CME » Player

Please install flash from ADOBE

Date: 04-05-2013 Role of Newer Calcium Channel Blockers in Hypertension

By Dr.(Prof.) Kamal K. Sethi

Role of Newer Calcium Channel Blockers in Hypertension


In last part of our session which involves couple of important topics including the one that has been assigned to me which says new calcium channel blockers in hypertension and many of you would be wondering what is new in calcium channel blockers.  We have seen so many of them and we have been seeing them for ages and decades and the good and bad aspects of the calcium channel blockers are well known to all of us.  Lets try to go back a little bit into the basics of our physiology and pathology and may be it will remind us of some of over medical school days before I actually bring in the actual subject that we are going to discuss today.  Now, we must realize that some years ago hypertension used to be considered a disease of the developed world and as is true with all lifestyle related diseases that are coming up, both hypertension and coronary vascular disease are going to be the major problems of the developing world in the next 20 to 25 years and as you can see here; although, prevalence of hypertension is going to increase everywhere in the world in the next few years including the established market economies, the major brunt is going to be borne by China and India and put together these two countries will have more than 500 million hypertensive individuals by the year 2025 and that is not a small number because the amount of healthcare cost burden that it puts on our system is beyond imagination.  Now, it has been talked about since yesterday that increasing levels of blood pressure produce complications and as the people grow older and as the society grows older as we are doing these days, systolic blood pressure goes up and with systolic blood pressure come in strokes.  In the medium, middle age, and the early old age diastolic pressures are important, but as people grow older systolic pressures become more and more problem as diastolic pressure you know start falling in the population.  Now there is a direct relationship between the occurrence of stroke and systolic pressure as we have been talking since yesterday, but what was recently pointed out was a comparison between the Asians and the Caucasians or the Europeans and the Americans and it has been seen that the impact of increase in systolic pressure on the occurrence of strokes is far worse in Asians as compared to the western countries.  This may be little bit of bias as far as this particular data is concerned because most of this data actually comes from East Asia which comprises a large number of individuals from China and Japan because we have much less number of studies available from India and the Indian subcontinent where resemblance to disease towards the western population is you know somewhat more than the Eastern Asian population, but nevertheless because we know that cerebrovascular accidents are particularly common in China and Japan, particularly the incidence of intracerebral hemorrhage is pretty high in both these societies, this data certainly points out to the fact that in Asia the effect of systolic, you see the slope of this curve in relation to occurrence of stroke with increasing age and increasing systolic pressure and you see a clear difference between the slope here which is shown for Caucasians vis-à-vis the one that is shown for Asians.  So, that means that we have to be little more cautious, even more cautious than what the western textbooks actually profess us to be.


The next question is about the choice of antihypertensive therapies, which has been discussed since yesterday again.  As far as individual antihypertensive therapies are concerned and this meta-analysis was eluded to by the previous speaker as well published in British Medical Journal in the year 2009 which showed the efficacy and benefits of various classes of antihypertensive drugs and basically this meta-analysis was brought in to you know discuss the issue of what happens with usage of beta-blockers in hypertension, but it sheds data on a number of other things and what is important is to know that all antihypertensive classes of drugs are effective, but what we need today is not just lowering of the blood pressure, as I said yesterday that hypertension is not a disease of the right arm, that you look at the number you brought it down and you are happy, but we are looking at the effects beyond blood pressure control and at the same level of blood pressure control with two or three different classes of drugs are we able to decrease organ damage, are we able to decrease the incidence of cardiovascular and other vascular disease, or other end-organ damage such as heart failure, kidney failure and so on and that is the question that is being asked today of antihypertensive therapy.


Now, here is the data that looks at coronary artery disease events and cerebrovascular accident events and you notice here from top to bottom, we have thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, receptor blockers, and calcium channel blockers versus any other class of antihypertensive drugs.  Each of them has been compared as a single class of antihypertensive drugs and again you notice here that and is well known to us, the angiotensin converting enzymes inhibitors definitely decrease the incidence of myocardial infarction and coronary heart disease events.  As far as strokes are concerned, diuretics and calcium channel blockers perhaps do better than most other classes of drugs.  Though, we know that perindopril has been able to decrease strokes in certain studies that we will be talking about or may be you already know about them but remember that it happened only when perindopril was combined with something else.  Either calcium channel blockers such as amlodipine or a diuretic, a thiazide type of diuretics, which was actually indapamide in most of the studies that have been conducted with perindopril.  So, this is something that we need to look at as to, are there any differential effects of various antihypertensive therapies in reducing different types of event that we are looking at.  Then, as we also know that most patients do not get controlled with a single antihypertensive drug.  We need to put them on to combination therapy and in the modern era of evidence based medicine again, the combination that we choose need to be evidence based.  Here is the data from the ASCOT study which shows a comparison of a combination of perindopril with amlodipine vis-à-vis atenolol and a thiazide diuretic and notice here that this combination reduced almost all types of endpoints that we see here, all cause mortality, nonfatal and fatal coronary heart disease, total coronary endpoints, fatal and nonfatal stroke, etc, etc. as compared to atenolol and bendroflumethiazide, but I do not want to go into the merits or demerits of this comparison.  The point I am trying to make is that combination therapy with various drug combination needs to be looked at critically to make a decision as to what do we choose for our patient.  Now, why it has actually happened that we had better outcome with a combination of perindopril and amlodipine vis-à-vis atenolol and bendroflumethiazide and one of the important explanation that has been given for this effect is that the actual blood pressure reduction was little bit more with perindopril and amlodipine based regime as compared to the beta-blocker thiazide based regime, but notice that the absolute difference in the blood pressure between these two arms was only about 2 mmHg systolic and approximately 1.5 or 1.7 mmHg in diastolic.  It is important to realize that when you are looking at the community or a country or a huge set of population even that little change in blood pressure actually results in a huge benefit to the population.  So do not dismiss a 2 mm difference in an average systolic blood pressure over a number of years, five years for example and here is the evidence for that, a meta-analysis you know carried out in a large number of individuals, a 2 mmHg decrease in mean office systolic blood pressure results in 10% reduction in risk of stroke mortality and 7% reduction in the risk of mortality by ischemic heart disease and that is one aspect of it.  But are there any other effects of these drugs beyond blood pressure control and that is what one needs to look at in addition to this and let me now with this background go back to physiology that I was talking about that we all learnt when we started our medical school, as to what is it that actually drives blood pressure in the body.


What are the drivers of blood pressure that we know and we know that blood pressure is basically governed by cardiac output and peripheral vascular resistance and the interaction of number of things that happen in the body, primarily the sympathetic nervous system and the renin angiotensin system are the two systems that drive blood pressure and depending upon whether or not they are working in the correct amounts in the body, at the correct level in the body, whether or not they are working in the correct combination, whether one has become in excess or the other has become in excess because of various reasons or both of them have become excess, you get various manifestations.  Basically, they have been there to actually work as a stress mechanism, to control the homeostasis because when you have changes in various things in the body like electrolytes or fluid volume or sodium levels or other things then they come to the rescue of the individual, but when they over shoot their activity because of some reason or the other, which we cannot go into detail now, you have a host of things that take place.  Sympathetic nervous system for example is one of the key contributors towards this.  It causes an increase in the contractility of the heart, venous constriction, increase in preload, you know that results in increase in peripheral resistance and similarly in the renin angiotensin cascade you have constriction and you have structural hypertrophy not only of the blood vessel but also of the cardiac myocytes.


How do we actually quantify human sympathetic nervous system activity?  Clearly, we know that the autonomic nerves produce single in the central nervous systems which are then transmitted to the rest of the body through sympathetic nerve ending and one of the ways by which activity of the sympathetic nervous system is measured is to look at the muscle sympathetic nerve activity (MSNA) and you will actually find this in number of publications on hypertension that keep coming up from time to time.  This records postganglionic nerve traffic and you also get your signals going to the kidneys through the sympathetic nerves that supply and kidney has a very rich supply of sympathetic nerves which start on the adventitia of the renal arteries and those nerve then travel right inside the kidney up to the level of these smaller blood vessels.  Now, when the nerve ending gets stimulated, and we will talk about it in a little while as to how they get stimulated, you have release of norepinephrine from the vesicles which are there at the end of these nerves and they are to be taken by the receptors of the end organ where they are being released.  Some portion of this norepinephrine is taken back by the sympathetic nerve ending, which is known as the uptake.  The uptake is taken back, neuronal uptake, and little bit then gets spilled over into the circulation as free nor adrenaline and that is what we actually measure in the plasma.  So, the other way to measure sympathetic activity is to look at the plasma norepinephrine levels and that is the other parameter that one looks at apart from the renin activity which is again something which is significantly driven by the sympathetic system activity.  We have efferent nerves that go to both kidneys and we have afferent nerves, which are also the sympathetic nerves which go out of the kidneys back into the central nervous system to give the feedback mechanism to the brain.  Not only this, we have cross connections between the kidneys in terms of sympathetic nerves, so if somethings goes wrong in one kidney as a result of structural damage or effect of disease, these signals are sent to the other kidney and both kidneys then start working in unison as far as, you know, the various defense mechanism or production of renin angiotensin system is concerned and then they send the feedback back into the brain and regulate the activity accordingly and that we call as the cross talk between the renal nerves which talk to each other and also they talk back to the brain and then once there is something wrong here, kidney impairment or dysfunction, there is an increase in the afferent activity and that sends signal from the brain through sympathetic nervous systems which amplify the central or systemic sympathetic outflow and there are various effects on the kidney which are very well known to you and also on the peripheral vessels, blood pressure, contractility of the heart, and an increase in the neurohormones.  I do not want to go into the details of all this, but the renin angiotensin system is very well known to you that these are the things which it does and apart from this angiotensin II also promote the secretion of antidiuretic hormone from the pituitary which results in water absorption and then all these you know increase the perfusion of the juxtaglomerular apparatus and that is how homoeostasis is brought about.


To summarize the adverse effects of sympathetic nervous system when sympathetic system works in excess can be at all these levels, vascular, cardiac, renal, metabolic level where there is insulin resistance and dyslipidemia and arthrosclerosis, but much more importantly at the immune level which results in inflammation, leukocyte activation, oxidative stress, release of cytokine and chemokine which results in cell apoptosis in various organ systems of the body including the kidneys, the heart, and various other vascular structures that results in loss of function, increase in intrastitial cellular matrix, replacement by fibrosis, and eventually complete functional loss of the organ that we are talking about and that is a very important effect in the heart as well as in the kidneys because both these actually bear the brunt of this kind of increase in sympathetic nerve activity.  The proof of whether or not actually an increase central sympathetic drive exists in hypertension comes from number of studies that have been published in the literature and if you actually look at the MSNA that I was talking about the sympathetic nerve activity in the muscles, you see as you go from normotensives to various grades and complexities of hypertension you see that the level of sympathetic activity keeps on going up.  High normal has higher level of sympathetic activity as compared to normotensive, a white coat has still higher level and borderline hypertension has higher and obvious established hypertension and borderline hypertension all have increased level of sympathetic activity.


When we cut off the sympathetic activity does it do any good and proof of the pudding came actually very early and I am lucky enough to get this slide, you see here that this paper was submitted to JAMA in 1931 and subsequently in 1952, the results of surgical sympathetectomy in the treatment of benign and malignant hypertension were reported in 24 patients and that was the big deal at that time because there were no antihypertensive drug available as you know and people did not even know whether we should treat hypertension or not and subsequently follow up data of this great man was published you know in the late 50s where you noticed the beneficial effects of surgical sympathectomy in essential hypertension provided beneficial effects on survival and here is the comparison of two groups of individual.  Group one are the patients with persistently elevated blood pressure, but even in those days you will noticed that there were astute physicians who said that this group of patient has minimum or no eye ground changes nor any abnormalities in cerebral, cardiac, or renal nerves and that is the only thing that they knew about hypertension in those days.  Vis-à-vis group 2 to 4 which had patients with increasing levels and amount of cardiovascular disease and this is at the age of 43 and this is survival rate of normal population when you start looking at them from the age 43.  Group 1 here has very mild you know or virtually no end organ involvement in hypertension and group 2, 3, and 4 have worsening grades of involvement of end organs.  In yellow are individual who received medical treatment whatever was available in those days and in blue are individuals who received surgical sympathetectomy and you notice that the survival of those who received surgical sympathetectomy in all these groups of individual was a lot better then those who received the then best medical therapy available to us in hypertension.  Now, the second aspect, let me go back little bit to the kidney and it just take 30 seconds to recapitulate that this is the structure of the glomerulus that we all know from our first year MBBS days that the glomerulus is supplied by these arterioles, the afferent arteriole actually enters the glomerulus and it is at this point of entry that we have juxtaglomerular cells which actually produces you know the renin and the filtration takes place in the glomerulus and then you have return of the blood back into the efferent arteriole and the urine is produced here and the various solutes and other things and then the mechanism of their reabsorption with the various tubules that are present in the kidney but most of the story is actually written in the glomerulus you know when problems of hypertension start and here is a little bit of diagrammatic representation of what happens with angiotensin II.  We know that angiotensin II does all these wrong things but it is it is important to remember that the eventual target of angiotensin II is the AT1 receptor and that I am sure all of you know about this.  It is known as the AT1 receptor and large majority of the AT1 receptors are located at the efferent arteriole of the kidney.  They are virtually absent from the afferent arteriole or may be they are present in very, very small numbers and that is a very important point to remember because when you give them ACE inhibitor or receptor blocker they dilate only the efferent arterioles, they do not touch the afferent arterioles and that is why in the patients of renal artery stenosis when you have low perfusion pressure here you suddenly dilate the efferent arteriole, there is no dilatation of the afferent arteriole, there is drop of intraglomerular pressures and you get under perfusion of the kidney and an acute onset of renal failure, but that was not the point that I wanted to make today.  Now, this is something that I want you to remember that most of these receptors where the ARBs or the angiotensin converting enzyme inhibitor work apart from the other effects that they have in the body are actually at the efferent arteriolar level of the kidney.  We also know the targets of the blood pressure today and I do not want to go back into these details.  This has already been talked about that we need less than 130/80 in various diseases that have been shown here vis-à-vis uncomplicated hypertension.  Now if we come back to the recommendations of the Joint National Committee seventh report, you know that ACE inhibitors are recommended for almost every type of hypertension with associated conditions which are listed here but more importantly inspite of the fact that we have evidence that stroke reductions are significantly done by calcium channel blockers, we do not see their recommendation in stroke prevention at all.  Calcium channel blockers are shown here in high CAD risk and diabetes and obviously in chronic kidney disease ACE inhibitors and angiotensin receptor blockers are the only two drugs that have been recommended and there are two aspects to kidney disease, one is the reduction of proteinuria and kidney damage that occurs as a result of direct reduction of blood pressure and that is common to all varieties of antihypertensive drugs and there is the second component of protection of kidney which comes as a result of certain specific beneficial effects that take place within the glomerulus with different classes of drugs and perhaps that is a reason why these two drugs are the only ones that have been mentioned in patient with chronic kidney disease.


Let me now come back to the question of calcium channel blockers, which is the major topic for discussion for today and as you all know there are six types of calcium channel blockers in the body.  L and N calcium blockers and then you have P, Q, and R and S is missing if you are comparing this with the ECG.  So you have P, Q, R, and T type of calcium channel blockers.  Most of the ones that we deal with as regards control of blood pressure and vasodilatory effects that are concerned, they concern with the L and the N type of calcium channel blockers.  The T-types are slow channel blockers located somewhere close to the sinus node and some other tissues of the heart, but today you know we would be mostly concerned with these.  The L-type of calcium channels are located in the heart and in the blood vessels and the N-type of calcium channels are actually located at the sympathetic nerve endings so it is through the activation of the N-type of calcium channels that the release of norepinephrine actually takes place from the sympathetic nerve ending and that was the reason why I made all this background you know to recapitulate certain things in physiology before we embarked upon the discussion on the calcium channel blockers and what is new in calcium channel blockers today.


Now, what happens is that when you look at the calcium channel blockers we have had so many of them in the past.  We obviously had the phenylalkylamines and the benzothiazepines namely verapamil and diltiazem, but mostly we have had the dihydropyridine type of calcium channel blocker which are mostly been used in the treatment of hypertension.  The first generation out of these was nifedipine, which was very rapidly acting calcium channel blocker, but the problem with nifedipine is that because it acts very rapidly because of severe and rapid vasodilatation it causes massive stimulation of the sympathetic nervous system.  It results in reflex tachycardia and release of norepinephrine and so many other things which has all the adverse effects that nifedipine actually lost all its, you know perceived or theoretical beneficial effects which were talked about on the endothelium, on the vascular wall, on atherosclerosis, and almost every thing and nothing was seen in terms of benefit coming out on nifedipine.  In fact when nifedipine was given to the patients of acute myocardial infarction, there was an actual increase in the death rate and then it was realized that it is because of the fact that there is reflex stimulation of the sympathetic nervous system and therefore they produce slow acting formulations because that is the only thing that they could do with this product and although that produced less sympathetic activation still there is a significant amount of sympathetic activation that takes place even with slow acting nifedipine and therefore second generation dihydropyridines were produced with the premise that if you slow their action perhaps you will produce less sympathetic activity and that was the major concern and why amlodipine became third generation dihydropyridine is because of the fact that it has very slow mode of action and because of that you know it produces very little sympathetic nervous system stimulation.  Not that it does not produce sympathetic nervous system stimulation, it also produces sympathetic stimulation, but it is slow sympathetic stimulation and much less as compared to any one of those that were previously available to us and that is why it became very, very popular, although this is also a neutral drug in terms of reduction in mortality in coronary artery disease or heart failure.  It has never shown any benefit as far as mortality in heart failure or ischemic heart disease is concerned and then subsequently, we now have fourth generation calcium channel blocker called cilnidipine which is known to all of you which has slightly different or additive effects in addition to the blockage of the L-type calcium channel that we are used to talking about and which are the ones which are primarily located in the blood vessels that result in vasoconstriction and the N-type of calcium channel blocker that I have just talked about which are involved in release of norepinephrine from sympathetic nerve ending thereby producing there effects on the kidney, on the heart, and on the peripheral blood vessels.  So, the blood vessels actually constrict because of two reasons in hypertension, one is that the L-type of calcium channels when they get stimulated and secondly the release of the norepinephrine from sympathetic nerve ending that works through the N-type of calcium channels.  Now, the nifedipine and amlodipine are pure L-type calcium channel blockers.  They do not touch the side at all where as cilnidipine has a dual action.  It blocks the L-type calcium channels as well as N-types of calcium channels and obviously when you block these calcium channels there is going to be reduction in the release of norepinephrine from the sympathetic nerve endings, thereby reducing the effects of sympathetic stimulation over the three end organs, that is, kidney, heart, and blood vessels.  I must admit that published data on cilnidipine is somewhat limited at this point in time.  This drug was originally developed in Japan where it has been used extensively in treatment of hypertension, but as we all know that unless the drug goes to America or to Europe explosive multicenter randomize clinical trials never come up because that involves lot of money and I do not think Japan has less money but I do not know why Japan never produces large studies which are to the tune of what we see from other regions of the world and may be we will be seeing some data about this drug in the future, but whatever little data is available about this drug let me quickly revise that with you.


Now, since amlodipine has become the gold standard in treatment of hypertension as far as the dihydropyridine calcium channel blockers are concerned all comparators would take amlodipine to see whether there is antihypertensive efficacy of equivalence and that has been shown in small studies.  This is a 339 subject data which shows that when cilnidipine given once a day reduced blood pressures to almost similar levels as amlodipine where the doses of cilnidipine used were approximately 12 mg per day here and about 5.5 mg of amlodipine per day in these two groups of patients.  Cilnidipine was actually titrated between 10 and 20 mg per day and amlodipine between 5 and 7.5 mg per day.  Now, there is some data on pulse rate vis-à-vis amlodipine and whereas in this half of the slide you see that there is an equivalent reduction of systolic as well as diastolic blood pressure and also the ambulatory blood pressure that has been compared between amlodipine and cilnidipine.  Actually, there was reduction in the heart rate from baseline when you compared amlodipine vis-à-vis cilnidipine.  The actual magnitude of difference in the heart rate was very small, maybe 2 or 3 beats per minute, but end of the day even that might become an important parameter as far as prognosis of the patient is concerned.  You see here that there was a 2 to 3 beat reduction in the average heart rate with cilnidipine and 2 to 3 beat average increase in the heart rate with amlodipine.


Here is a comparison of different calcium channel blockers on heart rate and when you look at the data here this is cilnidipine.  This type is L-type of calcium channel blockers, baseline 6 months and 12 months, and you see the heart rate actually keeps on becoming less and less with passage of time whereas it stays the same when use the other type of calcium channel blockers and obviously this is not surprising because when you have reduction in the sympathetic activity, obviously there is a possibly that heart rate will actually become less and as the patient stabilizes the heart rate may become further less with passage of time.  There is some data that is available to us on reno protection with cilnidipine as far as reduction of albuminuria is concerned.  This is a data on 339 hypertensive patients who were already on background therapy with ACE inhibitors and angiotensin receptor blockers to control their blood pressure and also additional therapies with beta-blockers or alpha-1 blockers or some time some of them were even on diuretics if the blood pressure was not controlled to target levels.


This is a comparison of an add-on with amlodipine or cilnidipine.  The final dose of amlodipine here was 6.6 and the final dose of cilnidipine was about 14 mg and the main outcome measures were changes in blood pressure, serum creatinine, urine protein to creatinine ratio which is actually better measure of the kidney function or proteinuria as compared to the collection of urine and measurement of simple protein alone, and after one year of treatment it was found that both the groups there was significant reduction of blood pressure, but protein to creatinine ratio was significantly decreased in the cilnidipine group as compared to amlodipine and here is data that you can see on the left hand side is the actual urine protein milligram per gram of creatinine and pretreatment in dark is cilnidipine, in light is amlodipine.  In pretreatment the actual amount of proteinuria was slightly higher in the cilnidipine group, but as the time went by proteinuria remained the same in the amlodipine group, but it kept on decreasing in the cilnidipine group and at end of 12 months you notice that there was significantly less proteinuria.  Almost every level of comparison starting from month one there was decrease in proteinuria in terms of percentage change which was maintained at least for a period of 12 months.  Now, subgroup comparisons, although, not confirmatory of anything but it showed, on the left hand side is cilnidipine and on the right side is amlodipine, that in all sub groups that were analyzed in this study where the baseline urine protein to creatinine ratio was more than 1500 or less than 1500 in people more than 65 or less than 65 years of age, men and women, people in whom blood pressure was actually brought to the target level or less, which is less than 130/85, and only 35% patients who actually got to that kind of level of blood pressure versus those in whom the blood pressure remained above the target level of 130/85 and various varieties of kidney disease that were present in them and cilnidipine faired a bit better than amlodipine in almost all the subgroups.  What was most importantly noticeable here was that even in those individuals in both the groups where the blood pressure could be decreased to below the target levels of 130/85 cilnidipine produced more reduction in proteinuria as compared to amlodipine and that is important because it shows that perhaps there may be additional effects on the kidney beyond blood pressure control.  This is again comparison with some other L-type of calcium channel blockers and it shows almost the same thing that whereas with cilnidipine you see that the proteinuria keeps on decreasing over the period of 12 months and that is a same thing shown in percentage proteinuria.  It does not change with L-type of calcium channel blocker.  In fact with many of the L-type of calcium channel blockers there is actually an increase in the proteinuria because of the reasons which are not unexpected.


A lot of experimental data is available and I will quickly run through it.  Norepinephrine secretion is blocked by cilnidipine which is actually shown here again.  This is by renal nervous system stimulation norepinephrine activity measured and this is again an experimental data that shows a comparison of change in blood pressure, heart rate, and norepinephrine levels between cilnidipine, amlodipine, benidipine, and nifedipine and notice that the rapidity with which the blood pressure actually drops with nifedipine and then comes back to that level vis-à-vis amlodipine which is slow acting and see the change in the heart rate.  Rapid increase in the heart rate with nifedipine and rapid release of norepinephrine in the system as compared to cilnidipine where you see the heart rate barely increases a little bit, the blood pressure is significantly decreased from one to three hours and there is very little change in norepinephrine.  Slight increase is seen in norepinephrine with amlodipine and lot more increase is seen with benidipine and with nifedipine.  Stress induced blood pressure increase is prevented by cilnidipine and that has been shown in a few subjects again and kidney injury, this is again experimental data where percent change in plasma von Willebrand factor which is a measure of injury as nephrologist would also perhaps talk about in little more detail.  You can see that there is a theoretical advantage of this particular drug.  Similarly, calcium channel expression in the rat kidney are decreased by this particular drug and there is an inhibition of angiotensin, obviously because of inhibition of the sympathetic nervous system activity which is responsible for release of angiotensin from the system by stimulation of the renin angiotensin system in the kidneys and here is vehicle then we have valsartan which decreases when you combine valsartan with cilnidipine there is a significant decrease in angiotensin II level vis-à-vis when you combine valsartan with amlodipine because amlodipine does not have any effect on the N-type of calcium channels and therefore less effect on the sympathetic nervous system as compared to cilnidipine and that could be corollary of that.  So, one expects the concurrent inhibition of sympathetic nervous system and the renin angiotensin system by cilnidipine and that has again been proven by this experimental study and as I said before, at this point and time we do not have very much big data in human beings in terms of outcome of other pathophysiologic changes that take place, but whatever little data we have one of this small study that was published few years ago actually looked at the diastolic function of the left ventricle.  Ventricular stiffness by the Tei index and it showed that cilnidipine improved diastolic function of the left ventricle in this group of hypertensive patients.  It is also said that it perhaps produces less pedal edema as compared to the other calcium channel blockers, but as we use this drug more we will realize this in our own personal experience, but that only time will tell.


Meanwhile, I would like to conclude that we have a new kid on the block in the name of cilnidipine, which is dihydropyridine calcium channel blocker which has dual mechanism of action.  It blocks both L and N type of calcium channels.  It causes vasodilatation without causing tachycardia, decreases the sympathetic nervous system activity.  There is evidence that it decreases proteinuria in the kidney.  There is a possibility that it might decrease the left ventricular mass.  There is a small body of evidence that is available and obviously one is hoping that this will be a versatile and a novel dihydropyridine calcium channel blocker.


Thank you very much for being with us this afternoon and I would just read this quote that “there is so much being published in the literature that it is not possible for any one single individual to read everything that is available about medical science or about any thing that is there for example and if physicians would read only two articles per day out of six million medical articles published annually in one year, they will fall 82 centuries behind in their reading.”


Thank you very much for your kind attention.