drug: it just makes clinical evaluation that much more difficult by taking away therapeutic blood level monitoring as a useful clinical tool. Dr. Roberts: Dr. Woosley, in your slide showing blood levels of moricizine HCl in patients on day 11, could you comment on why blood levels increased for more than half the patients? Dr. Woosley: You may be right, but it was my impression that blood levels decreased for more patients. What we are seeing here is a question of interpatient variability. Liver metabolism induction is something that isvariable, and some
October 16, 1987
patients may not be induced. Another possibility is the variability of protein-binding saturation playing a contributory role. Comment: On the slides shown by Dr. Woosley on pharmacokinetics, there was a very clear intercept on the x axis, indicating that there must be some threshold effect. As the dose increases, as plotted against the area under the curve, the curve does not pass through the origin. An inference may be drawn that a dose may be given that is so low that none of
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
47F
the drug enters the systemic circulation. So there must be some threshold effect, and perhaps some saturation, at least at low levels. This for me suggests tremendous interpatient variability. Dr. Woosley: Yes, this is yet another instance of the variable things that can happen. For example, a 10 mg dose may never reach the systemic circulation in one patient, whereas a 100 mg dose may never reach the systemic circulation in another.