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Date: 25-04-2013 Newer Calcium channel blocker and utility in Hypertension

By Dr. C. Venkata S. Ram, Hyderabad

This where the medical knowledge is going and that is why the meetings of this nature are very very important.  If you read 2 articles per day you will be 82 centuries behind.  So, that is the importance of meetings of this nature where a lot of stuff has been prepared for you and you can just experience it, enjoy, and hopefully apply it.


The reason why we treat hypertension, because hypertension is not a disease it is a disorder, you want to prevent the disease.  The complications shown here, on this side, are completely related to blood pressure.  That means, higher the blood pressure, greater is the risk of hypertensive encephalopathy, left ventricular failure, intracerebral hemorrhage.  On the other hand, majority of the patients actually have so called atherosclerotic complications of hypertension, which are not always related to the level to blood pressure.  This is completely dependent on the level of blood pressure.  For example, you will never see somebody with hypertensive encephalopathy with 140 or 102, unusual, may be children.  But majority of you, me included, we see so-called atherosclerotic consequences of hypertension.  So, high blood pressure is a big promoter of atherosclerosis, not just lipids.  Blood pressure, a hemodynamic abnormality, changes endothelial function in such a way that it causes atherosclerosis.  What we see on the skin actually happens in the body.  When you age, you develop wrinkling of the skin.  You do not see wrinkling of skin in young individual unless somebody has a rare disorder, progeria, but wrinkling happens only as a part of ageing process, but blood vessels undergo premature ageing and they actually have wrinkling of the blood vessels which we call atherosclerosis.  Atherosclerosis is nothing but wrinkling of the blood vessels.  This is what happens in people who have longstanding hypertension irrespective of lipids, irrespective of age, irrespective of tobacco consumption.  The only burden that you have is an increase in blood pressure; we call it hypertension, but see hypertension cause significant vascular toxicity by promoting atherosclerosis.  So, ladies and gentleman, when we treat hypertension, the goal is to prevent to a large extent so called atherosclerotic complication of hypertension.  All of you have seen this in many forms yesterday and part of today in Dr. Siddharth Shah's talk, I am going to comment on the role of calcium channel blocking drugs and the possible utility of new generation calcium channel blocking drugs in the treatment of hypertension.  I am not going to talk a lot on calcium channel blocking drugs in general, but I will focus on so-called the new generation calcium channel blocking drugs.  Dr. Amaresan mentioned that he does not use nondihydropyridine calcium blocking drugs that much because they are not that effective in the treatment of hypertension.  Certainly, they are not effective in patients with significant hypertension.  The first generation calcium blocking drugs were verapamil and diltiazem.  They are useful for some cardiovascular disorders, but not that much for hypertension.  The second generation calcium channel blocking drug is nifedipine, which is the first dihydropyridine calcium channel blocking drug, very effective in the treatment of hypertension, very useful in the treatment of hypertension, but it is not selective.  It is so-called non-selective dihydropyridine.  The third generation calcium channel blocking drugs are so-called cardioselective dihydropyridines.  Examples would be amlodipine and felodipine because their actions are localized to cardiovascular tissue.  So, that is the reason why they are called third generation or cardioselective dihydropyridine.  Amlodipine is one of the most popular cardiovascular drugs ever to be used in the world anywhere.  Because it is a broad-spectrum antihypertensive drug, lower the blood pressure with no effecting factors.  But the use of amlodipine is sometimes associated with adverse effects on proteinuria, on ankle edema and sympathetic activation.  It is an effective drug, but its tolerability could be limited by adverse hemodynamic effects medicated by sympathetic nervous system or by the physical problem of ankle edema.  The idea would be how to have a new type of amlodipine that maintains the efficacy of amlodipine, but offers freedom from side effects of amlodipine and the quest for so-called ideal dihydropyridine therefore has led to the discovery of cilnidipine.  Cilnidipine is superimposable on amlodipine as an antihypertensive drug.  That’s it.  The similarity stops there, then it separates itself in terms of freedom from so called dihydropyridine side effects and that is what I am going to talk about.


Calcium channel blocking drugs have no effect on bone metabolism, they have no effect on parathyroid hormone, and they have no effect on calcium metabolism.  The only thing that they do is prevent interaction between actin and myosin.  As you will recall from your cardiovascular physiology, actin and myosin are intercellular proteins.  When they embrace each other, when they handshake each other, the result is vascular contraction.  Vascular contraction is promoted, permeated, and sustained by this embrace that occurs between actin and myosin.  But this is a very unfriendly embrace.  It is a very painful embrace because it causes vasoconstriction.  Calcium channel blocking drug prevent this interaction between actin and myosin, so actin and myosin do not interact with each other, result is vasorelaxation.  One thing we always have to keep in mind is calcium channel blocking drugs have an effect only on cardiovascular system, but they have no effect on bone density, parathyroid metabolism, vitamin D metabolism, absolutely nothing.  It is purely a cardiovascular drug by preventing the interaction between actin and myosin and therefore causing vasorelaxation.  The reason why amlodipine has become such a largely used drug is its efficacy is same irrespective of the age of the patients, irrespective of gender, and irrespective of concomitant condition.  It is a so-called broad-spectrum antihypertensive drug because it is very user friendly except for side effects and you do not have to worry about the factors in selecting amlodipine-like drug.  But amlodipine is burdened with the adverse hemodynamic effects of tachycardia, sympathetic activation, increasing intraglomerular pressure, therefore increasing proteinuria and causing precapillary dilatation resulting in ankle edema.  Dihydropyridine, which is so useful as a part of combination therapy has to be developed that is as effective as amlodipine.  That means, amlodipine is a gold standard for CCB selection in the treatment of hypertension.  It should have broad-spectrum effectiveness like amlodipine, but the new CCBs, the tolerability should be higher than what we have seen with amlodipine.  Amlodipine's tolerability is somewhat limited and somewhat variable and should be used in combination with other drugs such as ACE inhibitors, ARBs and most importantly it should be free from typical dihydropyridine side effects and I will talk about the effects of CCBs on proteinuria.


Cilnidipine belongs to this class, some people call it third generation plus, some people call it fourth generation dihydropyridine calcium channel blocking drug because classical calcium channel blockade is through blockade of the L-receptor, namely, amlodipine, nifedipine.  By blocking the N-receptor you also are blocking sympathetic activation.  The non-epinephrine mechanics that occur in the cardiovascular tissue are mediated by the N calcium channel blocking.  This dual acting drug typically blocks L-channel vasorelaxation, blocks N-channel, namely, sympathetic inhibition modestly, which means it causes vasodilatation without causing tachycardia.  In fact, it causes slight reduction in heart rate.  It decreases sympathetic activity, decreases proteinuria, and for the cardiologist in audience, there appears to be a reduction in left ventricular hypertrophy and it appears to be a novel CCB.  It appears to fulfill many of the characteristics that I showed you in the preceding slide of a new generation CCB, what it should look like, how is should be prepared.  Cilnidipine because of its actions on blood pressure and heart, in addition reducing the sympathetic tone, pharmacologically it is a very interesting compound.  Only thing in clinical practice the clinical outcome we have to see in the future.  Sympathetic nervous system, we have not talked about in great deal in this conference so far, but sympathetic nervous system is an important parameter that governs the blood pressure regulation by increasing the peripheral vascular resistance and initially by increasing the heart rate and cardiac output.  In the pathogenesis of hypertension, the initial abnormality is activation of sympathetic tone, increased heart rate, increased cardiac output, but in the long run, the sympathetic activity causes peripheral vascular resistance to be high.  Sympathetic nervous system is one of the pathogenetic mechanism of sustaining hypertension.  When people were measuring noradrenaline as a parameter for sympathetic nervous system, it was not that useful because norepinephrine fluctuates so much, it depends on whether you are standing or whether you had a meal, it is not very reliable, but the new way of measuring sympathetic activities is to measure it in the peroneal nerve cum muscle sympathetic nervous activity.  This is the muscle sympathetic nervous activity actual physical determination of sympathetic burst.  In normotensive individuals, white coat hypertension, essential hypertension, masked hypertension.  In all grades of hypertension there is augmentation of sympathetic nervous activity in comparison to normotensive individuals.  There is increased sympathetic traffic in all aspects of hypertension.  Whether it is initial, sustained, or so-called masked hypertension.  Sympathetic nervous system is not a simple fight and flight mechanism, but it increases multiple mechanisms that cause cardiovascular damage, cardiac hypertrophy, platelet activation, metabolic syndrome, atherogenesis, etc.  Sympathetic nervous system is an important player in the pathogenesis of hypertension and that is why blockade of sympathetic nervous system has been used since the discovery of reserpina serpentina.


This is a diagrammatic representation of the new generation calcium channel blocking drugs.  By blocking the L-channel you cause vasodilatation or you prevent vasoconstriction.  By blocking the N-channel you decrease the nor-epinephrine release at the so-called neuroeffector junction.  When you block the nor-epinephrine release, because this is T-channel mediated, then you have an effect on the kidney, heart and blood vessels that is quite different.  The blockade of sympathetic discharge appears to have important and positive effects on the cardio-renal mechanisms and hypertension.  Sympathetic activity broadly speaking have multiple abnormalities in the human body over and beyond blood pressure; platelet aggregation, tachycardia, oxidative stress.  By the way, sympathetic activity is an important feeder for renin-angiotensin system.  So, they actually go together.  They cannot be separated many time and the consequences of sympathetic activity beyond blood pressure are coronary artery disease, cerebrovascular disease, etc.


Now, let us look at nor-epinephrine secretion in an experimental model.  The nor-epinephrine secretion rate at the baseline and it is during administration of cilnidipine and then you stop cilnidipine and the nor-epinephrine secretion rate goes up.  One of the experimental postulates that is fulfilled is by cilnidipine, although it is a calcium channel blocking drug, it appears to decrease nor-epinephrine secretion rate and you remove the drug and the nor-epinephrine secretion goes up.  So, there is a cause-effect relationship.


This is a slide, which is very important if you can pay attention to it.  I will start from right to the left.  Nifedipine; benidipine, which is nifedipine like drug; amlodipine, and cilnidipine all of them lower the blood pressure, but the effects of heart rate are different.  In all these 3 other drugs, they increase the heart rate, whereas cilnidipine decreases the heart rate.  Same level of blood pressure, but the changes in heart rate.  Nor-epinephrine secretion goes up with the 2 generations of CCBs, but there is no increase in nor-epinephrine secretion with cilnidipine.  This is a summation slide showing that all dihydropyridines cause reduction in blood pressure, but they have dissimilarities in terms of response and the heart rate and nor-epinephrine.  Similar blood pressure, dissimilar effects on sympathetic activation.


Somebody was talking about stress yesterday and cold pressure test, which is used to stress, increases the blood pressure.  When you put somebody's hand in ice-cold water and leave it there, it increases the blood pressure by sympathetic activation.  This is increase in blood pressure with cold pressure test and cold pressure stimulus but in the presence of cilnidipine significant reduction in sympathetic response and therefore increase in blood pressure.  I mentioned to you that amlodipine like drugs may have an effect on heart rate, they certainly do not reduce the heart rate, but this is effect of classical CCB on the right side and the new generation CCB here showing a modest reduction in the heart rate.  The reduction in the heart rate is not like a beta blocker, but there is more modest reduction in heart rate in comparison to no change or increase with classical amlodipine like drugs.  This is a comparative study looking at the heart rate response over a 24-hour cycle.  A reduction in heart rate with new generation CCB, 24 hours, which is very important and in the opposite direction with amlodipine.  So, we have 2 CCBs which have similar effects on blood pressure, but they have dissimilar effects on heart rate.


Now, few things on the kidney.  Dr. Amaresan has talked about the mechanisms of proteinuria in patients with diabetes where when you give RAAS blockers, you remove the so-called efferent arteriolar constriction and therefore you decrease intraglomerular pressure.  Calcium channel blocking drugs, dihydropyridine calcium blocking drugs like amlodipine, they actually have no effect on efferent arteriolar constriction, but they only have an effect on afferent arteriolar constriction.  Therefore, they actually increase intraglomerular pressure.  A drug like amlodipine, nifedipine by blocking this one but not interfering with effector increases intraglomerular pressure and therefore increases proteinuria in patients who have diabetic renal disease.  Now the question would be the differences between amlodipine and cilnidipine in patients who have proteinuria.  You will notice here with amlodipine there is increase in proteinuria, this is in patients with diabetes, where as with cilnidipine there is a decrease in proteinuria.  The only mechanistic explanation is what I have shown earlier, that the new generation calcium channel blocking drug because of the sympathetic blockade appear to block both efferent and afferent arterioles.  Due to the dual inhibition of afferent and efferent arterioles there is a reduction in intraglomerular pressure, reduction in proteinuria.


Now, this is in patients who have chronic kidney disease.  You will notice in patients who have chronic kidney disease, cilnidipine appears to reduce proteinuria whereas there is no change with classical calcium channel blocking drug.  Once again, 2 calcium channel blocking drugs having different effects on proteinuria.


This is a slide again showing a comparison between amlodipine and cilnidipine on proteinuria over a 1-year period.  You will notice only in the group that received cilnidipine there was reduction in proteinuria.  So, one of the differences between amlodipine and cilnidipine is the calcium channel expression at baseline in the kidney and during the renal denervation therapy there is deactivation of calcium channels and during cilnidipine therapy there is also reduced calcium expression.  So, there is actually a morphological correlate of what I mentioned to you pharmacologically.  When you give an angiotensin receptor blocker there is reactive increase in angiotensin.  Angiotensin goes up in the presence of angiotensin receptor blockers as a reaction and this is a reactive increase in angiotensin with ARB, but in the presence of cilnidipine you block the reactive increase.  So, it appears to have an indirect effect on blocking the renin-angiotensin system.  The attributes so far are that it is a sympathetic blocking drug, but it also behaves like a beta-blocker and it behaves like a RAAS blocker.  It is very very interesting how a single compound has so many pharmacological dimensions.  This is a slide showing with cilnidipine concurrent inhibition of sympathetic activity and also renin-angiotensin system.  Concurrently, very few drugs actually block the sympathetic nervous systems and the renin-angiotensin system as cilnidipine, very unique compound.  By itself it is behaving like a CCB, it is behaving like a RAAS blocker in the kidney, on the heart it is behaving like a beta blocker, very very interesting.


Lastly, one of the problems with dihydropyridine for the mechanism that was discussed is ankle edema, but the newer calcium channel blocking drugs because of both pre and post capillary dilatation, they decrease intrahydrostatic pressure and they decrease oncotic pressure.  Basically what you see in the kidney is what happens in the ankle.  Kidney and ankle are the same in terms of glomerulus. When you cause both pre and post capillary dilatation in the ankle you reduce the hydrostatic pressure, you reduce the oncotic pressure.


Lastly, because there are a number of cardiologists in this audience, there is a index called Tei index, which is a global index of left ventricular function which is a sum of isovolumic contraction and isovolumic relaxation divided by ejection time.  When you combine systole and diastole and divide it by ejection, it gives a global function of the heart, namely, left ventricular stiffness and this was one study which looks at the left ventricular stiffness or Tei index appears to improve.  That means it appears to improve both systolic and diastolic function in patients with hypertension.  These are not patients with heart failure or known CAD.  They may have CAD, but non CAD. The global left ventricular function appears to improve by multiple mechanisms.


Madam chairperson, Mr. Chairman, ladies and gentleman, then let me conclude by suggesting that from a pharmacological point of view, the new generation calcium channel blocking drugs by blocking the L-channel they causes vasorelaxation, by blocking the N-channel it blocks the activity of sympathetic nervous system in a very gentle fashion, not in a very profound fashion.  Ultimately, when we identify risk factors we have to prevent this from happening.  You identify risk factors so that they are not converted into disease and disability.  Person, patient, and disabled patient, that is the sequence that happens in hypertension, diabetes, and lipids and we are all assembled here because we want to protect public health.  Public health is a major, major issue in our country.  We will see what this year's budget coming next week, on 28th, how much budget allocation, it is very very small for public health, but we need to improve it.


Mr. Chairman, Madam chairperson, ladies and gentleman, the whole idea of treatment of hypertension is prevention.  We all have to become superior doctors.  Nothing wrong with transplant surgeons, nothing wrong with people who do dialysis, nothing wrong with doctors who are here who do CABGs, who do angioplasty, stent plasty, nothing wrong with them at all, but ultimately as doctors we have to go back to the dictum that have withstood centuries of human legacy and human civilization that we should strive to become superior doctors.


In summary, I have given you a pharmacological profile of a new generation calcium channel-blocking drug.  I talked about the biochemical pharmacology.  I talked about the calcium channel and biophysically how they act and I showed you the effects on heart rate, on proteinuria, on ankle edema, left ventricular function.  Looking at this drug, which appears to do multiple things being a simple compound, behaving like a RAAS blocker, behaving like a beta blocker, and behaving like other sympathetic blocking drugs and of course most importantly it retains its behavior as a dihydropyridine calcium channel blocking drug.  It has got some unique attributes and we have to see in clinical practice how this translates to the well being of the patient and protection of the patient from the ravages of cardiovascular risk factors.


With those remarks, Madam Chairperson, Mr. Chairperson, ladies and gentleman I conclude.


Thank you very much for your time.


Dr. G. R. Kane:  We are enlightened about this.  Before we ask people to ask questions, I have one.  Where should I use this drug at the present moment because it is already available in our market.  So, which are the patients where you would start this drug as a first line drug or you would keep it only as a second-line drug.  What is your impression about this?


Dr. C Venkat S Ram:  Unlike ACE inhibitors or diuretics or beta-blockers, CCBs are more broad-spectrum in general.  In the last JNC even suggested you can start the CCBs in general as a first-line drug.  You can start the patient as a first line drug, but most importantly it is very difficult to reach the goal blood pressure in any patient without a dihydropyridine.  So, it will be, I will not say competitor, but it will be an alternative to amlodipine in the treatment of hypertension.


Dr. Ramesh Dargad:  Sir, this drug has the reduction in the heart rate, is known.  This drug when combined with higher doses of beta-blocker, what will be the effect?  Second thing, this drug also has some effect on the AV node conduction, so people having a poor AV node conduction and combined with beta blocker, does it have any adverse effect, which, I think, will be some?


Dr. C Venkat S Ram:  Little bit of clinical judgment, it is possible.  It is possible of some caution in not further prolonging the conduction time.


Dr. C Venkat S Ram:  In pregnancy, always the topic comes up.  I think in pregnancy still the idea would be to somehow carry towards the gestational period as much as possible, but for the drug treatment of hypertension according to the guidelines the calcium channel blocking drugs are not the first-line for the drug treatment of hypertensive disorders in pregnancy.  It will be same drugs that you use, methyldopa, hydralazine, etc. but, calcium channel blocking drugs can be used as a third and fourth line if the blood pressure is not controllable and you want to gain few more weeks of gestation.  Only thing is calcium channel blocking drugs actually might prolong the gestational period due to the relaxation on the uterus.  Might, I am not saying they do, I do not think anybody knows.


Dr. Sandhya Kamath:  May I say something about pregnancy and cilnidipine.  So far amlodipine has just been established as a second line of treatment in pregnancy with hypertension and class I evidence is available, it is better not to use cilnidipine even though it is a calcium channel blocker in hypertension in pregnancy especially in the first 2 trimesters.


Audience 2:  Would you advice this in CHF (congestive heart failure) patients?


Dr. C Venkat S Ram:  In general, calcium channel blocking drugs are not the drugs that you think of for CHF or even diastolic dysfunction.  It they are used as a part of the treatment of hypertension it is different, but CHF by itself does not stand out.


Audience 2:  Since this has got additional beta blocking and RAAS blocking action.


Dr. C Venkat S Ram:  From a pharmacological point of view?


Audience 2:  Yes.


Dr. C Venkat S Ram:  Right.


Audience 2:  No clinical data is available on this.


Dr. C Venkat S Ram:  No.


Audience 3:  It seems to be a promising drug, but at the same time because of its multiple actions something like RAAS blockade and other things, it has to be taken with caution especially in pregnancy as you said because we never use RAAS blockade and even if it has little bit of that it should be, until the time we have data.  So, we have to collect data for indications other than hypertension.  We know today that it controls blood pressure.  If it controls blood pressure it is logical that it should be improving the outcomes, but that also we do not have data.  So, I think, I would not supplement amlodipine with this patients who are controlled with.  Well, if the patient is getting edema and you may think that he was getting controlled, I might substitute it as a beginning.


Audience 4:  Initial observation with cilnidipine alone, it appears to be a poor antihypertensive.  I think it will require having something along with, one observation. Another, is there any trial which has compared head-to-head amlodipine with cilnidipine?


Dr. C Venkat S Ram:  Only with cilnidipine/amlodipine I have shown the head-to-head .comparison.  I have not shown you the blood pressure, because they are very similar.  I have shown you the effects on proteinuria and other things, which are similar.


Audience 4:  As far as blood pressure lower capacity.


Dr. C Venkat S Ram:  It is very-very similar.

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By Dr.Siddharth Shah, Mumbai

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Moderators : Dr. C. Venkata S. Ram and Dr. Siddharth N. Shah