Transcript for:
Drugs Used in Congestive Cardiac Failure

now today we are going to talk about the drugs used in congestive cardiac failure right before really I go to the use of the drugs I will tell you some basic problems which are present in a patient with cardiac failure once you know the basic problems in a patient with cardiac failure then you will be able to understand what kind of drug will be useful to solve those problems first I will talk talk to you about the normal heart how the normal heart work and giving you an analogy then we'll talk about what happens in a feeling heart so let's go with a very simple analogy right and in this Synology I will make a graph right you know Frank starling's law Frank starring last states that whenever you know Frank Sterling's law you don't know it okay listen what is Frank's darling laugh according to Frank Starling law whenever you are filling the left ventricle or right ventricle with the blood if you put more blood in the right ventricle or left ventricle it will contract more if you will put less blood it will contract less it seems very logical for example here is left ventricle right let's Suppose there is more ventricular filling if there's too much ventricular filling then naturally at the end of diastole and diastolic volume will be low or high it will be high if there's more cardiac filling more venous return and diastolic volume will be high when end diastolic volume will be high then before the contraction stretch on The myocardium will be high because the more you put the blood into The ventricle more it stretches the wall of the ventricles it's very easy to understand even a small kid can understand that in The ventricle if you are putting more and more blood it is stretched more and more now Frank Sterling glasses more you stretch the ventricle move it contracts within physiological limit you should not stretch to rupture it basically myocardial contractility of the basic principle more you stretch the ventricle more it attracts it means more you put the blood in more it will eject so it's interesting calculation and if you put less blood it will eject less so it is intrinsic regulation that if more blood is coming in it will contract more strongly if left left less blood is coming in it will contact less efficiently is that clear now this is end-astolic volume and if we put end diastolic volume here I will make a larger diagram right that if we put n diastolic volume on the x-axis and diastolic volume right and here we put the contractility contractility of the ventricular all of you know when end diastolic volume is increased conductivity is increased isn't it right and this is the normal curve of a healthy heart right what we are showing in this healthy curve that whenever end acidic volume is progressively increased cardiac output or contractility is progressively increased now contractility can be measured by the stroke volume or it can be measured by cardiac or is that right now the point which you have to understand that normally heart is operating at which point heart is normally operating in a healthy heart how much is the end diastolic volume about 140 ml healthy left ventricle when it is fully you know loaded with the blood it is about 140 150 mm and then it will start contraction and normally when blood has one left ventricle has 140 ML and it will do healthy contraction about 50 blood will be ejected so what will be the stroke volume yes about 70 mm so it means when left ventricle has how much blood and diastolic volume is 140 right and at this end astrolic volume how much blood is going out 70 ml is that right so normal heart is operating at Point number one at this point normal heart is operating at this point now if you increase the venous return to the heart healthy heart for example you give me a drug which construct my vein then more blood will be coming to my heart then heart has to have more and astrology volume then heart has to have more contraction and more cardiac output is there clear if you give a drug which dilutes my veins the blood will pull into veins Venus return will decrease and cardiac feeling will decrease contractility will decrease so again if you give in a healthy heart for some talking about the healthy heart if you produce Vino constriction right that will take industrial volume from one for forty to Let's suppose 200 then naturally this in this direction contactility will move maybe out of 200 now it is ejecting 100 ml still it is maintaining how much reaction 50 percent is that right and if you give Vino dilator then end absolute volume is reducing contractility will also reduce any remove in this direction is that right so this is a healthy curve right in a healthy myocardium where increasing the industrial equal volume increases cardiac output decreasing and diastolic volume decreases cardiac output now we go to the what happens in a failing heart what happens in a failing heart now now you imagine that my left integral developer disease suppose ischemic heart disease and due to repeated ischemic attacks my left ventricular myocardium becomes weak and if my when my left ventricular myocardium becomes weak do you think it's contractility will increase or decrease then what will happen this type of heart which is having reduced conductivity power what it will do for a given 140 ml will it eject 70 mL no no at 140 ml maybe it will reject 50 ml is that right so I mean the whole Curve will drop down right now let me make the curve of a filling heart this is a curve of the failing heart what I show for every given and diastolic volume as compared to the healthy there's less cardio is that right if you increase end absolute volume in a field feeling hard for example you take a 200 again at 200 Normal Heart gives so much output but this heart is giving less output so what we really see the first curve was healthy hard curve function curve and this is filling hard curve what is the difference in them that even though both conditions by increasing and diastolic volume increase contractility but contractility produced by healthy heart is more and contractually produced by the feeling hard is less is there clear it means let's suppose I developed myocardial infarction and that myocardial infarction is a large area which is infected so large area of the left ventricle is not pumping well so immediately my cardiac output will drop because if a big area of left ventricle is infected and not pumping overall contractility of left ventricle will drop so what will happen there from point one my heart will start falling end point two so this is what will happen to a from healthy heart shift into a failing heart your contractility drop from higher level to low level on the graph now when contractility will drop then what will happen we'll make a diagram here about the hemodynamics of a failing heart let's suppose this is the heart which is very weak there's a very poor contractile heart now what should happen to this heart which is poorly conducted output is more or less cardiac output is less whenever cardiac output is less let's suppose this is corroded sinus when heart is poorly pumping blood flow to the carotid sinus is less and carotid sign as well in form to the central nervous system that blood pressure is falling now here is your central nervous system so in the feeling heart as cardiac output will drop is that right pressure in the sinus system will drop that will inform the central nervous system about the dropping cardiac output that will stimulate the which system Vaso motor system this is an emergency sympathetic nervous system is activated so that will lead to sympathetic outflow that will lead to sympathetic outflow when in the feeling heart when cardio got to drop then sympathetic outflow is decreased or increased increase sympathetic outflow is increased we'll talk about what is the purpose of this sympathetic outflow let's suppose this is right side of the heart and again you keep in your mind that here is the arterial tree and there is yes what is here Venus system and just make for understanding two capability Networks and we'll see now what really happens in the compensatory mechanisms and in this reference especially I would love to mention the role of kidney as well so that that role of the kidney and written Angiotensin system should be integrated that I will show here let's suppose this is the blood flow through kidney is that right now we'll see what really happens to this patient left ventricular contractility become less cardiac output become less pressure in the barrel receptor sensing system blood pressure sensing system we use less pressure level system brings sympathetic outflow now what the sympathetic outflow will do remember initially it will be good for the heart in the long run it will be bad for the heart how it will be good for the heart look here it will stimulate as anode it's pathetic outflow will stimulate essay load so heart rate will go up increase heart rate it will stimulate the ventricular contractility so positive ionotropic so increase in stroke volume so in this way these two things heart has done initially in a good way that as soon as blood pressure fall cardiac output fall blood pressure fall sympathetic outflow come heart rate increases stroke volume increases and when heart rate and stroke volume increase when there is increased heart rate into increased stroke volume what happens what will increase and heart rate increase stroke volume increase cardiac output increase so this is an attempt by the sympathetic nervous system to reverse the Fallen cardiac output now this attempt s good only for a short in the long run it's very very bad as sometimes you go into crisis and you you may do some short-term wires which are good for you and sometimes if those short term Mayors go for a long time they may become bad for you is that right why this is bad listen careful if failure is just for two hour five hour ten hours no problem but failure is for months and years increased sympathetic activity right that will produce pathology in the heart why what is the problem let me tell you what's the problem when sympathetic nervous system not only it is stimulating the and ventricular contractility sympathetic nervous system will also stimulate the arterial tree let's suppose these are the arterioles sympathetic nervous system is also stimulating the arterials sympathetic nervous system is also stimulating the Vineyard now what will happen listen carefully when arterials are stimulated arteries will dilate or construct if arteries are constructing it is good for failing heart or bad for failing heart it's very bad you know why because are getting constructed now then for left ventricle to push the blood from the arterial tree to venous tree becomes more difficult because arteriola construction lead to increased resistance for the left ventricle to push the blood from arterial side to the venous side so do you think heart will be happy with the situation or sad about this very sad it is already feeling hard it's like a sick donkey which could not perform well at the top you ask this donkey to perform against more resistance this donkey is performing against more resistance this is one bad thing which happens is that right another bad thing look at it you construct the vein Venus system construct the veins if all the veins become tight more Venus return more cardiac filling and if cardiac feeling becomes too much right heart will again suffer I will explain why now here we have to talk about a law which they know very well LaPlace is law what is that pressure is equal to tension by tension by radius Jim is good now this law you should be very clear about what is the mentioned meant by the tension tension is the power generated in the myocardial wall when myocardium contract you develop a tension in the wall and when myocardium develops at tension contacting my body will develop tension that produces the pressure here that tension results into what pressure this is the tension which produces the pressure so that cardiac output should be maintained Plus this tension is working on a radius of the heart now what is the relationship listen carefully if you increase the tension pressure generated are more and if you increase the radius pressure generated are less so we can say the pressure which left heart can generate pressure which left heart can generate right is directly proportional to tension and inversely proportional to radius is there clear now already there's a trouble this is a healthy heart or sick heart the sick heart its capability to produce tension is more or less less of course it is uh having a function and some of its part is not producing tension so total tension which this heart is producing fairly hard total tension which is producing is more or less less so write down here that tension in a feeling heart no this is a primary pathology tension generated tension which can be produced in a failing heart is less is that clear is hard so look at it the stupidity of the sympathetic nervous system short term benefit long-term damage what is the long-term damage I told you when long term arterials remain constructed long-term arterials remain constructed then it has to generate more pressure or less pressure it has to generate more pressure to push the blood through narrow arterials so this is a stupid thing that already it is very sick heart it cannot produce tension and from sick heart you are demanding more pressure the sympathetic nervous system is activated it will keep the arterial narrow and if arterials remain narrow then it has to produce too much tension to produce too much pressure so that it can push the blood through the system now it is just like a sick donkey and you are asking it to do work too much work is that right this is one problem so sympathetic nervous system it here it is doing a favor to the hemodynamics of feeling heart or it is producing a trouble for that it's a trouble for that trouble number one now look at the trouble number two heart is already working very hard against the very vessels which are progressively getting narrow another trouble starts simultaneously that it produces Vino Construction when it produces Vino construction sympathetic nervous system produce we know construction it is done with all the best intention or sometimes with the best intention you may even kill the other person sympathetic nervous system is doing good intention that it is leading to you know Construction intention is that if there is vino construction there should be more Venus return and if there's more minutes return there should be more cardiac output but the problem is this that if you're constantly keeping more Venus return it means cardiac filling is more if cardiac filling is more than radius is increase and if you are making the radius high can hard produce pressures no further fail so primary problem in a failing Hardware that it cannot produce tension primarily is that right due to that reason it could not produce a pressure to maintain the cardiac output secondary trouble come due to sympathetic nervous system that will construct the arterials so now heart has to pump against more resistance and pressure is required more than the normal situation and tension is less than the normal situation at the top when we know construction occur and diastolic volume become too much and radius increases so smaller tension divided by larger radius produces very little precious so what is happening to this unfortunate heart that intrinsic problem is this that there is capacity to produce smaller tension and due to increase venous return radius is more smaller tension divided by larger radius is producing two liter pressure so progressively hard capability to generate pressure is reducing but due to arterial contraction construction demand for pressure is foreign so what will happen to this heart look at it because it cannot produce pressure it means whatever is coming in can it push out no so what will happen to this heart it will dilate why it will dilate that normally initially it was receiving 140 ML and healthy situation ejecting 70 ml now it may be having 240 ML and ejecting only for DMI so every time it gets more blood and eject less blood so progressively dilate now look at the misery of this heart sick tension very poor and progressively radius is becoming larger and result is worth Progressive drop in the pressures Progressive drop in cardiac output that is why when heart becomes dilated feeling hard since real good doctor will get upset he knows a very good doctor know whenever Hearts start dilating it means radius is progressively increasing and if heart was already failing the doctor has an idea that tension development capacity is less and Progressive dilatation lead to further drop in pressure generation further drop in cardiac output okay this was one trouble so sympathetic nervous system in the long run is good or bad a bad now look the second mechanism which second mechanism is rain in Angiotensin aldosterone axis it comes with all good intention and kill the situation first sympathetic nervous system came to help and hurt the heart now any ninja transition system will come with good intention to help the heart but make the trouble for the heart now let me tell you what running Angiotensin system will do you already know if Hearts when heart will start feeling then renal perfusion is more or less if renal perfusion is decreased then naturally there is more rain in production or less rain in production so in this patient kidney will produce more renin more than normal now what are the reasons of more renin number one that blood flow to kidney is less so baroreceptor system of gesture globular operator senses that there is low flow and low pressure it will release renin secondly the there is less flow to the heart and sorry less flow to the kidney then filtration is more or less less when gulmarular filtration is less then the amount of sodium reaching to macular densa is more or less less so macular densa also senses there's something wrong and it also releases further increase in running at the top already sympathetic nervous system is overstimulated under stimulated it is over stimulated so from sympathetic nervous system some fibers are coming to the juxtapular operator operators what will happen more random so it means in feeling hard this Progressive increase in ran in now there must be some benefit in the biological system when there's so much Lenin you know it that renin will convert into gene into Angiotensin one and then Angiotensin converting enzyme Angiotensin converting enzyme will work on Angiotensin 1 and convert into Angiotensin do so it means in a failing heart there is Progressive increase in circulating levels of angioed answer to now there must be advantage of it and there must be disadvantage of this a biological system is doing this thing whenever renal profion is down of course Angiotensin 2 will become High now what are the advantages of angiotensin 2 in failing hard and then we'll talk about disadvantages as well we have just discovered that when there is less renal flow the more rain in Angiotensin Elder stereone X is stimulated right first tell me why what are the advantages because if body is doing this game that in failing hard it is increasing the rain in angiotensinaldosterone system there must be some sensible benefit and later on I will tell you there is also damage number one look when Angiotensin 2 is more plus aldosterone is also steroid is also more now you imagine look at the whole system when Angiotensin is more angiotestine constrictor length intention is that that when there is construction of the veins there should be more Venus return a more end diastolic volume so that there can be more cardiac output but actually fulfilling hard diameter will become dangerously increased so it will help or it will deteriorate deteriorate intention was good that normally in a healthy heart when you construct the wind increasing venous return usually increases cardiac output but in a feeling hard increasing venous return unfortunately increases the radius so much that further drop in the performance of the heart this is one good intention which turns out with bad result secondly Angiotensin II was trying to support the blood pressure because in cardiac failure blood pressure goes down so Angiotensin 2 to support the blood pressure does what is this arterioloconstriction when arterial construction is done do you think it is good for feeling hard or bad for failing hard bad for failing heart so there another trouble at it that now you have demanded more pressure from a failing heart is that right so what is happening Angiotensin one is Angiotensin 2 is producing Vino construction as well as arterulo construction but we know construction which is progressively increasing the radius and by arterial construction it is a progressively increasing the resistance against which heart has to bump is that right these are troubles then another trouble aldosterone is also there aldosterone will retain salt and water in the body the salt and water which is retained by the kidney will increase blood volume or decrease blood volume and increase blood volume will increase Venus return so ventricular filling is more in radiuses more it's good or bad what I'm trying to put in your mind the purpose of all this discussion is that patients with chronic heart failure they over stimulate sympathetic nervous system and these patients are chronically over stimulated raining angiotensinaldosterone system and both is chronically activated system really damage further to the feeling hard now another thing not only the system will produce Vino constriction arterial low construction and salt and water retention Angiotensin to stimulate sympathetic outflow and is a strong sympathetic outflow further arterial construction we know construction good for heart bad for heart bad for heart so it means these neuro humoral compensatory mechanisms are dangerous for the heart in the long run then attach to another thing which is very important if Angiotensin 2 level and aldosterone level remain chronically High they act as growth factors these are one of the latest news is that these substances are the chronically High the act as growth factors so what really happens Angiotensin 2 will stimulate the myocardial cells produce their hypertrophy and myocardial cells will abnormally start producing connective tissue do you think heart which is abnormally hypertrophic cells not normal hypertrophages pathological hypertrophy and geometry of the cell is abnormal at the top cells are producing lot of connective tissue do you think it's good hard or bad hard and at the top aldosterone produces fibrosis in the heart these are the very new research the Elder sterone when it is chronically High it produces fibrosis in the heart so this fibrotic changes and all distortions in the myocardial geometry eventually lead to Progressive failure of the heart that as months keep on passing will say heart is undergoing abnormal structural changes and abnormal morphological changes due to excessive stimulation of and this whole dangerous changes in the heart morphology in a lump sum they are called cardiac cardiac remodeling so this is another trouble is that right now you imagine that we have learned very well all these things are in the long run very bad for the heart now we apply these things here on the graph now we apply these things on the graph listen again go back what happened heart was performing at the normal position due to some disease contractility of the heart is reduced and cardiac output drop for the given and diastolic volume now stroke volume is less cardiac output is less at this point there is activation of sympathetic nervous system there is activation of sympathetic nervous system at this point and at this point when cardiac output has dropped sympathetic nervous system is activated as well as written in angotensin aldosterone excesses activated is that clear now what will happen due to this for example sympathetic nervous system produce we know Construction volume will increase rain in Angiotensin aldosterone system retains salt and water in the body and natural equally well increase angiotensin two produces we know construction and diastolic volume will increase so all these things will increase the end diastolic volume when they will increase the endosterolic volume heart will move from this point to this point progressively Point number three what we really see that end diastolic volume which was previously how much in healthy heart 140. now here it has become 240. but with 140 in healthy heart it was 70 ml out is that right with 140 in disease heart maybe it was only you can say 35 ml out is that right by retaining too much fluids in the body and producing too much construction what did we do we increase the endosolic volume too much but when n diastolic volume was increased we are expecting a big increase in cardiac output but unfortunately cardiac output is increased only mildly from here to here maybe 35 to 45 did it go to normal level no why it did not go one major reason was that The myocardium was weak and another reason was that we are constructing the arteries of course if you are increasing the end diastolic volume heart will love to contract and produce cardiac output but if you are constricting the arterial it means hard as to produce ejection against higher resistance and if hardest produce ejection against higher resistance can disease heart can produce that much output no due to that reason curve which was supposed to move upward it moved very little up Again by increasing the endosterolic volume biological system was expecting we have done great that filling the heart more we are going to have very big cardiac output but it does not happen because biological system is done stupid thing that no good thing it has done increase ventricular filling and bad finger is done arterial of construction and due to increase that your arterial construction cardiac output could not be increased as much as much was X expected so there's little increase in cardiac output so filling heart is operating now under which circumstances in the long run Point number three now if you don't treat this patient and patient keep on suffering with excessive amount of angiotensin too and aldosterone heart will undergo structural changes pathological remodeling and when heart will become too weak then what will happen it will further start moving to the dropping situation cardiac output will further drop you see end diastolic volume is progressively increasing but now cardiac output is increasing or not increasing do you think it's all happening good or bad it's bad so this is the Tonky with a lot of endospholic volume and has to work against too much resistance the back is breaking is that right and drugs have to work to improve it now let me tell you do you have the concept of preload and afterload right but do you have more or less I will just tell in a very few words what is preload pre-load is the amount of blood in the ventricle at the end of the dastly on which ventricle has to produce contraction so what is preload preload is load in The ventricle before the contraction and what is preload and diastolic volume so actually what is this increasing we say industry volume is increasing actually we should say there is preload increasing what is preload the load in The ventricle before it contract and what is after load after load is the resistance against which ventricle has to perform and that is the arterial of today onward you have to remember that if you produce Vino construction preload is increased volume is increased if you produce we know dilatation then blood will move less preloaded decrease and if you produce arterial construction after load is increased heart has to pump against more resistance and if you do arterial dilator drug after Lotus decreased is that right now with this graph we'll make another analogy here that let's suppose this is your heart I told you heart is a donkey let's suppose this is your heart right dislike donkey and this donkey has end diastolic volume here this is a load on the heart what is this this is the load on the heart before it starts performance is the right first look at the normal then go to the abnormal in healthy donkey usually it has how much here 140 ml and it will move upward and healthy donkey after moving against this resistance what is the resistance arteriola contraction total peripheral resistance after load so pre-load is over it and this this is after load after load so donkey carries the preload and performs against afterload and then it will of course then it will come back but it's a very stupid donkey you know what it will do out of 140 ml it carried it work on 140 ml it will leave only 70 ml here and bring 70 ml back with it and again Karim more blood and develop how much again and actually volume of 140 go up right so every minute how many cycles it will do 70 to 80 Cycles it relaxes here is the diastolic situation here's the peak of sustain and that's the only situation you take how much blood 140 ml normally it does have a 50 injection and then come back to this position and again take up the load and goes up then come back again this is what is happening the Synology is clear now in filling hard what happened first of all look at this this donkey is crying it's very sad let's look at the heart of victim now this is crying donkey why it is crying the reason being that it's one leg is broken three-legged donkey right this three-legged donkey now its contractility and performance is more or less now what you do this is normal preload now it was moving very slowly upward and it was taking less performance there so Central our system is sitting here and kidneys sitting here they think why the performance is less sympathetic nervous system fire as well as injured tension endosphereum system fire what are the results do you think now this three leg donkey which is a weak donkey when the compensatory mechanism Works preload is increased or decreased increase now look at it very weak donkey with extra load do you think it's a happy donkey a sad donkey very sad this is happens this is truly what happens to a failing heart that when feeling hard ones sympathetic nervous system is activated as well as Iranian ninja steering system is activated Venus return is more and this increased Venus return put too much load in The ventricle but this ventricle cannot contract so it will become more weak somehow it will go up and it will become so much confused that out of such a big load it will leave little load there and again slip back is that right another thing increased neuro humoral compensatory mechanism like sympathetic nervous system and radio transfer aldosterone system it will produce arteriola construction now look at it this angle has increased what do you think now this donkey has to go all the way up with more load this three-legged donkey right and compensatory mechanism is putting more preload and increasing this after load the resistance against which it has to perform reload is increased by Vena Sultan and fluid accumulation you know salt and water retention and after load is increased by articulo construction do you think it's performance will progressively improve or go down at the top chronically elevated you know what is this one will further make the health of the Donkey weak is that right so feeling hard as these troubles excessive preload excessive afterload and very weak contractility and progressively failing is that right now we want to help this donkey here is the pharmacology enters right we have correlated the physiology and pathology now we go that we have discussed this one normal curve physiology this is the pathology and now we'll see how this pathology can be reversed by pharmacology towards the normal thigh now what we have to do is very easy to understand what should we do if you want to help this donkey yeah what about preload should be increased or decreased right number one this is weeping too much so first treatment should be you should somehow reduce the preload donkey will pray for you right from a failing heart first management traches reduce the blood volume and venusita preload reduce the end asphalic volume second help is that it was going to work on very high resistance turn it down reduce the afterload pharmacologically when you want to reduce the preload you will give the drugs which should dilate the weight or construct the vein drugs which are we know dilators so point which you have to correlate The Filling heart is a sick donkey with lot of preload lot of endosolic volume you must try to reduce the Venus return to the heart so that load should be less so give winner we know dilator so that when veins will dilate look here and feeling hard you give the Vino dilator so there's less blood returning to the heart and advantage of Reno dilator is very easy that radius will reduce with given tension it will produce better pressure now correlate three things in your mind number one LaPlace is La number two alternative physiology number three is this graph all these things are Disturbed in a feeling heart when you give we know the letter or you give diuretics also to reduce blood volume you get it so we can give in order later and we can give diuretics diuretics do three things number one diuretics everyone knows produce diuresis excessive loss of salt and water and that reduces the blood volume and when blood volume is reduced when blood volume is reduced naturally Venus return is reduced and pre-load is reduced so diuretic number one they reduce the blood volume secondly diuretic also do we know dilator as well as arterial lodiator is that right so in a failing heart you must have vino dilator drugs you must have diuretics and both of them reduce the venusotan reduce the end diastolic volume reduce the Prelude so cardiac efficiency will become more or less right this is you imagine place of donkey and if you reduce the burden on you your performance will become less or more hopefully more but if it doesn't improve I'll tell you what we'll do the special drop for you now listen so what happens that we reduce the preload first you understand an analogy analogy will reduce the pre-lord donkey is Happy okay let's make it happy someone at least tears are still coming but somewhat happy right number one number two work on this when you reduce the preload end actually volume is increasing or decreasing so this will move backward now this pathological change will move backward Revenge you are giving we know dilator it will start moving backward is that right when it is moving backward and you have given vinodilators and diuretics do you think Venus return is more or less industrial volume is less so radius is now smaller radius same tension with smaller radius will produce better pressure cardiac output will go up is that right cardiac output will go up now one more thing that not only this why don't you reduce the slope also be merciful to animals animal rights are there including the heart yes number one reduce the preload plus you reduce the afterload and if you reduce the afterload you are going to be good your to your donkey you reduce it like this how you do reduce afterload or it is you know bananas now we need drugs which are arterial or dilator as well so basic principle is dilate the veins so let's Loot on the heart preload dilate the arterios heart has to pump against less resistance so pump will be more effective or less effective more effective is that right so what we are doing that when you give denote we know dilator you reduce the radius with the same tension you produce more pressures at the same time you give arterial when you reduce arterial or dilator the pressure to be generated are more or less when you do arterial load dilatation hard to maintain good output has to produce more pressure or less pressure less pressure so again remember when you it means that when you do arterial or dilatation what really happens that for example heart is here when you dilate the arterial what will happen conductivity will go upper cardiac output will go up or down cardiac output will go up so it will move like this what is happening as soon as cardiac output went up further reduction and then diastolic volume are you understanding so it will not go straight up it will go like this these are good news or bad news for the filling heart so this is the initial help try to reduce the reload on the Donkey and try to reduce the resistance against which it has to work most of the donkeys become okay most of the feeling harder okay with this type of management reduce the preload and reduce the after load is that right now what are the advantages of this thing listen now carefully when you give vinoda later than arterial load dilator please be attentive when you give artillery load a letter and we know the letter something very important cardiac output will drop or it will go up is when cardiac output will increase sympathetic nervous system is relaxed and increased sympathetic activity also degrees good news bad news it's good news number one number two when we know the preload is reduced and afterload is reduced cardiac output goes up so renal perfume goes up when kidney is well perfused rain in incidence and help the student system relaxes so you gain it's another good news so most of the time to improve the function of this donkey that is feeling hard is reduce the preload and reduce the afterload reduce the blood volume reduce the venous tone and reduce the arterial tone so give the Vino dilator as well as give the arterial to director but some donkeys are really very safe most of what I'm talking about special situation not about you special situation that what happens that for example heart is really very very bad you reduce you know too much load and you reduce the too much what is this dilated it should perform well but still working very less what we will do now you are angry forget about the donkey's right bring the whip out and start beating it please perform I'm going to die yes positive inotropic drugs the third group of drugs which will come into uh this situation is positive anotropic drugs so classically we should have we know dilators pre-load reducers rather write it down now this is the crust of management preload reload reducers and we need what's in afterload after load reducer this is a very Humane treatment of the Donkey is that right that reduce the burden on the donkey reduce the resistance against which it has performed most of the good donkeys will start performing but if donkey does not perform still then you go for severe stimulation and that is what is that thing positive and what they will do on the given endosolic volume they will simply take it upward or dopamine or do but I mean yeah do betamine and dopamine are basically intravenously constant infusions orally drug which is only available in America is digitalis is that right so anyway so or for example heart is very much failing at this point if you give positive inotropic it will simply go up that's right but when you give vinoda later than arterial loot dilators if you give purely without a letter to move like this okay now let me tell you these are the points heart is failing at this dangerous point now let's look at the graph the effect of the drugs if you give purely Vino dilator if you look at the purely Vino dilator it will move in this direction is that right because we know the letter will reduce the end acetylic volume if you look purely arterial or dilator it will move in this direction when our digital dilators performance will go up with increasing performance and diastolic volume will decrease is that right and if you give purely positive anotropic its performance will go like this is that right but when you give a combined drug all of them what really happens that heart moves from this curve moves into middle position right that you give vinoda later it comes here to give arterial load the letter it moves like this you give positive anotropic moves at this position right yes no no that you ready to do three things every doctor knows the diuretics only expel the volume out right this is not true actually long term use of diuretics number one reduces the blood volume number two produces Vino dilatation number of sweet produces that is why they are so commonly used in congestive cardiac failure because number one by reducing the blood volume diuretics by reducing the blood volume and by producing Vino dilatation they reduce the load on the heart pretty load on the heart and by producing some degree of arterial dilatation reduce the slope is that right but the most wonderful drug the most wonderful drug and systolic and cardiac failure now are considered Angiotensin converting enzyme inhibitors the best drugs which are presently considered are Angiotensin converting enzymes inhibitor let's look at the performance of those drugs how they correct the Disturbed pathology and its Disturbed mechanisms now we are going to talk about which drugs Angiotensin converting enzyme inhibitor of course they are captopril and allopril the synopril many drugs you can read it from the book The Point which I have to explain is when you put the patient on as inhibitors what will happen that Angiotensin 1 cannot convert into angiotensin two it means angiotensin two level will go down now look at the mechanism first we will discuss on the donkey but in your tension Inhibitors are doing atrial transient converting enzyme or capital is doing here then we'll talk about the okay here what captopril is doing here then I will talk about what capital is doing on this then I will talk about what Capital Grille is doing with this so that MC could come in anyways you should be able to handle that right let's suppose you give capital or analog apparel to the patient or feeling hard now what are the functions of capital main function is they should reduce the level of Angiotensin 2 plus they should increase the level of bradykinin these two things happen is that right because Angiotensin converting enzyme normally convert into tension 1 into Angiotensin 2 plus normally the same enzyme destroys the bradykinin so when you just block the enzyme by the captopril or an allopril when enzyme is not working Angiotensin one is not converted into Angiotensin 2 and bradykinin is also not destroyed foreign dilates the vein and arteries both number one number two it's good for the cardiac failure patient secondly this very significant drop in Angiotensin too now we'll talk about what happened to this donkey with drop in Angiotensin two when Angiotensin 2 is less when Angiotensin 2 level is less we know construction is plus surveillance will dilate so Venus return well decrease and that's really valuable decrease radius will decrease so pressure generated will be more when Angiotensin 2 produces wind A reduced into transition to level and failing hard reduced Angiotensin 2 level after the capital or analapril when they reduce they produce Vino dilatation Venus return to Heart decrease so and diastolic volume will move from four position to three position is that right so Angiotensin 2 by reduced in angioticin 2 level produce Vino dilatation which can reduce the preload reduce the end acetylic volume and from 4 it will move to 3. number two look here when you are doing window dilatation the load on this is more or less less so it is helpful this is one point that we can say Angiotensin converting enzyme Inhibitors captopril act as foreign less resistance so cardiac output will be less or more more and of course pressure to be generated are less is that right because it is dilated so second thing is that Angiotensin converting enzyme inhibitor drugs captopril also work as after load reducer so single drug can reduce the preload and can reduce the afterload it means single drug can reduce the load from here and reduce the slope that's the right third action look at the Angiotensin converting enzyme inhibitors when Angiotensin 2 is less when Angiotensin 2 is less aldosterone is less when aldosterone is less salt and water retention is less salt and water is lost blood volume is low when blood volume is low what will happen again preload is reduced so reducing Angiotensin 2 reduces the pre-load by two ways number one reduces the pre-load by inhibiting aldosterone activity the production by reducing the level the filter on reducing the salt and water retention or by increasing the salt and water expulsion from the body certainly by direct we know dilatation then there's arteriolo dilatation then look another function is achieved by reduced Angiotensin II what is the next function advantage of reduced Angiotensin to level I told you one is vinodulator other is articulator another is reduce Elder function which is a very big one more Advantage for reducing Angiotensin II I told you Angiotensin 2 is a very powerful stimulant of sympathetic nervous system indoor tension too increase Central sympathetic outflow Angiotensin tone stimulates the sympathetic ganglion Angiotensin 2 stimulates the sympathetic nerve ending so when Angiotensin 2 goes down with kept Operator Treatment then what happens when Angiotensin 2 is less then sympathetic activity becomes less when all the sympathetic activity become less we know validation further we know dilatation so we know dilatation a pre-load reduction is due to multiple reasons now if you don't just tell one reason and forget about someone asks you how into attention converting enzyme Inhibitors of captopril help a patient with a cardiac failure first concentrate all the mechanism which reduce preload number one when Angiotensin 2 is less Angiotensin to mediated we know construction is lost number two when injured tension 2 is less aldosterone is less salt and water is lost again preload is reduced third when Angiotensin 2 is less sympathetic activity is less and sympathetic we know motor tone is reduced all of these things are leading to pre-load reducers clear then Angiotensin 2 directly I told you the ninja turns into levels are less Angiotensin II mediated arteriolo construction is also reduced plus when Angiotensin 2 is less sympathetic output is less sympathetic activity is less so sympathetic system mediated arteriolo construction is also lost so it means two arteriola constructions are lost one is when you give captopril and the patient body two types of arterial Constructor influences are lost one was giving the captopril when you reduce angiotensin two so direct angiotensin two mediated arterial construction is abolished number two Angiotensin II in deficiency reduces sympathetic outflow so sympathetic system mediated arterial construction is also lost so donkey will be happy or sad happy is that right Mustafa really happy right so what we are talking about that Angiotensin to a captopril or analapril reduce the preload reduce the afterload now the same thing we can say in another way now listen carefully when heart is underfelled first listen Heart Is Over filled then under filled when heart is overfeld the pressure during the diastole on the wall is less or more more so we say diastolic stress on the myocardial world when you reduce the preload diastolic stress on the myocardial wall this it is a good news for the heart number two when arteries are dilated then systolic stress on the wall is reduced because heart is supposed to produce less tension and less pressures because it is beating against less resistance with the little activity it can produce good output so now two terms more I introduce that there's diastolic stress on The myocardium and there is systolic stress on myocardial Bond whenever you reduce the preload this reduced diastolic stress on the diastolic stress on the my ventricular walls and whenever you reduce afterload there is reduced systolic stress on the ventricular walls is that right when these stresses are reduced problems like hypertrophy will be increased or decreased problems like hypertrophy will be decreased so have two pillar or analapril the chronically reducing the renin Angiotensin aldosterone system activity they reduce the diastolic stresses on the ventricular walls as well as they reduce the systolic stresses on the ventricular wall which reduces the total growth stimuli on the ventricles and that help The ventricle to reduce or regress pathological remodeling you understand it plus I told you that high levels of angiotensin 2 and high levels of aldosterone can directly act on myocardial cell and alter the geometry alter their contractility and produce Force those cells it's very sad myocardial cells real function is to do contractility but aldosterone and high angiotensin two Force those cells to dysfunction first they become fat and then they become dysfunction what is dysfunction rather than contractility those cells start producing the start producing extracellular Matrix do you think this is the normal function of myocardial no it's just like that you are becoming doctor and someone asks you to sweep the something very dirty it's a misuse of you so if we make The myocardium free of the struggle that when capitals are given what happens that chronic growth stimulation abnormal growth stimulation by the introduction to an elder stereo is reduced fibrosis in the heart is reduced a pathological hypertrophy is reduced pathological production of and extracellular Matrix is reduced or simply we say methyl Progressive Progressive pathological remodeling is reduced but latest news are not only progression is reduced they say when you start these drugs after few months doctors have seen the already whatever pathological changes were in the heart that regress so in your attention to an elder stereo on The Chronic elevation were not only producing preload problem and after load problem but they were also directly increasing systolic and diastolic stresses on the myocardial wall plus they were stimulating the genes in a pathological way to produce growth and hypertrophy and essential Matrix everything is reduced we say geometry of the heart which was here when Heart come back here geometry of heart will become better the globular heart will become normal shaped heart what is the normal shape of the heart of course you should know your doctors doesn't it that left ventricle best performance wind shape I've just told you that one heart is failing progressively radius is increasing and feeling heart radius is increasing and it is becoming Global or hard every cardiologist will tell globular heart is a that hard why we were giving vinoda letter to reduce the end diastolic volume so that cavity should come not in balloon shape but in a normal shape we reduce the afterload so that heart pump will eject the retained and diastolic volume so that cavity should become normal and at the top an angiotensin two and Ultra Spherion are reduced geometry of heart become normal I want to know Jamie please what is the normal geometry of The ventricle what is the normal shape of the cavity it is not spherical that he says something like this I feel it is something like pure if you remember can't read no no use of medical terms he remember some fruit you remember some thing to go on medical term what is the normal shape of the left ventricular cavity elliptical is that right so spherical heart go back to its elliptical shape with Big Radius to smaller radius so we were discussing about the Angiotensin converting enzyme Inhibitors right and we have discussed in detail the role of angiotensin converting enzyme inhibited drugs in case of patients with ingestive cardiac failures and we have discussed the benefits as well but I would like to repeat few words again that Angiotensin converting enzyme Inhibitors uh not only reduce the morbidity but also reduce the mortality in the patients with cardiac failure right you know the reasons what are the reasons why the morbidity and mortality both are reduced one reason is that they reduce the preload and after load on heart on ventricles one reason is that these drugs reduce the preload and after load on the heart so naturally they reduce the stress on the heart so heart is able to work in a better way number two that these drugs pathological remodeling pathological re modeling process in a feeling heart right that also improves the T and mortality in the long run then these drugs also increase the patient's quality of life or you can say these drugs also reduce morbidity and mortality by reducing the chances of myocardial infarction reducing the chances of arrhythmia in these patients and reducing the chances of yes reducing the chances of chances of stroke in these patients right so all these things together right eventually lead to reduced morbidity and mortality in the patients with congestive cardiac failure right now again I will repeat that these drugs are one of the most important drugs in congestive cardiac failure and these drugs should be given in all the patients which with congestive cardiac failure right actually all the patients with reduced ejection fraction reduced ejection fraction whenever ejection fraction is less than less than 35 percent whenever ejection fraction is less than 35 percent right Angiotensin converting enzyme inhibited drugs show beneficial effects and it is stated that lower the ejection fraction better is the benefits more beneficial are the grants right now just name a few drugs of course one name right everyone knows that is captopril captopril about the captopril you must know that this is active drug is that right but remaining ACE inhibitors are basically Pro drugs and these Pro drugs have to pass through the liver to be activated the other important drugs in this group are envelope they are Anella list Sino Braille right Ramipril Rami prel and fosaino for Sino friend right now one thing which you have to remember that most of the Angiotensin converting enzyme inhibited drugs are pro drugs they have to pass through the liver and get hydroxylized over there and then they convert into active metabolites right the only active agent in this drug is captopril which does not require activation in the liver so important point about the capital is that it is an active agent does not require activation in the liver other drugs are Pro drugs and they need to be activated in the liver before they start their action another important point is that except for synop for synopril all drugs go out of the body through the kidney right again most of the drugs an Angiotensin converting enzyme inhibitor group they are eliminated through renal system except for synopril for synopril has balanced elimination it has balanced elimination from the body it goes out of the body through liver as well as from the kidney another important Point related with this group of drug is that all these drugs can be taken orally and preferably they should be taken empty stomach because food retards their absorption right now we will talk about some important uses of ACE inhibitors other than congestive cardiac failure right there are so many uses I will just talk about few important uses of Angiotensin converting enzyme inhibited drug one juice we have already discussed that is congestive cardiac failure especially when ejection fraction is reduced Second Use of this drug is that these drugs are very commonly used as anti-hypertensive agents so they are used in hyper tension right third important use of this drug is a group of this drug is that these drugs are used after recent Mi right patients with recent myocardial infarction right when someone develops myocardial infarction during the acute phase you must start Angiotensin converting enzyme Inhibitors so that on the injured heart on Infected heart ventricle area preload and after load can be reduced and stressed on the injured heart is reduced and they say that patient with the recent Mi who were started on the ACE inhibitors they also have long term reduced morbidity and mortality right then these drugs are very important in patients with diabetic nephropathy diabetic nephro Patty let me explain a little bit about the pathology of diabetic nephropathy and then I will explain how these drugs are good in diabetic nephropathy patients right look let's suppose this is the Nephron right and you must be knowing that here is a front arterial these are glomerular capillaries and here is different arterial this is afferent arteriole and this is different arterial and here are messenger cells here here are messenger cell and messenger now in diabetic patient write there are two types of problem number one basement membrane of glomerular capillaries is damaged and proteinaceous substance oozes out proteinaceous substance from the glomerular capillaries goes to the messenger and glomerular basement membrane and damages the messenger as well as glomerular basement membrane and this proteinaceous substances right which go to the messenger due to Disturbed permeability process here they lead to the growth of messenger and pathologies in mesengium right number two more important is that in patients with the diabetes they develop arterial arteriolocyclerosis they develop arteriolocyclerosis mean hardening of the walls of the vessels in afferent arteriole as well as these patients develop arteriosiclerosis in different arterioles again and diabetic nephropathy in diabetic patients they develop thickening of the world of the afferent arterioles as well as thickening of the wall of the different arterioles when both arterioles are constructed is that right the blood flow to glomeruli is reduced the blood flow to polymer lie is reduced and in these patients an important point is that Angiotensin 2 plays a very important role what is the role of angiotensin 2 that Angiotensin 2 act on The receptors on different arterial this is two Angiotensin 2 work on The receptors on different arteriole and keep them constructed and when did patients with diabetes right Angiotensin II normally act more on the effort arterial and less on the efferent arteriole because Angiotensin II has more receptors on different arterial and keep that constructed due to this construction there is glomerular hypertension there is high pressure in the glomerular and that further leads to leakage of proteinaceous substances and further damage to the messenger and messenger growth and expansion produces damage to the glomerular operators is that right now what we really do if we give these patients a diabetic nephropathy captopril related drugs or ACE inhibitors there are multiple benefits number one that in these patients ACE inhibitors is Inhibitors will reduce systemic blood pressure they will reduce systemic blood pressure naturally when systemic blood pressure is reduced by the ACE inhibitors overall damage by the systemic blood pressure to the glomerular structure is reduced number two when you have given Angiotensin converting enzyme inhibitor drugs right naturally Angiotensin 2 level go down and when angiotensin two levels go down because this drug is given captopril or analapril or related drug an Angiotensin II levels are less than Angiotensin 2 cannot keep the efferent arterioles constructed so what really happens that different arterioles dilate when different arterials dilate blood can easily move from the glomerular capillary to the efferent arterial and forward and pressure capillary is reduced it means this there is reduced glomerular hypertension there is reduced glomerular hyper tension it's worth repeating let me tell you in patient with diabetic nephropathy when you give the Angiotensin converting enzyme Inhibitors what really happens that Angiotensin 2 level go down and Angiotensin 2 with low levels cannot keep the effort arterioles constructed so there is slight dilatation of in front arterioles right when the slight dilatation of different arterials then blood in the global capillaries moves forward easily so pressure in the glomerular people the bed is reduced or we say that glomerular hypertension is reduced and leakage of you can separate initial substances right to damage the messenger and to damage the globular basement membrane is also reduced and that reduces the progression of diabetic nephropathy is that right then one more factor which is there is that overall reduction of angiotensin 2 overall reduction of angiotensin 2 also help in a very special way what is that special way you must remember now they say that Angiotensin 2 act as a growth factor act as a stimulatory growth factor for Messenger cells Angiotensin II can stimulate the growth factor act as a growth factor Angiotensin 2 act as a growth factor on the messenger cells and if you are giving naturally if endurance in two is acting as a growth factor on the messenger cells so it means it is also leading to messenger expansion and further diabetic nephropathy but when you give ACE inhibitor drugs Angiotensin II level is less not only effort arterials dilate right but there is less Growth stimulatory Action on the messenger cells and there's further reduction in the progression of diabetic nephropathy right so this was something about the Judas of angiotensin converting enzyme Inhibitors that these drugs are used in congestive cardiac failure these drugs they use used as anti-hypertensive agents these drugs are used as a very importantly used in dab to reducing the progression of diabetic nephropathy even lately they have deformed that Angiotensin converting enzyme Inhibitors are also useful in diabetic retinopathy is that right when there is angiogenesis in the retina there also that Pro that deteriorative action of the diabetes on the retina is also reduced in the presence of Angiotensin converting enzyme Inhibitors right after this now we will talk about some important side effects of Angiotensin converting enzyme Inhibitors right the adverse actions of captopril analapril and related drugs right one of the very easy way to remember the side effects of this group is that just right here have to Burrell right kept open the side effects of Angiotensin converting enzyme Inhibitors they can be easily remembered from the Capital World capital let's see how number one C stands for cough right that in many patients who take Angiotensin converting enzyme Inhibitors some of them develop dry cough right now why did one of the dry cough actually you must be knowing when Angiotensin converting enzyme is inhibited then bradykinin is not broken down because Angiotensin converting enzyme not only break down uh you can second word indutions in 1 into tensile two but the same enzyme is also responsible to destroy bradykinin so what really happens that when you are giving captopril and related drugs what really happens is that there is increased level of bradykinin which is not destroyed by the enzyme as enzyme is inhibited by the drug and increased level of bradykinin in the lungs right and some other mediators as well that produces in some patient's cough right so dry cough is one of the important side effect of the ACE inhibitors but you have to remember one thing that later on we'll talk about a drug that is called Angiotensin ARB is another group of drug is a r B's Angiotensin receptor blockers Angiotensin receptor blockers right these drugs do not produce the cough we'll discuss later why number one number two that these drugs sometimes produce angioedema NGO what happened patient may develop rapidly swelling of the nasal mucosa or throat mucosa in the larynx or pharyngeal area right and it may be very dangerous situation or swelling of the nose swelling of the lips swelling of the buccal mucosa and pharyngeal and laryngeal mucosa and that may produce life-threatening situation especially related with the breathing right in these cases why it happens there are two reasons there are two theories one reason is that in some patients accumulated bradykinin precipitates angioedema and second theory is that captopril and relative drugs is Inhibitors inhibit the complement one estrace inhibitor C1 esterase inhibitor when C1 esterase are inhibited Inhibitors are inhibited then complements are unduly activated let me tell you C1 St rays inhibitors we'll discuss this in detail in Immunology now what is this product but this substance is normally present in our body an important function of the substances it does not allow the undue over activation of classical pathway of complement system some people believe that ACE inhibitors inhibit this protein when this protein is inhibited then in some patients there is undue activation of classical pathway of complements and that produces lot of complement fragments like c3a c5a which produce activates the mast cells and Mast Cell release histamine and other vasodilator and increased permeability factors and Mast Cell release mediators may also precipitate angio edema anyway whenever you give ACE inhibitors and if a patient develops injuredema you must stop that drug immediately and usually within few hours injury might disappears then the next side effect is that protein Julia that is protein urea that in some patients ACE inhibitors right produce protein urea exact mechanism is not known but some authorities believe that basically these drugs activate some immune process against the glomerular basement membrane in some patients and that may precipitate protein urea then the next is T4 taste changes taste changes right probably these drugs interfere with the taste buds and disturb their function so patient is unable to enjoy his most delicious food and his taste perception is altered or taste is not perceived properly right then o for hypotension hypo tension now it's worth mentioning that hypotension is one of the very important side effects of ACE inhibitors right and this is something you must remember that some patients right when you introduce the first dose first dose of ACE inhibitors they may develop severe hypertension now why this severe hypotension develops right this type of sphere hyper hypotension hypotension is seen in the patients who have increased plasma renin leveled right patient with increase plasma renin activity what who are these patients these patients may be patient of congestive cardiac failure or patient who are solved depleted in these two types of patient patients with congestive cardiac failure and patients who are salt depleted right they develop increased rain in activity in the body and if you give such patient ACE inhibitors in full doses right they develop severe hypotension that is why in such patient if you have to start the ACE inhibitors you have to start very carefully you should give the first dose at a very low amount is that right that first dose should be much reduced and preferably when patient is going to the bed is that right so this is something important that this drug can precipitate hypertension especially first dose hypertension and the patients who have increased plasma renin activity and in these patients what should we do that we should give the first dose in a very small amount right then P for pregnancy actually these drugs should not be given in pregnancy right I must Draw Something Like This these drugs are phytotoxic as soon as diagnosis of pregnancy is develop if patient is on these drugs these drugs should be immediately stopped because these drugs can cross the blood placental barrier go to the baby and produce fetal toxicity so they are contraindicated in the pregnant females right and R stands for rashes right like many drugs these drugs may also produce rashes in the skin by interfering with the for example drug May bind with the skin components and activate the immune system against the skin or drugs May stimulate the mass health and release a lot of histamine and rashes are produced anyway these drugs may also produce rashes then another important thing is that these drugs May produce reduce I I for increased increased increased potassium level right and increase running level when you introduce these drugs first of all I will tell why the random level go up actually when you are giving ACE inhibitors then ingotensin one cannot convert into angiotensin two so body develops deficiency of Angiotensin II normally Angiotensin II inhibits the further release of renin but after this introduction of these drugs when angiotensin two levels go down right the ninja turns into is unable to inhibit The juxtaglomerular Operators and there's more release of RNN secondly when you are giving these drugs and Angiotensin II levels are less in the body naturally than aldosterone is not released so aldosterone levels are also less and you must be knowing that aldosterone is a hormone which retains sodium and water in the body and it lead to expulsion of potassium through the renal system again aldosterone is a hormone which normally retains salt and water in the body and expels potassium so naturally when aldosterone levels are less and the patient who is on the ACE inhibitors when aldosterone levels are less then potassium cannot be expelled from the body effectively and some patients May develop some degree of hyperthalemia right and L is for low what is low in this patient right number one angiotensin two level is of course low in these patients as well as aldosterone level is also Elder stream level is also low in these patients right do you have any question okay no question now we are going to discuss the Angiotensin converting enzyme Inhibitors and their comparison with a newer group of drug that is Angiotensin receptor blockers this new group of drug is arbs Angiotensin receptor blockers the important drug in this group are losartan Wells Harden candy certain again the important drugs are losartan well certain and can disorder now how do these drugs work arbs right they basically directly block the Angiotensin II receptors for example you must be knowing that Angiotensin II receptors are present on smooth muscle of arterioles this receptor is blocked by arbs right so Angiotensin 2 cannot work here Angiotensin 2 cannot work on articular smooth muscle receptor in the same way Angiotensin 2 cannot work on the venous smooth muscles right in the same way if arbs are there then ingotensin two receptors are blocked on Zona glomerulosa and Angiotensin 2 cannot work over there right so what these drugs are doing look at this is Angiotensin II angiotensin two work normally on the arterioles and produce arterioloconstriction it works in the veins and produce Vino constriction but in the presence of ARB is Angiotensin receptor blocker it cannot produce arteriola construction and cannot produce Arduino construction so these drugs arbs by blocking The receptors produce arteriolo dilatation as well as we know dilatation is that right secondly you know normally Angiotensin 2 work on Zona glomerulosa and produces Aldo sterone which lead to salt and water retention right but if you have given the patient ARB is the naturally Angiotensin 2 cannot work on its receptors and aldosterone is not released and salt and water is not retained in the body so up to now what did we learn that arbs by blocking the Angiotensin II receptors can lead to artery dilatation Vino dilatation when arteriolo dilatation is there you know total peripheral resistance is reduced and diastolic blood pressure goes down when we know dilatation is there naturally we what really happens Venus return to hard disk reduce cardiac output is reduced systolic blood pressure is reduced in the same way when ARB is block the action of angiotensin 2 on the Zona glow naruloza so aldosterone is reduced and salt and water is not retained in the body blood volume is reduced venous return is reduced cardiac output is reduced is the right hand systolic blood pressure is reduced due to these reasons these drugs are quite effective in patient with hypertension or we can say they are one of the very important antihypertensive drugs secondly by reducing the venous return to the heart that is reducing the preload and by producing artery load allitation they reduce the afterload so arbs produce reduction in pre-load and after load so stresses on the heart are reduced so these drugs can also be used as substitute of ACE inhibitors in patients right who can cannot tolerate Angiotensin converting enzyme Inhibitors is that right in the same way arbs also act on the Angiotensin II receptor right the block the endurance into receptor at other sites as well as you know Angiotensin II receptors are present on the sympathetic nerve endings right and arbs can block those receptors so Angiotensin 2 cannot stimulate the sympathetic nerve endings in the same way these drugs also block the action of angiotensin 2 on the hypothalamus where normally Angiotensin to produces thirst right those receptors are also blocked in the same way angiotensin two mediated if front artery yellow construction is also blocked by these drugs right so practically what we see that arbs are having lot of actions similar to Angiotensin converting enzyme Inhibitors the real difference is that Angiotensin converting enzyme Inhibitors inhibit this group of enzymes these are the enzymes ingotensin converting enzymes which are present in pulmonary vascular bad and these enzymes are normally converting indutions in one into angiotensin two as well as these enzymes destroy the bradykinin Angiotensin converting enzyme Inhibitors were blocking these enzymes so that there were there was less conversion of angiotensin and 20072 right and of course when ingotensin 2 is reduced Angiotensin to mediated actions are reduced so we can say that Inhibitors reduce Angiotensin to dependent action by reducing the production of angiotensin 2 but arbs reduce the Angiotensin to mediated actions by directly blocking The receptors of angiotensin too ACE inhibitors also do one more action that when they inhibit this these enzymes these enzymes not only convert Angiotensin one into angiotensin two but normally these enzymes also break down bradykinin and when these enzymes are inhibited bradykinin is no more destroyed effectively and Rising levels of bradykinin can produce cough and angioedema right so those patients who are given Angiotensin converting enzyme Inhibitors and if they develop cough or they develop angioedema right we can switch to these patients from Angiotensin converting enzyme inhibited drugs to arbs right because arbs will not inhibit these enzymes so will keep on undergoing destruction process right and does not accumulate and when bradycanion does not accumulate then coffee is not produce risk of angioedema is reduced right and because these enzymes are working in the presence of arbs even though indiotensin 2 is produced but because its receptors are blocked so Angiotensin 2 cannot work right so in a nutshell what we can say what are the uses of arbs the uses of arbs are number one that they can be used as substitute ah of angiotensin converting enzyme Inhibitors in patients with congestive cardiac failure where Angiotensin converting enzyme Inhibitors are not tolerant tolerated specially due to persistent dry cough or due to angioedema number two arbs that is Angiotensin receptor blockers they are also used as antihypertensive drugs is that right when we come to the side effects of these drugs arbs there is very interesting thing most of the side effects of arbs and indiotensin converting enzyme Inhibitors are similar we can say that adverse effects profile is same except arbs do not produce dry cough and they do not have a risk of angio edema so we have already discussed the side effects of yes Inhibitors so you can say all the side effects are also present for arbs except there's no cough and there's no injuredema and again it's worth emphasizing that both of these drugs are phytoxic both of this group of drugs are contraindicated and both of these drugs are contraindicated in patients with pregnancy or females who are pregnant you should not give AC Inhibitors and females who are pregnant they should not be given AR B's is there any question okay now we shall discuss the role of beta blockers in congestive cardiac failure right uh why the beta blockers are used in congestive cardiac failure it seems counter intuitive but let me explain why you know patient who has congestive cardiac failure it means chronically his heart is producing less cardiac output if heart is producing less cardiac output naturally and sympathetic nervous system is activated and if someone's sympathetic nervous system is chronically activated and congestive cardiac failure initially it may be beneficial that it increased heart rate increased contractility maybe support the cardiac output but in the long run if sympathetic nervous system is over stimulated in patient with congestive cardiac failure in the long run it produces dangerous complications for example that this may produce pathological pathological remodeling in the myocardial tissue right and heart may go into Progressive failure secondly increase heart rate may also deteriorate cardiac function so Studies have proved that judicious use of beta blocker not only improve the systolic function but also reverse the cardiac remodeling these days the two commonly used beta blockers in congestive cardiac failure are metoprolol Mito prolol which is the longer acting beta blocker and second is Carvedilol curvy do LOL this is a very very special type of drug why because this drug is not only blocking the beta 1 and beta 2 receptors but it also blocks alpha 1 adrenergic receptors right carbonyl Progressive failure secondly increased heart rate may also deteriorate cardiac function so Studies have proved that judicious use of beta blocker not only improve the systolic function but also reverse the cardiac remodeling these days the two commonly used beta blockers and congestive cardiac failure are metoprolol middle prolol which is the longer acting beta blocker and second is Carvedilol curvy the law this is a very very special type of drug why because this drug is not only blocking the beta 1 and beta 2 receptors but it also blocks Alpha One adrenergic receptors right carbidolol this blocks alpha 1 adrenergic receptors right as well as it blocks beta1 adrenergic receptors as well as it blocks beta2 adrenergic receptors so generally we see that this is Alpha blocker as well as non-selective beta blocker Carvedilol by blocking the alpha 1 receptor right it it produces arteriola dilatation and we know dilatation and when it produces arteriolo dilatation and Vino dilatation naturally what happens that when rtuled the dilated by Alpha One blocker action of the Carvedilol after load on the heart is reduced and when veins are dilated Alpha One blockade that will produce reduction and preload so we can say by itself for one adrenergic blocking action adrenergic receptor blocking action it reduces the arterial load alitation it produces that produces the arterial load dilatation and vinodalidation at the same time because it produces beta1 blocking action by blocking the beta 1 action it reduces the heart rate right which and secondly by blocking the beta one action it reduces the release of the renin as well right so again let me repeat it that in congestive cardiac failure beta blockers are now used but very important thing in severe and acute intractable cardiac failure beta blockers should not be started in acute phase very acute phase of ingestive cardiac failure beta blockers should not be given because the negative ionotropic but as soon as patient is little bit stable you should start the beta blockers carefully right so that patients you can say heart rate should reduce as well as patient should be not having chronic over stimulation of the Heart by the adrenergic stimulation so that cardiac remodeling should be reversed the detail about the beta blocker drugs and The Cider side effects and contraindications are discussed in the lecture related with the anti-anginal drugs right then we will talk about the congestive cardiac failure and roll off diuretics now we'll talk about congestive cardiac failure and roll off dye ureters right diuretics which are used there are two types of diuretics which are used in congestive cardiac failure one group is thiazides which are mild diuretics and number two is Loop Diuretics like frosamide right ferosamide or ethocrinic acid or there is vumetanide so thiocytes and Loop Diuretics these two groups are used in congestive cardiac failure thiazides are used in patients with milder problem is that right but if their sphere cardiac failure and you need lot of digresses then the drug of choices Loop diuretic so again thiazides are mild diuretics Loop Loop diuretics are strong diuretic and thiazides usually do not they lose their efficiency when there is significant reduction in GFR but the beauty of Loop Diuretics is that they keep on working even when GFR is significantly reduced so we can say with feeling hard and with feeling dropping GFR the drug of choice should be Loop digestive now we have to think that how diuretics help the patient in congestive cardiac failure right actually diuretics produce number one loss of salt and water that is diuresis and net resurices when salt and water is lost from the body then naturally blood volume is reduced and venous return is reduced ventricular filling is reduced pre-load is reduced so this is one way how diuretics help secondly diuretics also produce some degree of Vino dilatation that again reduces the venous return and preload right and thirdly diuretics also produce some degree of arteriologation and reduce the afterload everyone knows the diuretics produce dangerouses but you have to remember the diuretics also act as vasodilators is that clear to everyone now uh another diuretic which is sometimes used in advanced stage of failure is spironolactone that is spironolactone spironolactone spironolactone is a very milderative but it has a very special function that how it works spironolactone basically binds with the aldosterone receptor and when it binds with the Elder stereo receptor it antagonizes the action of aldosterone on the aldosterone receptor so we can say the patients who are given with given the spironolactone ah they are aldosterone loses its action you know a patient with congestive cardiac failure they are having higher level of aldosterone which is normally retaining salt and water and expelling the or throwing the potassium out of the body through renal mechanisms am I clear now when you give spironolactone what really happens that aldosterone mediated salt and water retention is not there right an elder stereo mediated loss of potassium is also not there so what are the advantages number one that it reduces you can say spironolactone reduces the salt and water retention in the body in congestive cardiac failure patients number two aldosterone also prevents the hypokalemia because spironolactone also sorry spironolactone also prevent the hypokalemia by preventing the action of aldosterone right and another very important thing is that normally high level of aldosterone stimulate the myocardial cells right this is very recent you can say finding that higher level of aldosterone ah chronically high levels of aldosterone as it is seen in congestive cardiac failure that basically stimulates the myocardial cells and these myocardial cells May undergo hypertrophy and spirulina spironolactone also blocks the eldesteron receptor within the myocardial cells so spironolactone also reduces the chances of aldosterone mediated myocardial remodeling pathological remodeling or pathological hyper trophy right but again don't forget spironolactone is meant for what Advanced stage of cardiac failure now we will talk about ingestive cardiac failure and role of direct visual dilators direct vasodilator there are two types of vasodilators are used they are Vino dilators and there are yes arteriolo dilators in vinodilator side the best drug which is used there is isosorbide dinitrate ISO sorbide die nitrate and on arterio the latercide the drug which is used is hydralazine which is a very potent arteriolodilator hydralazine we'll discuss hydrology in detail in antihypertensive drugs here I will only mention that in the patients of congestive cardiac failure who are intolerant to ACE inhibitors and beta blockers the patient with congestive cardiac failures which are intolerant to ACE inhibitors and intolerant to beta blockers right again the patients who have congested cardi failure and we cannot use due to side effects Angiotensin converting enzyme Inhibitors or we cannot use due to contraindication of the side effects the beta blockers then we use combination of isosorbate dinitrate as a vino dilator and hydralazine as an arterial dilator you must be knowing that arterio isosorbide dinitrate when it will produce powerful Vino dilator naturally venous return to heart will be reduced and and diastolic volume will reduce pre-load will be reduced and when you give the hydralazine with it it is strong arteriologer so total peripheral resistance is reduced and that lead to after load reduction in the feeling on the feeling heart so the combination of isosorbide dinitrate and hydrolyzine produces reduction in preload as well as reduction in afterload in patients with congestive cardiac failure so heart can perform better is that right but again I would repeat it that this combination of drug is usually used when patient is intolerant to ACE inhibitors and beta blockers today we are going to discuss about the positive inotropic drugs right which are used in severe heart failure positive inotropic drugs which are used in severe heart failure before watching this DVD you must avoid the DVDs which are about the basics of the heart failure but I will recap a little bit about the concepts related with the heart failure before I start explaining the drugs right now first of all we should be able to Define what is heart failure right before I go to the drugs let's have few important Concepts number one what is heart failure heart failure is a clinical syndrome it's a clinical pathological syndrome produced due to structural or functional defects in the heart which is produced to either there's some structural defect in the heart or there is some functional defect on the heart right so heart failure is a clinical pathological syndrome which is produced due to structural of functional defects in the heart with due to which due to which heart is unable to maintain enough cardiac output due to which heart is unable to maintain enough cardiac output to meet the demands of the peripheral tissue right remember what is the problem in heart failure heart failure is the clinical pathological syndrome which develops due to structural or functional defect in the heart right and the result is that heart is unable to maintain enough cardiac output right to meet the demands of the peripheral tissues now there are few terms and related with the heart failure let's discuss them as well for example heart failure can be classified according to the cardiac output of the failing heart heart failure can be classified according to the cardiac output of fill in heart for example according to this concept heart filler is divided into two categories one is called high output High output heart failure and other is called yes no output hard failure now let me explain what is high output cardiac failure and what is low output cardiac failure actually low output cardiac failure is more common one of the example of low output cardiac failure can be that let's suppose that here is your left ventricle and unfortunately this left ventricle develops ischemic heart disease or myocardial infarction and due to this ischemic damage to the heart myocardium cannot contract well so it is unable to it is unable to produce the normal cardiac output you know normal cardiac output is yes normal cardiac output is about five liters per minute is that right now if heart is sphereless ischemic and it has ischemic cardiomyopathy such heart does not have good contractility and rather than producing 5 liters per minute let's suppose it is producing only 3 liters per minute so of course three liter blood per minute cannot meet the demands of the body peripheral tissues so we say their heart is feeling to meet the demand of the peripheral tissues but while the heart is feeling to meet the demand what is the real cause real cause is reduced cardiac output so such situations were bought by demands by the peripheral tissue are normal Demand on the cardiac output by the peripheral tissues are normal but due to structural or functional defects in the heart heart is unable to produce even the normal cardiac output such such failure is called low output heart failure opposed to that there are some other conditions in which heart is doing its there is primary defectors there is exaggerated increase in the demand of the cardiac output for example patient with hyperthyroidism patient with hyper thyroidism if someone has severe hyperthyroidism right what will happen you know hyperthyroidism increases the metabolism all over the body when metabolism of the peripheral tissue is increased then oxygen demands are also increased and hyperthyroidism the demand on oxygen is increased too much and tissue demand more oxygen tissue demand more perfusion it means in hyperthyroidism hard has to produce more cardiac output to meet the exaggerated demands of the peripheral tissues now let's Suppose there is a patient who has hyperthyroidism with that he has some mild dysfunction in the heart and when hyperthyroidism develop right heart which was previously producing five liter now its step up ads cardiac output up to 10 liters per minute right but the tissue demand is 20 liters lesson okay five well of hyperthyroidism my peripheral tissues are demanding 20 liters of blood per minute and my heart increases cardiac output from 5 liter to term later and due to some intrinsic effect on the heart I am unable to increase my cardiac output more than 10 letters so in spite of the high output my heart is unable to meet the very exaggerated demand of the peripheral tissue right and this type of heart failure should be called high output heart failure in the same way in very severe anemias also there can be high output cardiac failure now another concept related with the cardiac failure and that is remember high output cardiac failure is less common low output cardiac failure is more common then another concept which is related with the cardiophilia is that that is left ventricular failure there is right ventricular failure and there's biventricular failure let me draw a diagram and explain it properly let's suppose this is the very simple diagram here is the left heart pumping the blood into systemic circulation from the systemic circulation blood is coming back to the right heart through the major veins the right heart will pump the blood to the lungs right so now let's suppose and this is from here the blood get oxygenated and then it is going to yes left side now one point which I want you to understand very important that between the left heart and the right heart there is systemic circulation and between the right heart and the left heart there is pulmonary circulation now if there are higher pressure in systemic circulation if systemic circulation become congested and high pressure the point from where fluid can leak out is stomach abilities fluid can leak out from where systemic abilities and if this pressure in the pulmonary system very high right the fluid which can leak out is pulmonary people rays is that right because fluid cannot leak look here for example if there is left ventricular failure now listen carefully if there is left ventricular failure my left ventricle is unable to pump valve now whatever it is receiving and cannot move forward so what will happen due to that reason back pressures will increase pressure will increase then left ratio pressure will increase then pulmonary are what is this arterial pressure will increase it is a primary venous pressure will increase but from the pulmonary vein fluid cannot leak out then pulmonary capillary pressure this is the pulmonary capillary pulmonary capability pressure will increase and eventually even pulmonary artery pressure will increase now in this case we can say left ventricular failure will lead to higher pressure in pulmonary circulation due to its back pressure due to back pressure but you know pulmonary arteries cannot leave pulmonary veins cannot leak only pulmonary pillars can leave so due to high pressure hydrostatic pressure is pulmonary capillaries will start leaking the fluid out and that will lead to pulmonary edema that will lead to pulmonary edema of course it clinically manifests as this is left ventricular failure leading to pulmonary edema clinically patient come with dyspnea orthopnia and paroxysmen nocturnal dyspnea now but if someone developed right ventricular failure if someone developed right ventricular failure then whatever right ventricle is receiving it cannot come forward so back pressure in the right ventricle will lead to back pressure increase in right atrium eventually right atrium cannot receive the platform major veins and all the systemic vein become congested and pressure now left if left heart is okay it's pumping into systemic circulation but right heart is feeling and cannot pump forward the point from where the fluid will leak out is systemic capillaries so all this will lead the capillaries which are present between the major arterial tree and measure venous tree right all the capillaries will leak and person will develop generalized the edema person will develop generalized edema so the point which I want to highlight is that left ventricular failure will lead back pressure to pulmonary edema right ventricular failure lead to back pressure and eventually generalized is that right now so one way to classify the cardiac failure is that some patient who come to you with failure if they are having pulmonary edema they are having which type of failure left ventricular failure the future of left ventricular failure important is pulmonary edema right and if someone has isolated right ventricular failure this person will develop systemic edema which is of course all over the body so we also call it generalized edema systemic edema right or generalized edema now some unfortunate people have right ventricular failure as well as left ventricular effect if both ventricle fails we call it biventricular failure and by ventricular failure right it is leading to congestion of pulmonary system it is leading to congestion of pulmonary system as well as leading to congestion of systemic system so simply call it an congestive cardiac failure from today onward when you talk to someone that there's congestive heart failure cardiac failure it means there's biventricular failure there right if someone is saying you see patient or bed number six has right ventricular failure of course is developing generalized edema if someone has pulmonary edema due to heart failure it is left ventricular failure and someone who has a demand both areas this is congestive cardiac is that clear there's no problem now the drugs which we are going to talk about the positive ionotropic drug they are used for low output failure they are not used for high output failure number one number two here I will explain that these drugs are also preferably used in systolic left ventricular failure or bioentricular failure usually not used in right ventricular failure is that right the drugs which we will discuss now positive anodropic then there is another way to classify the cardiac failure it's very interesting this is called forward failure forward failure and yes backward failure let me explain what is really meant by this forward failure you must make this diagram suppose someone has left ventricular failure now when there is left ventricular failure Suppose there is myocardial infarction and this percent developed failure it is a heart cannot pump while and when this heart cannot pump well right there are two things number one problem is that because this heart cannot pump well cardiac forward cardiac output will be less or more so they will be reduced cardiac output some clinical problem will be due to reduced cardiac output this is called forward failure right and some clinical features will develop due to backward pressure and you know that will lead to pulmonary edema that will lead to edema okay I don't understand the forward one I'm going to explain it don't you worry look huh this ventricle has two function number one it should maintain enough cardiac output forwardly to the peripheral tissue secondly you should not allow the back pressure into lungs that is backward function now listen if this heart is left ventricle is not pumping well can it supply enough cardiac output so cardiac output will drop and when there is the forward function is reduced we say left ventricle is showing features of forward failure what are the features of forward failure maybe sphere fatigability can this person who has low cardiac output can he walk well no is that right he cannot supply enough oxygen to the muscles so he is feeling all the time exercise tolerance is reduced the term which is sophisticated term which is used is the patient with forward failure of left ventricular situation they have decreased exercise tolerance they have decreased exercise tolerance and when we talk about backward failure right when we talk about backward failure what really happens that this pulmonary edema and person develops yes and orthopnea and cough this is the features of backward failure so what does it mean listen now carefully that if a patient come to you and he has pulmonary edema what is this left ventricular failure now in left ventricular failure some people have very severe forward failure and of course there will be very severe backward failure as well right in these patients will say patient of the left ventricular failure has some features signs and symptoms related with forward failure some signs and symptoms related with backward failure for example pulse is very weak blood pressure is low these are the features of forward failure and if you see that he cannot breathe well and there are basal repetitions right you auscultate in the basis of the lungs then these are the features of backward failure is that right so now next time when you go to a patient you will talk about it cardiac failure patient on the bed of the Cardiff patient you must juggle out your mind is it low output failure or high output failure right ventricular failure is it by ventricular failure or not is that right if it is left ventricular failure or right ventricular failure then you see what are the clinical features of the forward failure and what are the clinical problems due to backward failure is it difficult to understand it's too easy isn't it dangerously easy now there is one more one more concept and then we'll go to the drugs that is extremely important concept and you have to understand it very very clearly that is the concept of systolic failure systolic failure and diastolic failure diastolic failure now there is systolic failure and there is diastolic failure now what is the difference in systolic and diastolic failure let me explain look here suppose this is normal heart normal left ventricle has diastolic function as well as systolic function now what is the function of during diastole attention plays is very important concept what is the function of normal left ventricle during dazzling the Tire during the dazzling left ventricle should relax it should relax too much so that enough ventricular filling should be done is that right so it should not be stiff it should not be a hard ventricle during it should be ventricle which can very easily relax during the dash lay so that its chamber sizes enough to accumulate proper and diastolic volume is that right now and what is the systolic function for example this is the diastolic function that ventricle is relaxed well and it is properly filled during diastole and the same ventricle when it will show systolic function that it has to contract and it has to maintain when it is contacting it should maintain a very good pressure it should generate very good pressure right so that cardiac output can be maintained that left ventricle should develop enough tension in its wall it should develop enough tension so that it can produce enough pressures that with pressure it can push the blood to arterial tree so this is diastolic function and this is systolic function so diastolic function is with the relaxation of The ventricle and accommodating the blood and helping in the filling of The ventricle and systolic function is related with the contractility and related with the stroke volume and related with the ejection fraction that out of endosonic volume what is the fraction which is ejected is that right now heart can have two types of problem imagine someone has a heart in the diastole now look at this heart it is having some infiltrative disease right this heart is very much thick and it has some infiltrative disease right for example lot of amyloid material amyloiduces abnormal proteins are deposited in the material for example lot of abnormal proteins like amyloid proteins are deposited within the wine trigger and ventricle becomes stiff it will become hardened ventricular stiff ventricle do you do you think during dastly can it relax enough to accommodate if it is very thick wall hypertrophic ventricle or it is ventricle with lot of infiltrations can it relax well so during the diastole during the densely even though the mitral valve is fully open it cannot accommodate much blood right for example okay I will give you another example rather than filtration more common example is so very severe left ventricular hypertrophy if someone has extremely severe left ventricular hyper atrophy then left ventricular wall become thick and it become heavy and it becomes stiff and during diastole it cannot relax and if during the dastly it cannot relax right if during the daisley this cannot relax that what can it accommodate more blood or less blood less blood and it will lead to the features of backward failure because from the lungs blood cannot properly empty itself into phosphorus system pulmonary vascular system cannot empty itself into diastolically feeling hard so such heart which is extremely hypertrophic it is very thick it does not relax as well such heart is said to be which is said to be in diastolic failure because it failed to do its diastolic function because such heart fail to do its diastolic function that during the diastasis does not relaxes enough to accommodate enough venous blood is that right opposed to that we think of another heart so this was an example of a heart where there is what is there diastolic failure for example it was extremely very very severe left ventricular hypertrophy a common example so next time you go in the words you find someone has extremely hypertrophic heart but not dilated heart then we say this is diastolic failure is that right now we imagine another patient in him what really happens that ventricle has become very much dilated or due to any reason it cannot contract well now in this case it can accommodate enough blood but can it push the blood forward ejection fraction is reduced stroke volume is dangerously reduced and this is said to be systolic dysfunction this is said to be which dysfunction systolic dysfunction so we can say that if there is problem with the contractility of the left ventricle we say left ventricle is displaying systolic dysfunction if there is problem with that relaxation of the left ventricle properly then we say there is diastolism of course you can see it's a stolic dysfunction cardiac output will drop dangerously so features of forward failure will be pronounced and pure diastolic failure people patient has less blood coming in and but whatever is coming it is ejecting well so forward failure is not a big problem problem is backward failure right pulmonary edema is the real problem but if someone has this thing he will have forward failure a big problem cardiac output is dropped but with that eventually he will develop backward failure as well now again listen someone asks you that my patient has pure diastolic failure of left ventricle you must think nephratically is feeling and which component of the function is failing diastolic function is failing probably heart is different or heart is hypertrophic right and if I say or infiltrated or if I say that this person by patient has systolic systolic left ventricular failure it means the real problem is ejection fraction but I simply say there is left ventricular failure usually there may be if it is not specified it means that both type of failures presence is stolic and diastolic both of them am I clear so these are few very basic term we have I have not talk I'm not teaching you the full topic of heart failure we have already recorded this is just simple what is heart failure let me repeat it heart failure means they are hard due to some structural functional the fire's heart is unable to maintain enough cardiac output to meet the minimum requirements of the peripheral tissue it may be high output failure or low output failure high output failure means when heart is having peripheral tissue has a very exaggerated demands on the cardiac output right and heart in spite of increasing its output more than normal it is unable to meet the exaggerated demand of peripheral tissue so this is say the heart is producing high output but still failing to meet the demands this is high output heart failure low output heart failure is defined that a person in which due to some defect in the cardiac function or structure heart is unable to maintain even the normal cardiac output so cardiac output here is less than normal then we said cardiac failure or heart failure may be left front regular failure or right ventricular failure whenever left ventricle fail the back pressure goes to lungs so patients develop pulmonary edema whenever right ventricle fails then back pressure goes to the systemic veins so generalized systemic edema is that right and if both ventricles fails we call it biometrical failure because pulmonary circulation as well as Perfection circulation both become congested so we call it congestive cardiac failure is that right biometrical filler is congestive cardiac failure then for example if left ventricular failure is there and clinical features we developed due to reduced cardiac output they are called forward failure features and clinical features we go up due to back pressure and polysirculation some of the strategies enough blood so end diastolic volume cannot be even achieved up to normal limit so this is called diastolic failure it produces more backward failure then if some heart has problem with this contractility machinery and it contracts very poorly this is called systolic failure here again I will mention that the drugs which we are going to talk about they are used in systolic fairs left ventricular systolic failure not for the diastolic failure because these drugs is the contractility of course there is no fun in using these drugs then that's probably failure if someone has hypertrophic heart heart is not relaxing do you think the drug which stimulates the contraction is useful here no because yeah no but in MC equals it appears and people don't know what what to answer this is a very similar choices right so it's very easy to understand any drug which is positive inotropic any drug which increases contractility is not useful of course and diastolic failure but it's going to be useful in systolic failure so what we can say the drug which I'm going to talk about the most commonly is used in very sphere heart failures positive anotropic drugs are used in very very severe heart failure it these are really not used in early stages of failure right and these drugs are more commonly used in systolic dysfunctions of left ventricle right foreign otropic graphs right but before we go into detail of positive inotropic drug we should know what is positive ionotropy what is meant by the positive I know Tropi okay there are few terms which are very important to understand there is inotropy then there is chronotropic effect Chrono Tropic effect on the heart some drugs produce inotropic effect right okay inotropic effect some drugs produce chronotropic effect then there is another drug which effect action which is called dromotropic action bromo Tropic effect I will explain what are these things these five things you must be very clear what is inotropy what is chronotropy what is dromotrophy and then what is clinotropy foreign and then clino c l e i and no clinotropy right let me explain first you draw this diagram and then I will explain it to you let's suppose here is your heart these are the Atria here are the ventricles this is a fiber of septum in between now what we really need to understand that here is your conduction system of the heart this is essay node which is responsible for automaticity right here is Av node which is responsible for conduction of impulses from the Eritrea to The ventricle bundle of hairs dividing into bundle branches now listen chronotropy mean anything which changes the heart rate we say it there is chronotropic effect what is chronotropic effect anything which changes the heart rate that is chronotropic effect let's start with this this is effect on the heart rate for example epinephrine increases the heart rate it is positive chronotropic calcium channel blockers decrease heart rate that is negative chronotropic so chronotropy mean effect on the heart rate the chronotropic drugs are mainly working on the SA node the chronotropic action is mainly of the essay node Chrono Tropic effect right so again positive chronotopy mean increased heart rate negative chronotropy mean decrease heart rate right then next is dromotropy dromotropy mean the conduction velocity especially at the junction of h a and The ventricle you know there is Av node if conduction from Atria to ventricle become fast through every node we say there is positive dromotropin on the conduction conductivity of Av node right and again if conductivity is increased this is positive dromotropy of conductivity is decreased it is negative for example sympathomimetic drugs epinephrine then creates the conduction from atrial ventricle so we say that epinephrine has positive dromotropic action epinephrine has positive dromotropic action opposite to that calcium channel blockers block the even node they slow down the action of Av node the slow down the conduction through the heavy node so we say calcium channel blockers have negative Direction now listen correlate Justin sympathomemetic drugs are positive chronotropic as well as positive and if we talk about calcium channel blocker they are negative chronotropic and negative dramotropic or if we talk about beta blockers which block the action of epinephrine because beta blocker reduce the heart rate as well as beta blocker reduce the conduction through AV node so beta blocker drug like Propranolol they are negative chronotropic and negative so I hope these two terms are clear non trophy drama trophy now we come to the bathroom to understand the methotropic you must know a very important concept that normally there is normal automaticity in the essay node what is automaticity automaticity is defined as tendency of essay nodal tissue to undergo depolarization spontaneously because essay node every 0.8 second if your heart rate is 72 per minute it means snode undergoes depolarization every 0.8 second and then that depolarization which is spontaneously produced in as a node spreads over the heart does that right this is normal automaticity but let's suppose that if there is a purkinje cell here and let's suppose the cell is injured and it gets loaded with calcium and because this injured cell is loaded with Cate ions this restroom membrane potential become near to threshold and it has increased tendency to fire pathologically it has pathological automaticity as a node as physiological automaticity but due to injury may be some ventricular cells have a tendency to the these ventricular cells are irritated due to injury if some ventricular cells are irritated by loading of the cations this ventricle cell developer tendency to Auto fire is that right and this is called that's more Tropic action what is basmotropic action that bathmatography action mean that some tissue The myocardium is abnormally exciting automatic it has some tissue has developed abnormally increased automaticity right some tissue has developed now basmotropy is related with then what it is religion with abnormal abnormal Auto matte City right now any drug which increases the abnormal automaticity we say this is positive bathymetropic drug and any drug which reduces the abnormal automaticity is negative bathymetropic right actually most of the drugs like epinephrine epinephrine can stimulate the as a note so it is positive chronotropic it can stimulate the AV node function so it is positive dromotropic epinephrine I will explain today in later lecture that epinephrine load these cells with the calcium and increases also Batman city so that is positive bathroom Tropic drug as well is that right now we come to another yeah no actually what it is doing that epinephrine I will explain later that it increases the calcium load on the myocardial cell you should know three calcium loaders write it down every good doctor should know and myocardial cell there can be three things which can load it with calcium right one thing you already know that is chemic heart disease you know what that when there is ischemia to myocardium right cell membranes will not work well and calcium will be loaded in number two is digitalis that will discuss later how did you tell us load the cell with calcium and third calcium loader is third calcium loader is pathetic activity sympathetic activity now all of these are calcium loaders is that right now because all of them are calcium loader so they these cells become irritated with overload of cations and they automatically fire so all of these things lead to increased bathmosity they need to increase bathroomotropic action am I clear now all three of them right now we come to inotropy and clinotropy I will explain them that is the function related with this myocardial cell contractile cell look when this cell is electrically stimulated I will explain that calcium will go in and calcium will will increase actin myosin interaction and this will contract and tension will develop right now let's look at a graph that on stimulation how this cell develops tension this is the normal cell that during the systole is developed in tension like this then it is relaxation then there is dastly then again there is tension and then there is a relaxation and diastole right this is one systolic tension this is other systolic tension right and this is diastolic interval in between is that right now if you give epinephrine epinephrine will modify the contraction how it will modify number one this is the peak of contraction already at higher level and then it will relax like this now you see that this green graph is showing the action of epinephrine it means under the inference of epinephrine that the rate of development of tension is faster total tension which is achieved is more and rate of relaxation is also faster so there is no higher velocity of contraction and relaxation and higher degree of contraction as well right because if this graph or something like this then it was only strength increase but because graph also shift to the side it means not only strength of contraction increase but velocity of contraction and relaxation also increases any anything anything which increases the strength of contraction is said to be positively ionotropic and anything which changes are velocity of contraction that is called clinotropy right so what I can say that when there is sympathetic stimulation ventricle contract more strongly and this is called contractility [Music] anything which increases the contractility that is positive ionotropin anything which decreases the contractility is negative inotropy and anything which increases the velocity of constr contraction velocity of contraction and relaxation anything which increases the velocity of contraction that is said to be positive clinotropic and anything which decreases the velocity of contraction is set away negative clinotropic I think we have gone to Too Much basics right so now I can say listen carefully if I say that if I give you injection of epinephrine it is positive chronotropic it means it is increasing the heart rate if I say it is positive dromotropic it means it is increasing the conduction between a tree and ventricle if I say it is positive bathymetropic it means it is increasing normal automaticity and more chances of tachy arrhythmia and if I say it is positive ionotropic and clinotropic it is sympathetic nervous system or epinephrine is increasing the strength of contraction positive an entropy and increasing the velocity of contraction and relaxation that is positive clinotropy is that right but when we talk about beta blockers beta blocker or negative chronotropic negative dromotropic negative basmotropic negative minotropic negative clinotropic if you talk about calcium channel blockers all calcium dependent activities and heart are reduced calcium dependent activities in snod activities calcium dependent electrical activity in acid node and AV node both is calcium dependent and contraction in atrian ventricle is calcium dependent so what we can say if you give calcium channel blockers what will happen the patient will develop negative yes chronotropy negative dromotropy negative bathymetropic negative inotropy and negative when we are going to talk about positive ionotropic drugs it means we are talking about the drugs which are going to increase the contractility in the heart to really understand clearly that how these drugs increase the contractility mechanism of the heart first we should know that what is the normal mechanism of contraction right so very briefly I will discuss that how electrical events lead to Mechanical events in the heart how a myocardial cell after electrical stimulation undergo mechanical contraction right so let's suppose this is a myocardial cell I'll draw a myocardial cell here right and we shall see that how the cell on stimulation will undergo what type of electrical changes what type of ionic fluxes and what and eventually how these events lead to contraction let's suppose that this cell is undergoing depolarization when the cell is undergoing depolarization the step number one is that voltage gated sodium channels are stimulated any cell to contract first we should be electrically stimulated so when myocardial cells interval contraction first the interval depolarization process the path action potential pass through them right when action potential will come to the cell first of all voltage gated channels will open and there will be lot of sodium coming in now the restroom membrane of the cell was let's suppose minus 90 millivolt with the Sodium coming in it will become minus 70 and eventually it will become okay if you really want to know well then it will be taken to full depolarization or voltage-gated sodium Channel it will go to depolarization once the sodium has come in right the depolarization of this membrane why we call it depolarization again listen myocardial cells are normally polarized negatively the normal electrical resting membrane potential is minus 90 millivolt so normally these cells are negatively polarized electrically when lot of sodium comes in their negative polarity is lost negative electronegativity is lost so we say that for the negative polarization is lost or simply we say depolarization when the cylindrical depolarization phenomenon then depolarization sensitive calcium channels will open and potassium channels will open this is depolarization sensitive calcium Channel right now so what really happens there is a heavy influx of calcium so this is the calcium which is coming and right but during this is a plateau phase you know that if you draw it like this this is now Plateau phase and then revolarization phase what really happens that during the plateau phase some cations are coming in and some ketones are going out and K times which are going out are potassium so this loss of potassium so we can say that during the plateau phase calcium is coming in potassium is going out cell is gaining the calcium gaining the cations as well as losing the ketones so due to that reason electrical potential does not change but near the end right what really happens calcium channels stop but potassium channels become overactive due to this reason this very rapid loss of potassium and this massive potassium loss of potassium make the electrical potential again negative right this was minus 90 millivolt with sodium and flux electronegativity lost and it becomes depolarized then calcium was coming in potassium was going out the phase no change then calcium stopped coming in but potassium kept on going out and this was repolarization is that clear now this calcium which has come in this calcium this was extracellular calcium which came intracellularly this is called trigger calcium what is it called what is the function of the trigger calcium this will stimulate intracellular stores of calcium this International store of calcium is called sarcoplasmic reticulum it is very very rich and calcium is very very rich in calcium now this extra cellular calcium which has come in through voltage-gated Channel this is also called trigger calcium this trigger calcium as soon as it hits the sarcoplasmic reticulum there are calcium releasing channels here what are these calcium releasing channels here this massive release of calcium this massive release of calcium from intracellular store so what was the purpose of extracellular calcium to come in just to trigger the release of calcium from intracellular stores the purpose of this Plateau was to bring enough calcium in and this calcium is trigger culture it will trigger the sarcoplasmic reticulum to release massive stores of intracellular calcium and this will come into cytosol once this calcium appears into cytoso then what really happens here is suppose your sarcomere right and these are your actin filaments and here are your let's suppose myosin flowers filament right this is myosin filament now what really happens that these heads of myosin love to interact with special slits on what are these on Act 10 write these heads they properly shaped to interact there right so these are the points where which are made there by Nature so that what can work there head of the myosin should interact with actin right but the problem is this that there is a protein here which is covering this point and this protein is called tropomyosin and here is proponent what is this proponent and this is tropomyosin so normally this is a tropomyosin which is uh preventing The Binding of head of the that's head of the myosin with the actin now what really happens what is the function of calcium now now correlated that calcium actually binds with troponin calcium binds with proponents so this calcium which is coming in this we call it calcium Spark so sarcoplasmic reticulum produces calcium spark and this sparking calcium will come and bind here when calcium bind at these points the troponin special point and proponent is called proponent C then troponin will rotate like this and it will pull away this propromyosin and actin and myosin will start interacting and start moving the filaments and there will be sliding and there will be contraction and development of potential this is what happens during systole that will say that when your heart rate is 72 per minute then cardiac cycle is 0.8 second out of that during the 0.3 second there is contraction what really happens during those point three second that first of all lot of sodium comes in membrane depolarizes then depolarization sensitive calcium and potassium channels are activated calcium is abundant outside so it will come in potassium is more inside so potassium will go out right so cations are gained and lost so Plateau phase is there for about some time and eventually calcium stop coming in a lot of potassium goes out and membrane repolarizes but this calcium which is excess cellularly came in is called trigger culture it will fire on the what is this intracellular calcium stores which is sarcoplasmic reticulum and sarcoplasmic reticulum will produce the sparking of the calcium and this calcium which is released from uh sarcophantic reticolon will bind with tropo men proponent C and troponin C will pull away the tropomyosin from the myosin head binding site on the actin and actin myosin filaments will start interacting and when they start interacting these heads will move Inward and sarcomere will be shortened and every myocardial cell will become short and ventricle will contract and in this way tension will be produced in the wall which will translate into pressure right and with that pressure aortic valve will be opened and stroke volume will be ejected out am I clear is that right now we have already discussed that how depolarization can lead to contractility now we will talk about how repolarization triggers the diastolic relaxation during depolarization when lot of potassium goes out membrane again become electronegative that is minus 90 millivolt the membrane is minus 90 millivolt it means membrane is again polarized back to its negative state it started with minus 90 and it ended up again on minus 90. we say membrane is again repolarized negatively now as soon as repolarizes many repolarization sensitive you can say mechanisms are activated number one that special type of what is this a pump and this is not sodium potassium pump this uses the ATP but by breaking the ATP it gets energized and take the calcium out this calcium which was coming extracellularly in which came during the plateau phase it must go out and this calcium which is present here it should also go into back situation now this calcium will go by two mechanisms out one mechanism is calcium 80 phases what is this called This is called yes please calcium 80 phase pump 80 pages in the membrane right secondly there is another way to get the calcium out because calcium has to get out from the cell dress and this is very important to understand now this is a very unique type of stranger right this is a very very unique type of changer and this exchanger is calcium sodium exchanger what is this exchanger this is called calcium sodium exchanger normally what is happening that sodium from outside will come in through this exchanger and calcium from inside will go out so this is called calcium sodium or sodium calcium exchanger or antipolar in this way the culture an anti-port anti-fold a n t i p o r t antipode right yeah so what is happening that this antipode now listen if someone asked you that during depolarization during that aslay what really happens ventricle relaxes why ventricle relaxes because calcium which came in right started the whole contractile Machinery this should be back to its position so correction which came excess cellular culture which came in it will be pumped it will be going back to the extra cellular fluid through the sodium through the calcium battery phases and through the calcium exchanger amicler meanwhile as soon as this is no more depolarized right then it means no more trigger calcium is coming it means there's no more stimulation of it as soon as the stimulation closes these channels what were these channels these channels will be closed these channels are closed these are calcium releasing channels so it means further release of calcium is impaired or stopped not only this here are also there are special type of now you can recognize what is it this is your friend you have seen it previously yeah these are calcium 80 pages so it means that there are calcimative phases present in the sarcoplasmic reticulum also so these calcium metal phases are very very sensitive to voltage as well as cell become repolarized they become very active and whatever calcium has gone out they will recumulate they will take it back right so this calcium through these calcium what is this 80 Pages which are activated during diastolic phase at the onset of dashley rather I should say at the end of the firstly these calcium 80 pages are activated and very rapidly to take the calcium back they pump the calcium back they accumulate the calcium back into okay listen when calcium become less here when calcium level become less here then calcium detaches from tropo troponin and it goes back and when calcium troponin does not have calcium it will again insert the tropomyosin between the myosin head and actin and now actin myosin cannot interact so there will be no interaction between actin and myosin and sarcomere will relax and when lot of sarcomers will relax cell will relax tension in the cell will be reduced eventually whole myocardium will lose the tension and it will become relaxed tissue and now ventricle welfare again let me repeat how really repolarize how that or they were on set of diastole we have to remember that onset of dastly means that now ventricle is going to relax it's going to lose myocardium is going to lose the tension how it will lose the tension for losing the tension actin myosin interaction should stop how actin myosin interaction can be stopped by reducing the calcium level which was right and how the calcium level can be reduced by two ways that calcium can be pumped to extracellular environment and calcium can be pumped into the once calcium goes back naturally actin myosin interaction is lost and that lead to what type of diastolic relaxation but there is one thing please concentrate on this concept that during whole this process you see sodium came at two places in number one sodium came during depolarization number two sodium is coming through diesel calcium sodium exchanger and this sodium should not accumulate in because during whole this process we said calcium came in calcium went out we said calcium was released from here it is taken back is that right but during depolarization sodium came sodium is coming into this myocardial cell during everyday polarization and sodium is also come in when intracellular calcium is going out and during the exchanger process do you think the sodium should be allowed to accumulate answer is no at the same time during every action potential potassium is lost so do you think potassium should be lost forever answer is no so we have to restore calcium sorry we have to restore sodium potassium balance for this purpose now this is your beautiful friend this is sodium potassium 80 pairs so what it will keep on doing right this well sodium potassium materials whatever sodium is coming in it will take out right even this sodium and whatever potassium was going out it would take that potassium and the production which was lost that will be brought back so this is right what is happening that it is bringing the sodium is taken out and potassium is brought in and this is called sodium potassium 80 bases in this way during depolarization now listen carefully let's sum up the whole process during deposition sodium come in it will go out through sodium potassium it depends during Plateau phase potassium was going out that will be brought back to the cell by sodium potassium 80 phase during Plateau calcium was coming which were triggering the release of calcium from intracellular store right and leading to contractility this calcium which was accessible coming in it is taken back through calculating phases and calcium sodium exchangers is that right then whatever calcium was released by sarcoplasmic reticulum is right that will be recaptured by calcium 80 Pages present in the sarcoplasmic reticulum is there any question so in this way contraction will be followed by relaxation is that clear right okay now we are going to discuss that house pathomimetic drugs produce positive ionotropy or how epinephrine and related compounds increase cardiac contractility right so for that purpose let me draw you know what type of error energy receptors are present on The myocardium they have beta1 receptor for example this is epinephrine here it is epinephrine or norepinephrine now this epinephrine work on special type of receptors and these receptors are able to bind the epinephrine but these receptors have something very unique they pass through the membrane seven times that is why these receptors are called yes what type of receptors seven pass receptors these receptors are called seven pass receptors right these are this is a special type of receptor present to myocardial cells for epinephrine and these have this is a extracellular domain and they are having intracellular domain right extracellular domain binds the epinephrine intracellular domain gives signal to the cell that epinephrine is there once the epinephrine binds here once the epinephrine binds here this seven pass receptor is stimulated another name for the seven path receptor is Serpentine receptor because it is like snake so we call it Serpentine receptor right because the serpentine receptor is for adrenaline so we call it also adrenergic receptor and this is called beta1 adrenergic receptor you know the Alpha One hydrologic receptor of the beta one Hydro energy receptor the beta two hydrological receptors the type of adrenergic receptors which are present on The myocardium are beta1 adrenergic receptor now these beta 1 scepter when epinephrine bind with this the internal domain of beta1 hydrological receptor is stimulated this will stimulate an intracellular protein which is called G stimulatory protein right G stimulatory protein has three component is Alpha stimulatory there is betas and Gamma component now what really happens that as soon as epinephrine bind with hydrologic receptor adrenergic receptor internal domain stimulate the alpha component of G stimulatory protein why we call it g protein because normally when it is inactive it is binding GDP but as soon as this is activated it bind GTP so when it is activated it loses the g d p and it acquires here triphosphate so as soon as this molecule acquires loses the diphosphate guanasin diphosphate and acquires the GTP it become highly energized this highly energized molecule will kick its friends away it's very arrogant now he wants to develop some special new relationship right so this Alpha component Alpha stimulatory after stimulation loses the GDP acquires the GTP and GTP bound Alpha stimulator component is extremely active and it binds stimulates you can say a special type of molecule and this molecule when it is stimulated right this molecule has a special enzymatic domain right so epinephrine stimulated the adrenergic receptor hydrologic receptor stimulated the alpha component of G protein Alpha component of G protein activated this enzyme and this enzyme is called Adeno cyclase this enzyme is called adenaline cyclase and this enzyme is capable of now converting the yes this is able to convert what is this ATP into yes excellent that this will convert ATP into cyclic A and P so what is really happening that when epinephrine is acting on the myocardial cells intracellular cyclic amp levels are going up right intracellular cyclic MP levels are going up this cyclic amp level right the the cyclic amp will drive another you can say enzyme and this cyclic amp sensitive enzyme is called protein kinase C what is the name of this enzyme protein kinase say so what really happens you put the first messenger here epinephrine previously doctors never never hold this molecular chain they only knew that we put the first messenger epinephrine here and in the cell cyclic MP goes up so doctor said this is the first messenger and this is the second messenger now they know their first messenger bind with the receptor receptor activate the intracellular regulatory G proteins G protein active weight the effector adenylial cyclists adrenaline cyclists convert the ATP into cyclic amp cyclic amp drives the protein kinases which enzymes this drives protein kinases right and these protein kinases are very happy because they are stimulated once this protein kinases are stimulated what will they do you remember there were calcium channels here right these were called l-type calcium channel and what was the function of these channels that they were providing the trigger calcium during the plateau phase right so what this protein kinase C is going to do this protein kinase C if this is the l-type channel right this is a calcium channel what protein kind of C is going to do it will lead to yes it will lead to phosphorylation of what is this l-type channels and when these channels become phosphorylated they become more open and when they become more open then calcium coming into cell will be less or more there will be more intracellular there will be more intracellular right so what does it mean we have studied a molecular command system which is controlled by the epinephrine that epinephrine stimulate a whole molecular event which eventually lead to increase in intracellular culture is that right and of course then this additional calcium is additional calcium which has come in right it will be stored into sarcoplasmic reticulum and when this additional calcium is stored into sarcoplasmic reticulum what really happens that next time next contraction additional calcium will be released and additional contraction will be there and in this way epinephrine through whole this molecular system loads the cell with extra calcium this extra calcium gets stored into sarcoplasmic reticulum so during now sarcoplasmine reticulum is overloaded with the calcium so during every action potential with every depolarization it releases excessive amount of calcium and during every Sicily there is excessive um strength in the contraction of myocardial muscle is that right yeah it can but actually what really happens whenever calcium is present here during systole it will bind here but during the Ashley whatever calcium is here right it will be immediately powerful to pump here because as for there are calcium pumps here calcium 80 phases they are using heavy amount of ATP to keep the this area free of calcium during diastably so that there should be good diastole they should good relaxation but this calcium is coming in especially during the polarization it can bind here but after that eventually if epinephrine work for 10 minutes or 30 minutes lot of calcium which has come in the result will be after 30 minutes that there will be overloaded calcium stores in the cell because whatever calcium additional calcium is coming eventually it will add to the store and every time calcium is released from store and it is again restored is that right I'm going to tell you in a nutshell if there's a very big dog after you right chasing you all right now you need you want to run away so you need more cardiac output or less cardiac output do you need more guarding output so epinephrine is released right and yeah and this epinephrine will come to the heart this epinephrine will work through this mechanism on essay node and load the calcium in as anode so that's in order to fire more AV node will have more calcium it will conduct more myocardial cell will have more calcium it will contract more so heart rate will increase contractility will increase cardiac output will increase and you are able to run away from the dangerous dog I hope you have one one advantage right then secondly in many other conditions on sympathetic overflow occur your heart rate and contractility this is sympathetic stimulation is that right now question is this that once sympathetic nervous system stimulate your heart your heart remains stimulated forever it is transient stimulation transient so it means that naturally this epinephrine which is binding here it will be destroyed by the enzymes in the liver right and git and its metabolites will go out of the body but what happened to the cyclic amp we have to understand what happened to this yeah what happened to this cyclic amp if it remains for long time inside it will keep on accumulating too much calcium so it has to be destroyed as well for this destruction this is a very special type of enzyme this is a very special type of enzyme which will break down a cyclic nature and it will convert into simple amp and simple amp cannot drive this right and there's a special enzyme here okay you will tell me the name of this enzyme right it is destructive enzyme it destroys the cyclic destroys the cyclic amp and let me tell you just to remind this that you have to tell me some people who yeah what this is cup of what t this is what caffeine caffeine does it blocks the sometimes so it does not allow cyclic amp to break down is that right so you have to tell me what is the name of this enzyme phosphor diastras this enzyme is called phosphodiesterase phosphor diastases so now what really happens that sympathetic sympathomimetic activity will increase cyclic ampic and phosphodite stress is destroys cyclic amp is that right right now uh uh break uh break down the cyclic campaign to simple amp right which is not active is that clear to you now we can talk about the drugs which work on whole this system this is the normal and natural system this was normal electrical excitation and contraction this is normally how adrenergic system and Machinery is already available for this is the normal adrenergic Machinery which is normally available molecular Machinery to enhance the calcium input do you have any question after this no now we come to the drugs first of all we come to the digitalis you know this jealous group of drugs we also call them cardiac glycosides there are three okay let me write here there are three drugs which are positive inotropic right there's no place but still I would do an effort right here somewhere right so now I will write down the three positive ionotropic drugs group of drugs one is digitalis group Digi tell us the two drugs which are available in this digoxin in this group digoxin and other is DG toxin right digoxin is more commonly used so one group is digitalis or digoxin which can stimulate the contractility in the heart other group of drugs are called the sympatho magnetic drugs like dopamine and dobutamine I will explain how they work dopa means and do buta Main and third group of drug is here it is DG tell us right and third group of drugs is fast food diastras inhibitors right like amrenon m renon and mil Ray none now I'll tell you how these drugs work if this diagram is very clear to you then we can start on this is the third one million phosphodiesterase inhibitors now first of all we will talk about how digitalis work one thing should be clear to you if I am saying all these drugs are positive inotropic it means all of them are increasing contractility if all of them are increasing the contractility it means all of them increase intracellular calcium level the basic the class of understanding is all these drugs which are positive an entropic somehow should be able to increase intracellular level of calcium so their contraction should be more now we have to see that how calcium level is increased first of all we will deal with digitalis you know where the digitals work look here excellent this is the point that digitalis work DJ Dallas did you tell us binds with what is this so sodium potassium pumps because digital is bind with sodium potassium pump so what really happens that it binds with the pump and slows it down did you tell us bind with the pump and slow it down look at it now pump is very sad right and it's weeping because what has stuck with it did you tell us digitalis is bound with that and it binds reversibly and slightly inhibit the pump if pump is inhibited can the sodium go out please tell me the sodium which was going through this pump this sodium will start accumulating in then so it means primarily did you tell us bind with sodium potassium 80 phases inhibit the sodium potassium it pages and increases intracellular sodium and it increases intracellular sodium Now log if winter solar sodium is too much look attention if intracellular sodium is more than normal will the external sodium love to combine if there's more sodium n then concentration gradient which was moving the sodium excess cellular to n is reduced if extracellular sodium is not coming in then will this pump work exchanger work no so primary primary When a Stranger will not work can calcium go out no so calcium will keep on accumulating in because the sperms stop so calcium accumulates and this is a very important point in concept to understand that if someone asked how the digitalis work you say that digital is primarily work on sodium potassium 80 bases on the Sarco polymer membrane or myocardial cell membrane the inhibit the sodium potassium metabases then if sodium influx from the cell is reduced when sodium is increased in the cell then extracellular sodium gradient moving the sodium n is reduced when the tendency of sodium influx is reduced right then exchanger cannot work so actually we can say digitalis primarily and it slows down sodium potassium edifiers but secondarily by increasing intracellular sodium digital is secondarily slows down the sodium calcium sodium calcium exchanger and when sodium calcium stranger is slow then cells will start accumulating calcium now loosen now during if you have digitalized the patient if your patient is digitalized now during every action potential calcium will come in but can it go out properly no so this calcium which could not go out will be captured by sarcoplasmic reticulum and gradually stores of calcium and sarcoplasmic reticulum well increase are you understanding and when sarcopologic reticular calcium stores will increase then with every B every action potential extra calcium is released an extra contractility is there and we say digitalis has produced positive minotropy digitalis has produced positive I know trophy right this is one how the digitalis work as a positive ionotropic agent now let's see how dopamine and dubule vitamin work are you interested to know that yes sir yes sir okay it's so simple just please what's your question yeah they keep on working because some of the calcium that's good you should not close all the doors otherwise there will be too much calcium in the cell and cell May undergo apotosins we have to slightly increase the calcium in the cell to get beneficial effect of contraction so calcium 80 phases keep on working but calcium sodium exchanger slows down so calcium it was supposed to go through this pathway that some calcium is retained remember too much calcium in the cell is toxic for the cell slightly you want to increase the calcium right is that clear yeah this is the mechanism of action of digitalis does it clear right now we come to if someone asks you how the dopamine and dopetamine stimulate the heart it's so simple it's wonderfully simple look at here dopamine and doputamine are capable of binding to this receptor here is dopamine right and here is dobutamine this is dopa Main and here is do buta mean it's so easy to understand that both of them they actually stimulate this point so it means what they are doing they bind with beta1 adrenergic receptor dopamine and dobutamine are beta1 hydrologic receptor stimulator that is so simple I think there's any fun in explaining how the contractility will increase now no you know it let's just recap the dopamine and dobutamine bind with beta1 adrenergic receptor stimulate that that stimulate intracellular G proteins G stimulatory that stimulates adrenaline cyclists that increases the cyclic ampere level increase cyclic acid levels overdrive the protein kinase C which phosphorylate the calcium channels and when these calcium channels are phosphorylated these calcium channels are phosphorylated they remain open for longer time and during every trigger extra calcium is coming and eventually that is also stored and released for more effective and stronger contractors now the third group American it's too easy first I tell you in the coffee and caffeine what really happened that caffeine that we take you know after taking too much coffee you feel your palpitations and heart rate increases what's the reason actually caffeine inhibits the phosphodious phrases right and increases cyclic ampy level here it is not the in this case we are giving to the patient uh drug amerine or will rain on right of the Islam is now really excited now what really happens this was the you can say drug which was breaking down the cyclic amp what was this look this was going to it will break down the cycle it is cycle breaker right cyclic amp like clutch clutch it breaks on the cycle right what really happens this is which enzyme what was the name of this enzyme phosphor die stretches phosphatization so these are the phosphodite stresses right which actually break down the cyclic amp right and this phosphodiesterase is are inhibited by the drugs look here this is the drug right and what this drug is doing hammering on it it destroy the phosphodiesterase Inhibitors what is the name of this drug right there's hammering on this this is amarenon and millery known so the function of amberenon and melanon is to inhibit the phosphodiesterasis and when phosphoto stresses are inhibited cyclic empty levels will go hi and if cyclic empty levels are increasing of course this additional activity of the protein kind of c and that will lead to a phosphorus extra phosphorylation of calcium channels and more calcium is loaded and that more calcium richer stores and during every Sicily extra calcium comes and heartbeat more powerfully so all these drugs help the heart to load with slightly extra calcium so that it contracts more strongly and its systolic dysfunction should be corrected right it certainly become better why we were giving this drugs because there was systolic failure because heart could not contract well right yes yeah protein kinase a is an enzyme which phosphorylate the calcium channels and protein is C sorry protein when cycling came look American phosphod diastasis there's one very interesting drug which works on different type of phosphodasterism there's a wonderful drug which inhibits a very unique type of special type of phosphodiesterase that is that group of phosphatase are called phosphodie stress five type the name of the drug you must be knowing it because when that drug is given then cyclic GMP in the male organ is not broken and you get powerful world-class reduction right so but here thank God Viagra does not work here is that right that Viagra or sildenafil inhibits the fast food diet stresses which break down cyclic GMP in the male organ just a link between but caffeine is a little bit different caffeine can go to the South myocardial cell or smooth muscles on the neurons and inhibit those phosphodastrases which break down the cyclic that is why in the presence of caffeine sympathetic nervous system activity is increase because sympathetic nervous system produces its action by increasing cyclic MP and caffeine does not allow cyclic MP to be broken so action of sympathetic nervous system is exaggerated am I clear yeah drugs yeah they are structurally different than caffeine right and but they work at same enzyme where the caffeine were is that right but they are not just caffeine you can say that they are not caffeinated drugs they are very different molecules and I will tell you later when will tomorrow we'll study these drugs in detail that they are very dangerous drugs because sometimes they inhibit it so much and it become protein kinase it becomes so active too much calcium in and too much calcium in too much calcium in will bring the take the restroom potential near the threshold and automaticity is a dangerous tachy regime I will start we'll talk about that in next session today we are going to talk about you tell us in detail right did you tell us is a group of compounds which increase contractility of the heart right and this group of compounds because they increase the strength of contractility of myocardium these drugs are called positive ionotropic drugs right out of this group two are commonly used out of this group one is digoxin digoxin and other is yes DG toxin digitoxin digoxin what do you think which should we use more digoxin is used much more right it has some advantages over digitoxin and it's very commonly used right this uh if you have to use the digitalis group of drugs the preferred choices digoxin right you must be knowing why it is preferred over digital okay do you know which one has short half-life and which has long Half-Life because if you which one is the the one which has short half-life that has less chances of processity so can you tell me out of them which has short half-life which has long half-life how you know it yeah the simplest thing it's even spelling the less the drug with less balance has short half-life and Drug which has longer spellings it takes it has longer Half-Life so the advantages the digestion has shorter half-life shorter half-life for example it is only 36 hours right or you can say one and a half day and the digoxin digitoxin has a half-life of half-life of 5 days then which will start action earlier the smart one this is the smart one it has less spellings right that is More's balance so it's it's section start mechanism of action start if you give this drug it started section around 20 minutes within 20 minutes and this started action uh about after 60 minutes right then protein binding of course which are short half-life should buy input to protein less which has long half life it means it is sticking to plasma proteins more right so it binds with the plasma protein about 30 percent of it plasma protein binding plasma protein binding and here the plasma protein binding is about 90 percent and then there's a very important difference digoxin goes out through rapid pathway through renal right its clearances renal excretion it is freely filtered in Global line but Digi toxin you know Digi toxin has longer spelling so you have to remember look here digitation has long longer spellings so so it has longer Half-Life it by it takes longer time to start its action digitoxin more strongly bind with plasma protein and because digitoxin is more spelling just a funny way to remember it should make a need a bigger organ to go out what do you think kidney is bigger or liver is bigger liver is a larger organ so actually the digitoxin has to go out through hepatibility system so it first gets metabolized you must get metabolized there and after that it goes out of the through a better building system and of course through git this point is important clinically because that preferred if you have to use the digitalis group of drugs the preferred drug is digoxin it's a smarter drug right shorter duration of a shorter you can say half-life early faster onset of action less protein binding and cleared through kidney Other Drug digital toxins you know look at it it's in its name it is written that it can be acting as a toxin is that right digitoxin you don't find toxin in the digoxin do you so whenever you see digoxin and digitoxin toxin within the digi toxin should remind you it can produce more toxic and complications so usually it is avoided so when we really use this drug second line drug only when patient has significant renal problems if someone has Chronicle or failure and you really need to digitalize the patient then you should prefer failure if patient has ah relatively good functioning kidney digestion should be the drug of choice right then how the digoxin produces how the digestion produces positive inotropy we have already discussed very very briefly we will review it what really happens basically there are in the myocardial cell membrane there are special type of pumps and these forms of sodium potassium 80 Pages what is that look here this is sodium potassium 80 phase it is doing primary active transport or secondary active transport just for a basic concept this is doing primary active transport or secondary Active Transfer it is primary because whenever there is active transport using the ATP directly that is primary active transport normally so what it is doing it is taking the yes sodium out and bringing the potassium n is that right what we discussed that digital is digital is yeah this is digitalis it binds over the spam I think it's sitting in a very awkward position it sits on the sperm your digitalis sits on this pump pump will work fast or slow slow so what really happens that when digitalis is binding the sodium potassium 80 phases there's intracellular sodium accumulation right intra cellular sodium increased right that will lead to contrast after digitalization intracellular sodium well increase and when intracellular sodium is increased now we have to remember there is a special exchanger and what is this exchanger doing yes this is uh you can say sodium calcium exchanger normally it allows sodium to come in and it allows the calcium to go out is that right when it is formed this exchanger when this exchanges is working it is bringing the sodium n and taking the calcium out now the formulas of this exchanger listen very carefully the performance of this exchanger depends on that how fast sodium is coming in is that right it means it depends on the gradient of sodium ah concentration gradient in excess solar and intracellular sodium once you have digitalized the patient when you have digitalized the patient intracellular sodium is more there's an increase intracellular sodium when intracellular sodium is there there's already extra sodium do you think sodium will love to come in no so there is reduced gradient for the sodium to move from extracellular environment to intracellular area when there is reduced movement of the sodium right that will reduce the total activity of this stranger so naturally even less sodium is coming and through this exchanger there will be less calcium going out through this exchanger right now so in this way blocking the sodium potassium ATP is primarily increases intracellular sodium but when intracellular sodium is more that fills the exchanger and that secondarily increases intracellular calcium and this calcium which is unable to go out is captured by special intracellular operators what is this sarcoplasmic reticulum and what the separatus will love to do that it has special type of calcium 80 phases it has special type of what are these pumps calcium 80 Pages what is the function of this calcium 80 phases that during the repolarization process during the diastole right these calcium 80 phases actively transport the extracellular extra excuse me we have to correct it what is the basic function of this calcium 80 phases that once myocardium is relaxing right during that time they are pumping the intracytosolic calcium what is this calcium this is in the cytosol right intracytosolic calcium to the sarcoplasmic place right so we can say that these are calcium capturing calcium capturing mechanisms what are these calcium 80 phases they will they will actively transport calcium from the cytosolic area to sarcoplasmic reticulum so in this way when this ah due to impaired performance by the exchanger when calcium is retained into cytosol it is immediately stored into sarcoplasmic reticulum so the result is that in the sarcoplasmic reticulum calcium concentration become very very high as you know in sarcoplasmic reticulum how the calcium is stored there are calcium binders you know you want to know the name of that calcium binders they are okay this sequester the calcium the special proteins here I will show you for example this is the protein here this protein has points here and who will fit in these points calcium calcium will stick to this point so this protein is calcium binding proteins or more truly we say these are calcium sequestering protein these are calcium sequestering protein so their name is very simple calcium sequestering proteins are called simply strains see quests trends so we can see here sarcoplasmic reticulum is very rich and else equestrians so that whenever pump bring the calcium in calcium will get bound to calc sequester is that right so when if patient remains digitalized for longer time it means in the digitalized cell sodium level is more so naturally calcium level will become more due to impairment of this exchanger that will lead to extra calcium loading into sarcoplasmic reticulum and now whenever depolarization will come under digitalization action there is more calcium loaded here now whenever depolarization will come during deposition sodium comes in is that right now let me tell you the mechanism of depolarization right sodium comes in then it is followed by during the plateau phase there is incoming what is it incoming potassium is this my friend potassium is going out and calcium is coming in what is this calcium extracellular calcium so during Plateau phase of the action potential extracellular calcium Come n and this extracellular calcium act as a trigger calcium this calcium is acting as trigger culture and this will act on what sarcoplasmic reticulum and when they will act on the sarcoplasmic reticulum then calcium releasing channels will be opened and sarcoplasmic reticulum this is called triggered calcium and now because it is overloaded with calcium so it will release normal amount of calcium or extra amount of calcium so as compared to normal situation there's too much calcium released right so patient myocardial cells which are digitalized write these cells under the influence of digitalis retain more calcium stores in the sarcoplasmic reticulum and on arrival of action potential especially by the during the influx of trigger calcium they release massive amount of calcium and this calcium remaining story you must be knowing you this calcium will bind with the yeah this calcium will bind what is this thing right this calcium will bind with proponent this is proponent this calcium will bind with the troponin and troponin this is what is this Ropo myosin so when calcium will bind the extra calcium will bind with extra troponins proponents will work more effectively and pull away the tropomyosin between The Binding sides of myosin head and so what what really happens that this is pulled away and when this is pulled away right actin myosin interaction is more effective and there's stronger contact number right so whenever digitalis eventually lead to more slowly calcium loading and more calcium level is during every systole more calcium at over on the proponent and extra work on proponent extra you can see changes in the extra tropomyosin and there will be better Intex interaction between the actin myosin filaments and that will lead to better contraction and when there is better contraction we say there's positive ionotropy so this is how digitalis work is that right now this section of digitalis is something which most of the doctor know but this is one more action of digital is only very good doctors right but that action is extremely important clinically so what is the second action of digitalis now I'm about to be impressed by you up to now we have discussed that one action of the digoxin or digitalis is that it increases the intracellular calcium what is the second action of did you tell us please digoxin it has two actions right one action which every doctor knows every good doctor knows that it increases intracellular it's a calcium loader right and due to this calcium loading we can say that digitalises are positive I know profit drug you know do this calcium loading what is the second very important action of digoxin yes what is the second most very important injection in action of digoxin yes if you don't know should I mention that is this drug is only very good doctor know this this drug is also stimulant to vagus system right so it is Virgo tonic drug we go tonic drug this increases the Vega Stone now we'll see that if you know the both actions you can really talk in very good way then what are the net action of digitalis from the heart let me draw heart here this is essay node this is Av node and these are your conduction pathway this is bundle of His and right bundle branch and left now this is your heart we have to see what are the actions of digital from your heart now we are going to see the actions of digital Plus on the heart you know that right Vegas supplies the what is this right vehicle supplies that's a node and left because mainly supplies excellent a little better night to be here get left with us supplies maybe not this is right Vegas and here it is now first the direct action on the heart calcium loading so number one it loads the calcium in directly this drug loads the calcium in asinode it loads the calcium in Atria it loads the calcium directly in what is it AV node and it loads the culture man or kanji fiber and it loads the calcium on contractile myocardial is that right this is a direct fraction of digitalis when digitalis work on SN order they directly load it become loaded with calcium atrial muscle become loaded with calcium AV node become loaded with calcium conduction pathway become loaded with extra calcium and what is this Contracting myocardium ventricular myocardium also become loaded mixers these are direct action right then there are indirect action indirect action are through neuronal system that wig digitalis also stimulate Vegas so vagal activities increased or decreased any vehicle activities increase vehicle activity mainly work on yes on snodel AV node very little vehicle activity on Atrium and almost no vehicle activity on ventricle this point is very important right that sympathetic and parasympathetic action on heart right I will draw this black as sympathetic receptors sympathetic receptors are present on essay node sympathetic receptors sympathetic receptors are present on Atrium please draw this diagram sympathetic receptors are present on receptors are present on what is this conduction pathway and sympathetic receptors are present on ventricular myocardium actually adren allergic receptors are present all over the heart concept which I am trying to make the adrenal energy receptors are present all over the heart so catecholam means they have action on all the heart catecholamine has acetodection atrial action AV node action per congest system action and ventricular action this is the action of sympathetic nervous system but parasympathetic nervous system has action on essay node it has receptors on snode it has receptors on AV naught very few receptor on HR almost no receptor on granted now what I'm trying to put in your mind I'm trying to emphasize that when there is adrenergic activity right it will change the activity of enhanced activity of snod Atria AV node and ventricles but when there is parasympathetic activity parasympathetic activity will influence the heart mainly by action on snodl AV node is that clear so we can say that where a sympathetic nervous system we can say epinephrine or sympathetic nervous system has Global action on heart write it down the word that sympathetic nervous system has Global action on heart if you have friend or not epinephrine or other sympathomimetic drugs like dopamine but parasympathetic nervous system has only selected or limited action on hard only on snod and AV node now look at this thing that once you have understood this concept now we see that calcium loading is a direct action this is a direct action of digoxin on The myocardium but vegotonic action is indirect by changing the value tone it changes the cardiac function now Vegas is essay node stimulator or inhibitor inhibitor yes it is parasympathetic nervous system and it means Vegas is negative chronotropic Venus is negative chronotropic influence Chrono tropic influence is that right and here left figure says negative dromotropic influence bromo Tropic influence right right wages positive a negative chronotropic so it means that when right Vehicles is stimulated sinus as a node activity is reduced and then left vehicles are stimulated and of course it is stimulated it means the immunodal activity is reduced now you see one thing the direct action whenever any myocardial area is loaded with the calcium it is stimulated now listen the calcium which is put in as a node it is trying to make it positive chronotropic by direct loading of the calcium is positive chronotropic influence but indirect vehicle activity lead to negative chronotropic and legal activity dominates over as anode so acid node will be under negative chronotropic or as anode will be in a nutshell as a node will be inhibited in the same way when calcium is loaded on AV node calcium stimulates the AV node but there is more action by the vagus and vagal action dominates due to this reason AV node is also inhabited so we can say did you tell us right inhibits the acid node inhibits a heavy node but when digital has load the calcium in real myocardium and when did you tell us load the calcium and ventricular myocardium right there's no opposing action by Vegas on initial myocardium and ventricular myocardium so until myocardium is stimulated and ventricular myocardium is also stimulated so now you should say that due to its direct action stimulate atrial and ventricular myocardium but due to indirect vigotonic influence it inhibits the sinus activity and noodle activity you get it so this is the you can say the gist of understanding that when you digitalize the patient right due to its direct action it is loading it is stimulating atrial and ventricular myocardium and due to its indirect ergotonic influence it is yes it is inhibiting essay node and AV node now you look at it the beauty of this concept is that if you develop look if you develop toxicity of this drug you do any mechanism it should develop toxicity of digoxin then toxic doses of digoxin will produce sinus bradycardias and noodle bradycardias but it will produce aerial tachycardia than ventricular tachycardia so what a funny situation this same drug can produce bradycardia as well as tachycardia so a patient when it is heavily digitalized and if it if you develop toxicity then what really happens that sinus and noodle radialism will occur neutral and ventricular let me tell you combination of this let me give you an example of this combination if this digitalis toxicity there is strong heavy nodal inhibition and as anodial inhibition right and if you notice too much inhibited right can you take all the impulses down no so we can say when AV node is inhibited too much in toxicity it will produce AV noodle blocks because this is negatively dromotropic action right and AV node cannot take all the impulses down through the from The Atrium to The ventricle is that right but it may produce digitalis will over stimulate what is this over load it with the calcium so these are ectopic foci you know when calcium is too much loaded in actual myocardium or ventricular myocardial cells when calcium is too much loaded then restroom membrane potential becomes near to threshold and then what happens that these cells develop abnormal increased automaticity an abnormal increase automaticity is called bathroom Tropic action so what we can say is a very funny drug that by action here it produce negative chronotropy by action here it produces negative dromotropy by loading the myocardial cell to make them positive inotropic and positive bath motor because of mechanical action mechanical advantages of loading the calcium and there are electrical disadvantages of loading the calcium so let's suppose that extra calcium in digitalis toxicity produce atrial tachyaarythmia that will produce atrial their resting membrane potential become less negative or more near to threshold so ectopic Foci uh May Fire too much in the atrium and there may be atrial what is this the key cardio now on ECG on ECG if you find a patient who has atrial tachycardia with Avi nodal blocks right they say it is digoxin toxicity until proved otherwise this is the most classic presentation of digoxin toxins state most classical presentation of digestion toxicity on on ECG is that patient has supraventricular tachycardias with immunodal blocks you can understand that due to calcium loading there are supramentricular tachycardia and due to vehicle activity Avi nodal inhibition there is heavy nodal block so you can see this is a an easy you will find combination of as well as thma is that right so when this combination is there right right when this combination is there then you should suspect digitalis toxicity is that right uh again let me repeat it that on EKG what will happen let me tell you normally first of all draw the normal EKG and then I will show you the this EKG with this pathological change yeah we'll go into detail later but I will just tell you only this one now what really happens on ECG that normally CG is P wave what is this PR segment then QRS t first I tell you what will be the changes listen this is ST segment ST segment is coming on ECG and this P wave is making what atrial depolarization ST segment is current passing through AV node write it down P wave is due to it will depolarization ST segment is current passing through heavy node QRS complex shows depolarization supplied in The ventricle depolarization spread in ventricle and ST segment shows when Plateau phase when you can say ah deep all the ventricle is depolarized or no current is flowing and T wave shows repolarization of ventricle it shows depolarization of ventricle MX layer now what is happening to the heart let let's see on ECG on a digitalized heart SA node and AV node are stimulated or inhibited inhabited due to indirect vigotonic action so first thing will be when current is taking longer time from Adria to go to ventricle when you are digitalize the patient Vegas is inhibiting the AV node if we note is inhabited it will take shorter time to conduct the impulse down or it will take longer time longer time if it will take longer time look at the ECG change that P wave is coming at its time but current is taking very long time so then QRS will come so what is happening that ST segment is for a long in their time scale or if you put P wave with it this is ST segment and if you put the P wave also with it it become PR interval so what will happen PR interval will be shorter for long so patient who are digitalized they may have PR interval per long what is the cause of prolonged p r interval remember ST segment has at the end of the P wave at the beginning of QRS but PR interval is at beginning of the P wave up to the beginning of QRS so although this is a rule all those phenomenons and drugs which inhibit the AV node lead to PR interval prolongation all the drugs which inhibit the AV node lead to PR interval prolongation I hope you will remember that did you know what are those drugs at least tell me one drug which can prolong the PR interval digitalis right good so one drug which can prolong the PR interval is digitalis what are the others look draw it here what are the drugs which are making it prolonged one is digital as digoxin what is the other AV naught conduction depend on calcium so calcium channel blockers calcium Channel blockers then every node is stimulated by sympathetic system if you inhibit AV node will be slow so beta blockers then there is a drug called adenosine right adenosine act on AV node and bring lot of potassium out of every nodal cells adenosine act on the IV node and forces the Avi nodal cell to lose potassium of course the production come out even though it will become too much inhibited and negative so it will be listen adrenocene again let me tell you digoxin by right on the mechanism digoxin by increased vehicle tonic activity right inhibit the heavy node calcium channel blocker block the calcium channel so immunodal action potential is inhabited beta blocker reduce the sympathetic activity on AV naught and even nodal activity is inhabited is that right you know sympathetic activity also normally load the AV node with calcium yesterday we discussed then adenosine is a very short acting immunodal inhibitor sometimes it is given when you want to inhibit the heavy node for very short time adenosine when it bind with AV nodal cells it opens their potassium channels so AV nodal cell will lose potassium and if a lot of potassium come out of the immunodal cells AV nodal cells will become more electronegative if normally they are minus 60 millivolt now there will become more electronegative due to loss of cations due to loss of data ends and if you not become too much electronegative can just simulate it no so this is what adenosine does it is also immunodal blocker so all these drugs are heavy nodal inhibitor and another mechanism is also immunodal inhibitor look here if you stimulate here carotid massage this will stimulate the vehicle outflow when you do rotate massage it increases the vagal outflow that also inhibits the heavy node so the one physical method I have mentioned four group of drugs I have mentioned which are immunodal inhibitor all of them will prolong PR interval but right now we are talking about action of digitalis on the ECG so effect of the digitalis on ECG we have talked about right now is that if this is our classical ECG right now what really happens that this become very much prolonged so we can say that due to vehicle stimulation digoxin inhibits the AV node and due to negative chronotropic action due to inhibition of Av node current takes longer time cardiacom pulse take longer time to move from Atrium up to ventricle and PR interval is prolonged then another thing this is PR interval another concept is q t interval QT intervals start from the onset of the tube wave QRS complex and it goes up to the end of T wave right this is called Q D interval is that right now QT interval means what it is beginning of the QRS it include the ST segment and it include the T wave up to the end U2 interval now what is the clinical importance of this look here QD interval signifies the significance of Duty interval is it is telling you the spread of an onset and spread of ventricular depolarization the duration for which ventricle remains defolarized and spread and termination of ventricular revolarization so it means that QT interval is a duration from the onset of ventricular depolarization up to the termination of ventricular ization is that right Claire now listen I told you that when you are loading the cell with calcium they become positive inotropic as well as they become positive clinotropic inclinotropy I told you that there is increased velocity of contraction that's the right there is increased velocity of contraction now QT interval look here can be modified by calcium load when there is more calcium in the cells due to internal shrink look here calcium make the cell myocardial cell more effective or less effective now calcium make the myocardial cell more efficient or less efficient more efficient that is why we are giving the calcium loading drug like digoxin right so if you keep in your mind that calcium May calcium loading to the cell makes a myocardium more efficient it means not only it will contract more efficiently but it will undergo depolarization repolarization more efficiently and if this whole process is occurring more efficiently it will take longer time or shorter time if you are efficient you take for some work longer time shorter time shorter time now again let me repeat it calcium loading make the myocardial activity more efficient is that right within physiological limits after that toxicity will start now when you load the calcium more in myocardial cells right not only mechanical activity is more efficient ventricular electrical activity is also more efficient due to that reason the patient who are digitalized there's more efficient depolarization and repolarization so total the onset of depolarization time up to the offset of completion of repolarization time this time should be increased or decreased this should be decreased so what really happens that QRS t is reduced now look at it now look at the upper upper ECG pattern and lower ECG pattern upper has shorter PR it has a normal PR and normal QT interval here as compared to normal after this is digitalized heart as compared to the normal what is happening VR interval is prolonged and as compared to the normal QT interval is shortened UT interval is shortened is that right so PR interval is prolonged and cured interval is shortened now I want to tell you some more thing I will not go into detail of electrical changes but almost every doctor knows that in ischemic heart disease there is changes in ST segment and T wave and ischemic heart disease there are changes in ST segment and T wave is it easy to understand now what what happens in ischemic heart disease which make the ST segment T wave to change that is the current of injury that is the current of injury current of injury during ischemic heart disease load the myocardial cell with calcium here digitalis is also loading the cells with calcium now you draw a parallel in your mind as a concept heart disease right it also loads the calcium and did you tell us did you tell us it also knows calcium due to calcium loading in ischemic heart disease cells are ischemic and the cell membranes are not working well and extra cellular cations like sodium and calcium may be loaded in the ischemic or injured or infected cells also lead to intracellular loading of sodium as well as calcium so this thing is common in ischemic heart disease and this here the cation loading is too much and we call it current of injury and that current of injury produces changes in ST segment and T wave then here T wave may be elevation or T wave may be inversion you remember or ST segment may go up or ST segment may go down so we can say very simply ischemic heart disease by loading the myocardial cell and producing the current of injury brings ST segment and T wave changes now look at the parallel here digital is even though there is no ischemia but did you tell us but it's also loading the cells with sodium and calcium so it will also change the ST segment and interior so do you think you need to remember it it's very simple so PR interval is prolonged Q D interval is shortened and there are yes there are ST segment and for example SP segment may be elevated or depressed and T wave may be inverted is that right so there are three changes on the ACG classically what are those changes due to AV nodal inhibition there is PR interval prolongation due to more efficient depolarization reposition uterine turbulence shortened and due to calcium loading cationic loading ST segment and T wave changes are also seen there yes Jamie is it clear right okay after this we will come to another concept but before that we'll take a break now we will talk about how the hemodynamic parameters are Disturbed in heart failure and what is the impact of digitalis on those hemodynamic parameters let's start with the very basic that is the principles of starling's law you know that if you increase here is n diastolic volume and here is cardiac output right and you know it that normally in a healthy heart and diastolic volume is about 140 ml in a healthy heart first I will talk about healthy heart and asphalic volume is about 140 ML and we know in a healthy heart if you keep on increasing end diastolic volume it means you are feeling the heart more heart has intrinsic regulation that more you fill in more it produces output right so more you put the venous return more you fill the ventricle more you increase the end-astrolic volume there is more stretch on the myocardial fiber and there is stronger contraction so we can say that in a healthy heart within physiological limits if you keep on increasing and diastolic volume actually you are increasing the cardiac output so this can go like this this is the normal function curve right now we have to see that in this normal function curve what happens in heart failure number one and then we have to see what how did you tell us correct the problem first look at the normal point where heart is operating heart is operating normally at this point that in a healthy heart n digital volume is about 140 ML and cardiac output is about 5 letters is that right this is a normally operative points suppose point a right now if this healthy heart suffers with extensive myocardial infarction or this heart is suffering with suppose chronic ischemic heart disease repeated ischemia do you think that then its power of contraction is increased or decreased it is decreased it means for a given end diastolic volume it will produce less cardiac output is that right so curve should go upper curve should come down it should come down so what really happens in cardiac failure we can say this curve should be depressed like this and in a feeling hard hard with poor contractility at end diastolic volume of 140 ml rather than producing five liter it will produce maybe only two letters suppose two and a half letters cardiac output has dropped so we can say that this is the cardiac failure point a was the healthy point and point B is the failing hard right so we can say that what has happened that Dynamics hemodynamic performance of the heart has shifted from point A to B when there has been structural or functional defect in The myocardium and myocardial contractility has dropped yes what's your question yeah of course this is of course a very good question by Jaime you say is it low output cardiac failure of course it is low output cardiac failure because we have divided the cardiac failure into two categories yes high output cardiac failure at low output cardiac failure right digitalis is given only in low output cardiac failure and we are talking about low outcome cardiac failure now right yeah most common cardiac filler is low output cardiac failure now point a will shift to the point B now cardiac output drop now what will happen in a failing heart up to now we have not given the drug now we're so far failing hard hair cardiac output is less if cardiac output is less now you imagine my heart is pumping less blood carotid sinuses overfilled or underfelled underfelled so baroreceptor will fire they will report to the central nervous system that blood pressure is falling cardiac output is falling from central nervous system sympathetic activity will increase so at the point B as soon as cardiac output drops there is activation of yes number one sympathetic nervous system sympathetic activity is increased this is one thing which will happen automatically second thing which will happen that as soon as your cardiac output will drop not only baroreceptors will increase the sympathetic activity but do you think renal blood flow will be more or less when cardiac output drop renal blood flow will be more or less it will be low it's blood flow when cardiac output is less blood flow going to the kidney is less when kidney are underperfused there's activation of renin angiotensin aldosterone system so it means that star number two is that by by acute drop in cardiac output there is activation of renin angiotensin aldosterone excess is that right now we see what really happens let me draw here is the left heart and here is the right heart now what really happens that what will be the impact of sympathetic nervous system and what will be the impact of renin angiotensin aldosterone axis in the failing heart sympathetic nervous system will do one thing good and one thing bad in the same way any Angiotensin system will also do few things good and few things bad now what are the good points good point is for example when raining Angiotensin aldosterone system is activated aldosterone will retain the water aldosterone will retain the water and sodium so it means body will retain salt and water after the onset of failure under the direction of aldosterone this retained water will increase the blood volume right kidneys are under the effect of aldosterone kidneys are retaining salt and water the salt and water will add to the blood volume blood volume will be increased when blood volume is increased of course Venus return is increased right when venous return is increased it means cardiac filling is increased when cardiac filling is increased it means and diastolic volume which was 140 it may become more maybe it become 200 and more so what really happens that by activation of rain in Angiotensin aldosterone axis especially eldosterone retains salt and water through renal mechanism this retained salt and water increases your blood volume this increased blood volume lead to increased venous return and increase cardiac filling and this increased cardiac filling will increase what is this and the astrology volume so it means now point B right after this compensatory mechanism will start shifting in this direction is that right this is one thing secondly sympathetic nervous system will increase the heart rate and also increase contractility right so that will increase lock sympathetic activity will increase this axis a little bit look here this was by the salt and water retention and this was by the what is this there's some contraction increased by sympathetic nervous system plus one thing more sympathetic nervous system is we know Constructor as well as arteriola Constructor but first I will talk about sympathetic nervous system will construct the length as well as indutions to also constrict the arteries and veins so it means when these mechanisms become operative they construct the veins when there is Venous construction can blood stay into winds no blood is pushed back to the central system so due to Vino construction also due to sympathetic mediated we know construction and angiotensin two mediated Vino construction there is increased venous return When there's more venous return to the heart and diastolic volume will further increase so Y and diastolic volume is increasing number one due to aldosterone mediated salt and water number two that we know a sympathetic nervous system and angiotensin two mediated yes with Aveeno construction is that right this was good because endosolic volume is increasing and increase in endosolic volume is associated with some increase in contractility now but there is a few things which are happening bad what is the bad thing which is happening yes no the very bad thing sodium and salt retention in the beginning is good because it will increase the cardiac output the bad singers artery rules are constructed so pathetic nervous system construct the arterials Angiotensin II construct the arterioles so left heart can it pump well into very much constricted artery roller system it is already filling hard and now you increase the afterload after load the load against which it has to pump arterial construction so the increase in cardiac output which we were expecting that will be partly nullified by increasing arterial construction so by increasing and diastolic volume we were expecting a big increase in cardiac output but unfortunately the same mechanism construct the arterials and partly nullify the beneficial action so cardiac output is increased only slightly and now Hardware shifts from point B to yes where it is Shifting to point C now look at the point C at Point C rather than two and a half later now it is pumping three later there is some Advantage there is some Advantage due to these compensatory mechanisms but now heart is operating at higher end diastolic volume heart is operating at higher and diastolic volume right and compensatory mechanisms are operating for a while this is good that the slight increase in cardiac output but in the long run it is very very bad why it is bad yes Ahmad can you tell me it is bad okay this is one reason what other in the long run the most important thing which happened look pulmonary congestion is here as well as there yeah it's more severe because fluid is retained this is one thing I'm asking why is this all thinly filter remains like this and heart keep on operating under strong neuro humoral compensatory mechanism why it is bad for myocardium because heart will undergo Progressive failure and I will tell you why the reason being that walls of The myocardium are under normal stresses or abnormal stresses walls of The myocardium are under normal stresses when they are operating here or abnormal stresses the abnormal stresses they are receiving too much fluid they are unable and yeah they are receiving too much fluid and they're pumping very less this is a very bad thing right and this chronic abnormal stress Alters the expression of the genes of the myocardial cells myocardial cells genomic expression Alters under chronic stress this very important point to understand and these cells start decreasing their myosin production they start producing extracellular Matrix more and heart eventually become more the myocardial convert into poor quality myocardium this is extremely important because these days they say we must do something not only for a for short term increase you know not to be happy with short-term benefits of these things a very long term bad things due to these neuro humeral compensator mechanism what are the bad things what are the real disadvantages that if these neuro humeral compensatory mechanism operate for longer time they increase too much stress on the wall of The myocardium and under chronic stress genomic expression changes and myocardium expresses less you can say effective on tactile proteins it expresses excessive amount of myocardial cell make extracellular Matrix which is not good for the heart and we say due to neuro humoral chronic activation myocardium will become a very very poor type of myocardium is that right this is the bad thing this is the price you pay for neuro humoral compensatory mechanism write it down one classical sentence that sympathetic nervous system and renin Angiotensin aldosterone system they are neuro humoral compensatory mechanisms which are good in the initial stages of cardiac failure cardiophilia but in the long run they were deleterious effect on The myocardium that is why you know these days the doctors are very much concerned that they should give Angiotensin converting enzyme Inhibitors and cardiac failure they are giving the patients with the you can say beta blockers so that stress on the walls should be reduced another problem which occur that at this point LaPlace is lies not in the favor of the patient you know what is laplace's law LaPlace is last states that pressure pressure generated by a cylindrical container is directly proportional to the tensions in the wall when myocardium contract when sarcomere's contract they produce tension in the wall and it is pressure generated as inversely proportional to the radius now look at it this law is very important when you understand the cardiac failure and the action of the drugs in a failing heart you know pressure is required for the cardiac output if there is no pressure generated in the Lumen there cannot be any cardiac output so we need pressure building in the lumen to get the cardiac output but to build the pressure in the Lumen we need good tension in the wall so tension in the wall acting on the radius right eventually produces pressure now look what is happening very bad thing that as hard from here it was a smart heart right as hard as feeling neuro humoral mechanisms are retaining salt and water and increasing the venous return and end diastolic volume is increasing so what is happening to radius increase so what is happening when heart is moving from this point to this from B Point hard shift to the C point during this process it is progressively increasing its radius it is progressively increasing its radius right so with the given tension no the word we should use with the given tension the myocardial power to produce tension at point B and C if tension power is the same increasing radius decreases the pressure so do you think it's good for hard or bad very bad so actually what really happens neural humeral mechanisms are good initially but progressively they lead to dilated heart and dilated heart are bigger radius and when it has a bigger radius larger radius with the given tension which myocardium can produce feeling myocardium can produce it is producing lesser pressures right at the top you are producing arteriolo construction so it's a big trouble now heart is here now we see what happened with digitalis you give the digital as you digitalize your patient right when did you you know that digital as well eventually we have discussed into detail how it will load the myocardial cell with calcium and how troponin tropomyosin will be acting and how actin myosin interaction will start and heart contractility will increase now here we give digital as a point C what we have introduced digoxin once the person is properly digitalized for a given now listen for a given end diastolic volume for example now it is 240 ML patient has end diastolic volume of 240 ML and then you digitalize it was a dilated heart as cardiac output will now under the influence of digitalis will decrease or increase increase so it means after the digitalization for a given endosolic volume cardiac output should go up now look at this is what is happening so patient will shift from point C to point d right for every given end diastolic volume cardiac output will increase so it means this will be the Curve okay we can make the D up to here this is what average doctor will tell you but you have to learn more than this how did you tell us will bring further changes this is what everyone can understand you digitalize the patient this positive inotropic action and from point C it will shift to the point d but the true story goes beyond it what is the true story look at 240 ML of industrial aquarium heart is pumping more efficiently heart is able to produce less tension or more tension so digitalis put the digestion here digoxin has increased the power tension in the wall now when tension will increase in the wall pressure will be increase when pressure will be increased ejection cardiac output will increase then ejection fraction will increase now look here Hardwell contract more strongly so it will throw more stroke volume out and if heart is throwing more stroke volume out after the digitalization if Hearts starting ah throwing more stroke volume out so what will happen that and diastolic volume will start reducing heart will become more dilated or less dilated let's dilate it so look at the beauty that mechanism will start moving backward now I'll tell you how this beautiful thing happens and somewhere hard adjust here at this point now look look this is the star point now the true lead what digital has did the direct action of digitalis was that due to positive ionotropy it took the Dynamics from point C to D is it clear but due to this increased contractility and increased cardiac output other deleterious effects or bad effects will be reduced how listen first of all when cardiac output will increase renal perfusion will encourage when renal perfusion is increased rain in Angiotensin aldosterone excess start relaxing when it starts relaxing salt and water retention become less than salt and water retention become less it means because there's less salt and water start washing out so when salt and water is less in the body then blood volume is less than venous return is less and when venous return is less than endospholic volume is less so at D Point what really happened you can write here that increased renal perfusion relaxation of the Indian Angiotensin aldosterone access less salt and salt and water retention less venous return Dynamics move backward number one number two of course when cardiac output will increase then Barrel receptor stimulation for sympathetic nervous system is decreased so sympathetic nervous system also relaxes renin Angiotensin aldosterone system also relaxes so compensatory mechanisms are relaxing now it's very easy to understand and sympathetic nervous system will relax we know construction will be less when Angiotensin 2 is relaxed reduced then we know construction is also less so reduce sympathetic outflow after increasing the cardiac output at Point d the reduce this reduction in sympathetic outflow this reduction in Angiotensin II level both things reduce the we know what construction veins dilate and veins dilate my friend veins will accommodate more blood so venous return is reduced when venous return is reduced to the heart cardiac filling is reduced and cardiac filling is reduced now there are three mechanisms you should explain that at Point D cardiac filling will start reducing one reason that at D Point salt and water retention is less and venous cardiac filling is less number two we know dilatation is there right due to sympathetic relaxation and Angiotensin to relaxation so let's finish the turn now look at the beauty the less Venus return is there radius is reducing and when radius is decreasing it's a good news of bad news it's excellent news we want the pressure generation and now did you tell us direct look now digital has directly increased the tension and indirectly by relaxing the neuro humoral mechanism it decreases the radius and when radius will decrease increasing tension and decreasing radiation sorry radius not radiation radius the pressure generation will be less or more increased is that right that is a secondary Factor it produce story is not yet over very important point the most wonderful point that sympathetic nervous system when it goes down and Angiotensin cooldowns arterial relax and when arterials relax the pressure required pressure required to maintain the cardiac output is more or less listen if arterials relax now heart is beating against more resistance or less resistance less resistance so it has to generate less pressures so now the whole Dynamics are changed in laplace's law pressure tension over radius now go step by step when you digitalize the patient first tension went up look at you have to talk about all these three things the attention went up when tension went up cardiac output became more right it was able to produce more pressure so result was there there was more pressure when pressure generated were more cardiac output was more sympathetic nervous system started relaxing raining Angiotensin system started relaxing so sodium load in the body is reduced and we know dilatation is there so blood volume is reduced and venous pooling is more venous return is less radius is reduced right when radius is reduced now increasing tension reducing the radius produces very efficient what pressure this pressure was this was increased in pressure due to his tension this is increasing pressure due to reduced radius so dilated heart turn back to smarter heart a smart heart is more efficient heart is that right now look at it now pressures you are generating more but the pressures are required to overcome the resistance against the blood flow in the arterial tree the pressures were required for what purpose so that you can maintain cardiac output to the peripheral tissue that was the purpose now but when sympathetic nervous system went down when Angiotensin 2 went down even arterial relax so with this pressure blood flow will be really very good and cardiac output will be maintained excellently so what really happens now here where it was originally 140 ml it went to 240 ML now it is about for example 180 ML now at the end as trolley volume of 180 ML let's suppose it is maintaining four letter Dynamics are not normal but close to normal with less you can say retentions of salt and water basically yeah first look look at it this was a healthy heart attention it's a healthy heart first cardiac output dropped then endospholic volume Progressive will increase then it took the cardiac output up and reduced the and diastolic volume is that right this is the how did you tell us Alters your hemodynamic pattern parameters of cardiovascular system Emma clear at this stage when heart is operating at B stage we say there is cardiac failure but uncompensated this is cardiac failure and company stated but here when neuro humoral mechanisms are activated it is still failing at Point C but it is compensated failure so this is say that there is at Point C there is compensated compensated cardiac failure is that right so this is what we have integrated now if there is any McQ like this you can handle with but yeah this very high sympathetic activity and there is a higher initial tension aldosterone activity it is good for a while it is very bad in the long run why it is very bad because with this sympathetic activity there is strong tension on the stress on the walls then too much fluid retained and dilated heart strong stresses in the wall then Angiotensin 2 and sympathetic nervous system constricting the arterioles feeling hard already donkey is tired at the top you are forcing it to go against resistance is that right so this thing has done initially beneficial by increasing under diastolic volume but bad thing all these things increase the stress on myocardium and a failing heart myocardium keep on working under high stress it becomes progressively failing mechanism is that right so this is what we have achieved with this then now something interesting in cardiac failure some initially we use diuretics and we use Angiotensin converting enzyme let me tell you integrate those drugs action on the same what is this graph let's suppose your heart is operating here and you are patient with heart failure and your doctor does not give you digitalis he says let me try first diuretics no it is going to work let's see how why to go up and come down why don't you move like this I will tell you exactly how happened for example you I gave my patient with the cardiac failure Angiotensin converting enzyme inhibitor like captopril or analapril right now we are giving the drug renin Angiotensin aldosterone excess system I need to be needed to relax is that right or we can say simply the drugs which I'm giving I'm not trying you are at patient is operating at this point but this time I'm not going to give digoxin this was action of digoxin direct action and then indirect action this term I'm going to give Angiotensin converting enzyme inhibitor now listen what will happen when you give Angiotensin converting enzyme inhibitor then Angiotensin II level in the body become less or more less an aldosterone level become less so what really happens when you give this drug and of course with that I have to give diuretics right so we are reducing the Elder we are reducing the Angiotensin 2 and with diuretic we are reducing salt and water load now you imagine these two drugs we introduce at this point what will happen when salt and water is less and salt and water is less it should move in this direction is that right and when Angiotensin 2 is less veins will dilate it will still move in this direction is that right it means that when we are giving this drug Angiotensin converting enzyme Inhibitors and diuretic actually we are reducing diuretic reducer total blood volume and when total blood volume is there that will lead to what now LaPlace is love with the new drugs will give diorated total salt and water is reduced so total venous return is reduced and what will happen radius of the Hardwell reduced so this is the advantage of diuretics now we look at the endurance and converting enzyme inhibitor the effect on the laplace's law and effect on the graph the indutions in converting enzyme inhibitor number one reduce Aldo again aldosterone is reduced to salt and water is reduced so reduces further reduced and both these things will move it towards backward this is one thing secondly when Angiotensin 2 is reduced then we know construction is reduced when's dilate conveyance dilate less venous return going again radius is reduced you get it again radius is reduced it means that if progressively radius is reducing with the given tension pressure generated are more are you understanding because we are reducing the radius of the heart so with the same contractility we have not given any positive inotropic agent we have not given any positive analotropic agent so with the same failing tension when we reduce the radius hard start producing better pressures when it does better pressure so it starts increasing cardiac output so it means but it this will not truly move like this actually it will initially move like this is that right it's moving like this am I clear then something will happen what is that one injured when cardiac output pressures are more cardiac output is more sympathetic nervous system will relax arterioloconstriction will relax Angiotensin 2 is less are that will also further relax the arteriola construction so when most of the arteries will relax what will happen the resistance against which heart has to pump is less so at given end diastolic volume at given end diastolic volume heart will produce more ejection or less ejection if arterioles are relaxed listen again no let me repeat it you people are sick again concentrate we gave diuretics and Indian attention converting enzyme inhibitor they reduce the blood volume reduce the radius of the heart they relax the veins right so again cardiac filling was less radius was less is that right so when radius was less for given tension it could produce more pressure if it was producing more pressure if it was producing more pressure than cardiac output is more when cardiac output is more that further reduces the intrinsic you can say sympathetic outflow sympathetic outflow was high due to low cardiac output when cardiac output will go up sympathetic system will relax now arterials will relax when arterials will relax when arterial will relax now the same pressure will produce more cardiac output and at the same end-astrolic volume cardiac output will be more and it will jump like this we'll jump like this we reach to the same point now the clinical saying is that when a patient comes with heart failure first use these drugs and if if they are not enough still patient develop symptoms then you come for digoxin you know why the reason being digoxin has a lot of toxicity these drugs are not so toxic Angiotensin converting enzyme Inhibitors and diuretics are less toxic drugs digitalis has high risk of toxicity this is one reason that due to concern about the safety of the drugs rather than going through this root rather than going from root number c to D then to star point it's better to come from C to let's suppose e and then to the star point the safer route the root look you can reach at star performance of the heart through this unsafe route or you can come through safe route am I clear and actually another Beauty there truly this root goes very fast when you use endotensin converting enzyme Inhibitors and diuretic truly this root goes like this because as soon as andersonic volume is reducing pressures are increasing and cardiac output is increasing so for explanatory purpose you can say that Vector backward then Vector upward but the net Vector is upward and backward so this is a combination of use of diuretic sand Angiotensin converting enzyme Inhibitors is that right these are the safer drugs number one number two the long term survival is increased in patients who are on diuretics and Angiotensin converting enzyme inhibitor the reason being that these drugs reduce that tension on the wall you know aldosterone level when they are high now they have discovered a new thing average doctor knows that aldosterone work on kidney but excellent doctor knows aldosterone at high concentration just disturb the genetic expression of myocardium now they know every doctor knows that Angiotensin to work on veins Angiotensin to work on arteries Angiotensin releases aldosterone right Angiotensin produces thirst Angiotensin work on kidney somewhere directly but excellent doctor knows that if chronically High Angiotensin 2 is there it will disturb the myocardial genetic expression that is so neuro humoral compensatory mechanisms are bad in the long run for the heart right because High Elder stereo and high look there are two things number one they produce the tension on the wall it stresses on the wall they were bad number two allele as this point elevated level of Aldo and elevated level of angiotensin two they disrupt the myocardial cells genetic expression so these days they say that Angiotensin converting enzyme Inhibitors and diuretic right they are excellent that not only they correct the hemodynamic they reduce the Elder level and reduce the Angiotensin 2 level and reduce the pathological remodeling going in The myocardium is that clear so what is the principle when a patient comes with heart failure it's better to give first ACE inhibitors diuretics and some in some situations the beta blocker if all of them don't work well then you go for digitalis why did you tell us is left at the end because a good drug but with a lot of bad side effects now we shall be discussing about the clinical uses of digoxin again it's worth reminding that digoxin is not the first line drug for cardiac failure right why even though it's a good drug as far as inotropic action is concerned but it has a lot of side effects which we will be discussing shortly because this drug has lot of side effects and it is a very narrow therapeutic window due to that reason this drug is not considered firstly in drug in case of ventricular failure right it is used only when you have used other less toxic drugs and those drugs fail for example you should use diuretic for cardiac failure with that you should also use idiotensin converting enzyme Inhibitors as well as in some situations beta blockers right these drugs diuretics Angiotensin converting enzyme Inhibitors and beta blockers they are less toxic as compared to digitalis number two because these drugs diuretics ACE inhibitors and beta blockers these drugs uh you can say reverse the neuro humoral compensatory mechanisms because they inhibit the neural immoral compensatory mechanism so they reduce the long term pathological remodeling going on in The myocardium and due to that reason not only these drugs reduce the symptoms they also increase long-term survival so they have a Advantage because such drugs density is the long-term survival when when but when we talk about the digoxin digoxin is very effective in reducing the symptoms of left systolic left ventricular failure but along with that it produces a lot of side effects it increases the risk of tachydery as it increases the risk of myocardial infarction due to such toxic effects ah long-term survival is not increased by use of digitalis digitalises specially used in the patients with left ventricular systolic failure systolic failure and this left ventricular systolic failure at Advanced stage right intractable left ventricular systolic dysfunction remember this is not useful in patient with right ventricular failure and it is not used for the patient to be diastolic diastolic failure right so in these two situations digoxin is not used write it down and put a cross on it so that you remember the right ventricular failure isolated right ventricular failure this is not very effective in case of diastolic failure against this drug is not effective this drug is meant rather all positive an entropic drugs are meant for the patient who have severe intractable systolic dysfunction so this was one juice that this drug is used in severe intractable left ventricular systolic failure but there's the another juice there is one more use second uses the patient who have heart failure with irriterial fibrillation I will explain why in that particular situation it is very useful right that is second group is that patient who are having heart failure heart failure with Plus they are having atrial fibrillation they are having atrial fibrillation right now question is that what is very special about this thing where digoxin is really considered very useful let me explain it right now what we can say that let's suppose you understand just explain this is your heart now here is essay node I'm going to explain why digoxin is excellent drug in a patient with heart failure with atrial fibrillation right here's S node and this is the electrical window between the Atria and ventricle that is the AV node go along with bundle of phase and bundle branches right now when we say someone has let's first concentrate on atrial fibrillation if I say someone has chronic atrial fibrillation what is happening in atrial fibrillation in atrial fibrillation the electrical activity in Atria is more than 350 per minute remember this is not the mechanical activity this is the electrical activity the electrical activity in the Atria is right when we say there is atrial fibrillation it means electrical activity in the atrium is more than 350 per minute in such fever relating Atrium there are multiple electrical currents right Patient has multiple depolarizing current which are simultaneously trying to stimulate the Atrium and what you really see that the multiple electrical vectors which are present in the atrium and these multiple electrical vectors are hitting the AV node at a regular interval at a very frequent and irregular interval neutral fibrillation there's too much electrical activity in the Atria and electrical impulses right from the HM are hitting the AV node at very high frequency and at irregular intervals now the major concern here is look the major concern here is that all this increased electrical activity from the atrium should not pass to The ventricle because if most of these electrical impulses through the AV node pass to The ventricle they will precipitate ventricular tachy arrhythmia a nightmare again atrial tachy rhythmia is not dangerous why because the real cardiac output is maintained by ventricles cardiac output is maintained by the ventricles ventricles are the real pumps Atria are the primer pump if you just play a role in filling The ventricle only 20 percent what is the role of hm the it that listen they are just acting as a primer pump ventricular 80 filling is passive initial contraction contribute only 20 percent of ventricular Phelan if a patient is having atrial fibrillation then electrical activity in the atrium is so fast the mechanical activity cannot catch up so fibrillating Atria even though electrically very fast becomes a mechanical failure so fibrillating HR don't pump is that right but still cardiac output is maintained well due to which activity ventricular activity now if lot of electrical impulses from The Av node pass to the failing heart or ventricles then ventricle will develop tachyarrhea and you know if ventricular electrical activity goes beyond a certain point then ventricles also fail as a mechanical pumps is that right so the first line line of management should be that we should terminate the atrial fibrillation but if we cannot terminate the atrial fibrillation atrial fibrillation the resistant they are refracted refractory they are persistent then we are left with only with one choice that we inhibit the AV node so that lower story should be protected from upper story and electrical dysfunction again the only choice we are left with is that we should give some drug which can inhibit the AV node so out of 400 400 impulses 350 plus impulses or out of 400 impulses only may be 70 or 18 pulses should go down so that ventricular response rate should be under control so that atrial fibrillation does not precipitate ventricular right so if some patient has left ventricular failure with that he's having atrial fibrillation digestion makes a wonderful drug why because already you know that digoxin loads the myocardial cell with calcium so it increases systolic contraction so it is good for failure right secondly you know that digoxin right it stimulates Vegas also when it stimulates the Vegas vagus actually when vagal tone to AV node is increased when wiggle tone Vega you know digoxin increases the Regal input to asinode and AV node both right and when AV node is under digoxin induced stronger vehicle stimulation vagus inhibits Ivy node so until patient is digitalized Vegas is over stimulated it is inhibiting the AV node and it does not allow the AV node to take too much emphasis from The Atrium to The ventricle right so what we learn now digoxin is primarily to function it is positive inotropic drug as well as this is Wego tonic drug and this special combination of use right this combination of action of the digitalis or digoxin can be used very successfully in the patient who has heart failure along with HL fibrillation so heart failure will be managed by positive anotropic action of the drug and uh atrial fibrillation if it cannot be corrected then Vegas is of course stimulating the vagus so that even node should be inhibited through the vehicle action and if you notice kept inhibited constantly then even if it are fibrillating there are very few impulses going down a ventricular response rate is under control and the risk of that atrial is reduced this risk is reduced am I clear right no confusion right then another situation which is very interesting uh you know that when you are digitalizing the patient attention please when you digitalizing the patient you are loading the even atrial cell with the calcium not only myocardial cells are loaded with calcium myocardial ventricular cells are loaded with calcium but atrial but atrial myocardial cells are also loaded with extra calcium and this extra calcium which is loaded over here right that irritate electrically the Atrium so sometimes a very strange situation occur that patient who come with atrial flutter plus patient has ventricular tachycardia right if you give him digitalis or digoxin then atrial flutter May convert into because it has irritated so it may convert into atrial fibrillation the actual flutter is electrical activity around 252 350 minutes again irritial flutter is when electrical activity in the atrium is somewhere between 252 350 per minute and atrial fibrillation is that electrical activity in the atrium is more than 350 per minute is it clear now there is very interesting situation when you give digoxin it irritial flutter May convert into atrial fibrillation but but ventricular tachycardia may be reduced response rate response rate in ventricle is reduced so if patient was having atrial flatter after digitalization May convert into atrial fibrillation apparently it looks bad but at the same time digoxin inhibits the AV node due to that reason a ventricular tachycardia let's suppose it was 180 beats per minute right it becomes only 80 beats per minute so this is one of the very classical situation in which patients come with atrial fibrillation with ventricular tachycardia right you give you digitalize the patient and then what happens that it will flutter May convert into fibrillation right apparently it looks as if patient is deteriorating but actually the real aim of therapy is not at the atrial therapy aiming at controlling the ventricular response rate right so by by inhibiting the every node digoxin Universal impulses going from the Atria to The ventricle right so what we see look here here it will flutter was leading to ventricular tachycardia after the drug it it has gone to atrial fibrillation but there is no ventricular tachycardia rather ventricular it is controlled response rate in ventricles the response of The ventricle to the electrical impulses coming through the AV node right now we come to the adverse effects of digoxin what are the side effects of digoxin already you know that digoxin has two mechanisms it's worth repeating again and again it loads a myocardial cells with calcium so it has a tendency to over stimulate the electrical activity in the Atrium and ventricles but at the same time it stimulates the vehicle output due to that reason it slows down the acinodal electrical activity and inhibits electrical activity in the AV node digitalis toxicity or side effects right adverse effects are side effects of digoxin now this topic is very important the reason being if some a patient developed digitalis toxicity it is potentially a fatal complication and with proper management you can save the life of the patient right when we talk about side effects of digoxin ah number one side effects may occur in the git [Music] right as you know it stimulates the weight as it produces autonomic upsets right so autonomic Supply to Jade is also irritated and it may produce anorexia nausea and vomiting right this drug May produce anorexia nausea and vomiting again no need to remember it most of the drug do that the second is the most important problem this side effect everyone there's so many drugs which do but second side effect is the most important these are cardiac side effects right cardiac side effects now let me draw a heart here and let me tell you what are the cardiac side effects now what are the cardiac side effects again basically on SA node it act as inhibitor you know by vehicle stimulation as the node is inhibited and again by vehicle stimulation it act as inhibitor to the AV node as well right these two actions are due to Virgo increased vehicle activity right but because it loads the myocardial cell with the calcium due to that reason it stimulates stimulates myocardium as well as it stimulate ventricular myocardium of course the stimulation is mechanical as well as electrical this mechanical stimulation is useful for us this mechanical stimulation right myocardial contract more strongly and there is also electrical stimulation because when myocardial cells are loaded with the yes please calcium the restroom membrane when these cells are loaded with cations or calcium then resting membrane potential become more near to threshold and sometimes estimated potential touches the threshold and myocardial cell develop a normal automaticity they develop an increased tendency for abnormal automaticity so in the Atria and ventricle abnormal electrical and ventricle right these ectopic Focus every start and the atrium in The ventricle they may produce initial taxi arrhythmias right now listen that they can produce it shall take your arrhythmias neutral tachycardias rather atrial premature beads right it will tachycardias atrial flutter and even flutter May convert into HL fibrillation so this is progressively getting more worth because if you wait till myocardial cell occasionally fire this is actual premature beat if they start regularly firing fast then we say there's actual tachycardia but if firing rate is more than 250s between 250 to 350 then we say there is atrial flutter is that right then we say there is actual flutter and if a rate becomes electrical stimulation become more than 350 per minute then we call it ritual fibrillation in the same way when ventricular electrical is stimulated patient may develop increase ventricular premature beats for example there is an ectopic Foci right overloaded with calcium and occasionally firing ventricular premature bead or if it is regularly firing fastly this topic Focus this may lead to ventricular yes tachycardia that may lead to ventricular tachycardia and stimulation electrical stimulation become faster and somewhere between 250 to 350 per minute then we say there is onset of ventricular flutter but if dude if there are multiple ectopics okay and all of them are firing simultaneously and there are 100 more than 350 electrical impulses in The ventricle per minute then we say there's onset of ventricular fibrillation which can be fatal onset of ventricular fibrillation which can be fatal is that right now at the same time if there is too much effect on S Note right then it may produce sinus bradycardia bradycardia because asinode is inhabited or if it's too much inhibited it may produce sinus rest that there's no acinodal activity as anode failed to fire in the same way when there is too much evenodle inhibition what will happen it may lead to Noodle blocks noodle blocks because current from AV node is not going down appropriately you know normally current from the Atria go to The ventricle through a normal evenural delay normal Avi nodal delay is about 0.1 second but when even node is inhibited by increased digoxin mediated vehicle activity right then inhibited AV node may pass less current from media to The ventricle it may produce heart blocks noodle blocks or other name for the same situation is yes heart blocks or another name for the same situation as junctional block junctional blocks so we can say that digitalis by increasing the vehicle activity on the AV node can produce noodle blocks or hard blocks or junctional blocks now in this particular case one point which which we need to understand is that if every impulse from listen if every impulse from The Atrium goes to the ventricle if every impulse from The Atrium is going to The ventricle but with undue delay but with undue delay right because the situation is called first degree heart block so what is first degree heart block when every impulse from The Atrium is going to The ventricle but with undue delay for example normally pulse which is coming from HDI and going to The ventricle should be held at AV node only for point one second but if every impulse which is going from hm to The ventricle if it is held here for 0.2 second but always released then it means this is first degree heart block so when digitalis toxicity start first initially uh first degree heart block will start after that what will happen that some impulses will be allowed to go down from Atria to ventricle and other impulses may be totally blocked and not allowed to go from a chair to The ventricle it means block has increased right for example out of 100 impulses 13 pulses of 15 policies go down and 50 do not transmit through every node right so it means now block is increased and some of the atrial impulses are conducted Through The ventricle and other uh other initial impulses could not pass through the inhibited AV node right so this is called yes second degree heart block so what is the difference in first degree and second degree heart block in first degree every impulse from Atria passes through the AV node and goes to the ventricle but every impulses most of them pulses are unduly delayed right but in case of second degree heart block some of the impulses will reach from Venture from ATR to The ventricle through the heavy node and other impulses will be aborted or other impulses will be failed to pass through the AV node then if the molotoxicity develop even would become too much inhibited then none of the atrial impulses will be going down if none of the HL impulses go down to the ventricle this is called yes please third degree heart block in patient with a third degree heart block we will usually we need artificial pacing of the heart right we need the pacing of the p-a-c-i-n-g pacing of the heart Now by all this discussion what you really see that the positive point was that it was increasing the mechanical activity of Atrium as well as increasing the mechanical activity of ventricle these were the two positive thing but over stimulation of Atrium and ventricular thing right that lead to tendency of Israel Tech Academia and ventricular tachythmia right so it will take it and ventricular direct action of digitalis by loading these cells with the cations but there is also a tendency for sinus bradycardias as well as noodle bradycardias in case of sinus bradycardias and nodal bradycardia why it is there this is indirect action of digitalis or digoxin by stimulating the Vegas Vegas which inhibits that right so these this is then third type of side effects are and the central nervous system even though the major action of this drug is in the major action of this drug is on the heart but did you tell us also disturb the electrical activity in the central number system and when electrical activity in the central of a system is Disturbed that may produce Central of the system side effects for example it may produce fatigue right it may produce fatigue it may produce headache right confusion delirium okay let's clear this terms what is meant by confusion what is meant by confusion yeah patient is disoriented in time place and person patient is disoriented who they are who are the people around them where they are uh what are the time what is the day right so patient is confused or we say that the patient is disoriented and time pleasant person and what is delirium what is delirium yes vector what is delirium no no Panic is an art delirium yes Jamie what is delirium it is transient acute confusional state with Hyper excitability write it down someone is acutely confused with a hyper excitability then we say he is Delirious yes no they are more confused and they are acutely confused and with that they are hyperactive right for example if a person is Delirious he look at you and he feel you are a very big lion coming to him and he jumps away from the bed and run away right it means he's hilarious he because he were confused he could not could not perceive you well right even the doctors may be perceived as angels and confusion or they may be perceived as something very dangerous and patient may run away from the bad River from the operation table when he is Delirious or once I have seen a patient who was delirious that he put a big slap on the person who was doing physical examination of the patient because he thought that maybe doctor is exploring something inappropriate in an inappropriate way right so patient was confused so he really had a chance to misbehave right yeah uh if uh one person half of the lady can be fill the panic look a panic is a medical term uh which is used for very severe acute anxiety Panic is a medical term which is used for very severe acute anxiety but during the Panic patient is well oriented in time place and person and delirium patient is not aware what is the time what is the place what are the persons around right he is misperceiving everything with that he is severely acutely confused and he's hyperactive some patients are acutely confused and they are drowsy they are not going to beat you but if there's a patient who is severely confused and hyperactive and he perceived Victor as a big cat then either he will run away or he will jump on you depend on his cat lover or not is that right so what I'm saying the Delirious patients are acutely confused hyper excitable hyperactive patients right then another thing is that these patients May develop blood Vian this is this Blood VN may be due to autonomic disturbance to the ciliaris and with the blood VN some patient may develop even yellow VM yellow VN that they think that every color shade has some yellow shade right and even Sometimes some patient under the digital stocks toxicity they may perceive things are too small we call it micropsia or the thin they perceive the things which are too big then their original size you call it macrobesia right so what really happens is sometimes some of the patient micropsia or macrobesia macrobes CR right in micropsia for example you are six feet tall but the patient is having microbesia he may feel you are only four feet tall or if he has a macrosia he may feel that you are nine feet tall is that right so these are again distortions in the processing of visual information in central nervous system is that right so these were the side effects but discussion of side effects of digitalis should never be completed until you don't know that under what circumstances patient has high chance to develop toxicity and how to treat and prevent toxicity and how to treat toxicity now right so now I will talk about the circumstances which act as a predisposing situation for digitalis toxicity as I told you that digitalis has a very very narrow you can say therapeutic window and the difference between the therapeutic dose therapeutic concentration in the blood and the toxic concentration in blood is very less because therapeutic concentration and the toxic concentration are very near so if you don't manage this patients carefully they tend to go under toxicity and again toxicity is having risk of death due to these ventricular tachy arrhythmias is that right now we will learn that why some people have more chance to develop digitalis toxicity and how we can prevent that and if toxicity develops how to manager manage it right so now we shall talk about the what are the conditions in which which act as predisposers for digitalis toxicity the most important single most important point if you have to remember is the potassium level in the blood Let Me Explain how you remember in the beginning I told you that if this is myocardial cell and this is sodium potassium 80 pairs is that right and I told you that digitalis will bind here and do its action digoxin digoxin will bind on the sodium Prussia midi phases and you can imagine ah just for remembering purposes that potassium and digitalis compete at the sodium potassium 80 phases it's one of the very easy way to remember that potassium and digital srn competition digitalis mean digoxin right here so they are in competition to bind with it now due to any reason if patients develop hypokalemia if your potassium levels go down what will happen digoxin has less chance to work or more chance to work more chance to work yeah and if digoxin is working more it will overload with cell with pathological amount of calcium and that may precipitate uh with dangerous arrhythmias is that clear it's so easy to understand that potassium levels are extremely important in these patients because patients who are in heart failure if their potassium level is fluctuating too much you cannot digitalize the patient in a stable way because if due to some reason they develop hypokalemia then with the same concentration of digoxin in the blood there will be extraction of digestion for example if my potassium level is 5 Milli what is the normal potassium level normal potassium level is between 3.5 to 5.5 Milli equivalents per liter and you must know all of you right as you know your own names because a little fluctuation in potassium level can be Federal for the patient right what is the normal potassium level it is somewhere between 3.5 to 5.5 Milli equivalents per liter now let's suppose if my attention plays if my potassium level is 5 ml equivalents per liter and you digitalize me and then my blood concentration of the drug is okay and you get the desired action but after three weeks due to some reason my potassium levels go up the same therapeutic dose and therapeutic concentration of the drug May convert into toxic concentration because when potassium will go down in my blood then it tells us extra chance to work on these sodium potassium 80 phases load these cells with extra amount of calcium and too much calcium uh you know that it electrically irritates these cells and there's a higher risk of tachy regimenas question is this that why why the question potassium level will fall answer is most patient who are ventric heart failure patient they are already under the yeah diuretic so whenever you digitalize the patient the chances are patient is already on diuretics and if you really know Loop diuretics and thiazides they are potassium wasters do you know that or not Loop digenetics and thiazides right these diuretics ah lead to they lead to loss of potassium in the urine so a patient who are on Loop Diuretics and thiazides they have attained density to develop hypokalemia and if at the same time these patients are digitalized and patients develop hypokalemia then digitalis toxicity will set in amicler you are not clear listen I'm a patient with cardiac failure right my potassium is 5 Milli fluids per liter and you are just a digitalis dose and get the good therapeutic action and my heart start working good right you are happy and you I'm also happy now because I'm a cardiac failure patient so I must be already on the diuretics also and if I'm using diuretics there's a probability that if you are not giving you are not taking care of a potassium level or if you are giving me Loop Diuretics or thiazides there's the tendency that I will develop hypokalemia right because either potassium wasting diuretics and when my potassium level will go down from 5 to Let's suppose ah three Milli equivalent per liter then this previously good concentration previously the therapeutic concentration of digitalis will now convert into toxic concentration because potassium level has gone down and potassium is no more opposing the action of the digoxin a digoxin will work more and it will produce toxicity is that right am I clear yes properly digestion excellent understand it eventually that we have to maintain potassium level very carefully within the normal range without much fluctuations if you really want a very good digital section excellent production should be high yeah potassium should not fall down even should not go up even hyperkalemia is bad right but hypokalemia is more dangerous hypokalemia and how you can prevent hypokalemia hypokalemia can be prevented by giving supplemental potassium or to Loop Diuretics and thiazide diuretics you can add potassium separin diuretics you know potential spraying diuretic we do not allow the potassium wastage rather retain some potassium in the body like spironolactone or a myloride or Triumph terrain right so spironolactone or triumphyrin or myeloride these are potassium sphere in the ureters so it's very wise that when a patient has severe heart failure and you are going to digitalize the patient it's wise that with the production of wasting diuretic either you give supplemental oral supplemental potassium or you combine these potassium wasting diuretics with the potassium sparing diuretus so their potassium level remain stable another ion is that which is like potassium competing with digoxin is magnesium so magnesium level should not fall also and magnesium is usually wasted when you have very severe vomiting for example if a patient start did you tell us toxicity he will develop nausea and vomiting and if he is vomiting he starts losing magnesium out of the body and reducing magnesium also increases the toxicity of digitalis right so we have to take care about the potassium level as well as we have to take care about magnesium lava then another important Point are you understanding are you going conceptually or you are just yeah you are really going now another thing it is written that it is written that even calcium level in the blood influence the toxicity of course digoxin loads the calcium and if you develop hypercalcemia toxicity is more or less more yes you are so intelligent to guess it that patients who have hypokalemia or a hypercalcemia have higher chances to develop toxicity right so if you're why because if you have high level of plasma calcium then digitalis will extremely overload the cells and precipitate arrhythmias is that right which may be fatal so yes please what's your question before to give give a passion digitality you have make uh Epson excellent he has a very intelligent comment he's saying before digitalizing a patient is it good to take potassium level and calcium level and magnesium level I don't say it's good it is absolutely mandatory to take the potassium level no wise doctor ever starts giving the digitalis to the patient without without knowing the Baseline potassium level is that right I told you in these lectures I'm teaching you step one as a step two as well as step three plus I'm making you a good doctor yes I think all of you love digital as toxicity is there any special relation with you yes Jamie you have any special question yes no magnesium level really the risk is too low potassium level can be high and low calcium level can be higher and low usually there's hypomagnesemia and that is due to vomiting is that right so when will manage the toxicity of vomiting will be okay and magnesium will be corrected now so now you understand that what can produce toxicity number one by reducing the electrolyte competition for digoxin by reducing the magnesium and potassium number two toxicity can be done digitalis mediated arrhythmias can be precipitated by helping the digoxin to load extra amount of calcium for example to increase the calcium in the plasma any person who develop hypercalcemia is a higher risk of developing digitalis toxicity is that right then of course one more thing do you know some other condition which can load the myocardial cell with calcium why don't you tell me yes other beta1 stimulant beta1 receptor stimulant in very after a few minutes I will told to tell you that a patient right patients who are heart failure patient they can be treated with dopamine or dobutamine last time we discussed the heart failure patient can be treated with dopamine and dobutamine both of them can stimulate beta1 adrenergic receptor and overload the cells with calcium you remember pathway dopamine and dopetamine or epinephrine will stimulate beta 1 hydrologic receptor stimulate G stimulatory then adrenal cycle is increased intracellular cyclic amp that will stimulate protein kinase a and protein kinase a will phosphorylate the calcium channels and more calcium will be coming in what does it mean whole story it means that with digoxin which is already loading the calcium if other calcium loading conditions are combined toxicity will be precipitated so patient who is digitalized if you develop you can say very severe a sympathetic overflow he has a chance to develop ment or he is given others sympathomimetric drugs which are beta1 stimulant like dopamine or dobutamine he has a very high risk of developing toxicity so we can say sympathomagnetic activities in patho mimetic activities right because the pathomagnetic activity also loads the myocardial cells with calcium especially if it stimulate beta1 adrenergic receptor we stimulate beta1 adrenergic receptor when the stimulate the beta1 electrologic receptor like this may be endogenous epinephrine okay let me write it this may be endogenous epinephrine or norepinephrine are it may be yes dopamine which is used in cardiac failure sphere cardiac filler or dobutamine the buta Main right so these can also load these are also calcium loaders right and if somehow Unfortunately they are combined with the digitalization the natural risk of digitalis toxicity is very high can you tell me one more condition which can load the cells with cations please tell me myocardial ischemia you remember that myocard during sphere myocardial ischemia infarction myocardial cell membranes are disrupted a lot of calcium and sodium may be loaded inappropriately in the injured cell at the Top If patient is already digitalized there will be onset of very very dangerous ventricular tachy arrhythmias let me repeat it you know disrupts a cell membranes right and when cell membranes of myocardium are not working well then they accumulate lot of sodium and calcium and at the Top If you are digitalizing the patient also then both in together put so much cation in the cells the dangerous tactical arrhythmia may be precipitated yes please Jamie of course now Jamie comes with a very wonderful idea he says that should he digitalize the patient with a hyperthyroidism answer is no because in patient with hyperthyroidism increase T3 T4 he has a very big trouble what is the trouble patient no patient who have hyperthyroidism t3t4 go into myocardial cell and stimulate the genes of adrenergic receptors so under the influence of increased T3 and T4 myocardial cells Express extra amount of adrenergic receptors and they are over sensitive to hydrologic Drive endogenous heterological drive and they are already overloaded with calcium at the Top If You digitalize ventricular tacherymia will start so patient with ah thyroid toxicity right a patient with thyroid toxicity is should not be given you can say digitalis so we can say for digoxin thyroid toxicity is contraindication why I can repeat it that if a patient has right high level of thyroxine circulating thyroxine if means patient has thyrotoxicosis this T3 T4 can go into myocardial cell even go into myocardial nucleus and myocardial cells nucleus t3t4 bind with the receptors and those receptors over Express the genes for adrenergic receptors so actually under the influence of excessive tct4 myocardial cells Express extra beta 1 adrenergic receptors on their surface so myocardial cells becomes sensitized to the endogenous epinephrine and norepinephrine is the right with normal level of endogenous epinephrine and norepinephrine myocardial celled by virtue of having more receptors or oversensitized and loaded with the calcium right at the Top If You digitalize the patient I think there's a formula to kill the patient is that right increase yes you're right it's a very simple thing that anything which loads the myocardial cell with cation is contraindicated for use of digitalis why don't you tell me myocarditis someone has inflamed myocardium if someone is suffering with acute myocarditis and heart is failing please in this failure don't give digitalis because when there's myocarditis myocardium is inflamed then myocardial cells are again getting more they are injured if myocardium is inflamed it means myocardial for example you develop very severe viral myocarditis or you develop very severe romantic fever myocarditis is that right now myocardium is severely injured and inflamed so it is loading less great eyes or more cations more cations should we use digitalis answer is no right so in patients with myocarditis a patient with Rheumatic fever-related myocarditis so viral myocarditis a patients who are having this severe ah ischemia to the heart a patient with thyroid toxicosis we should not use digitalis as inotropic agent right then so what we really see that we have to see when we use the digitalis remember this drug is very dangerous this drug is very dangerous so you have to always look at electrolyte balance electrolyte balance you need to look at concurrent illnesses illnesses like there should not be rheumatic fever they should not be thyroid toxic causes there should not be any situation which can stimulate the heart and with that you must look for yes you must look for other drugs which are contraindicated other drugs used other drugs used for example quinardine should not be used quinardine I will explain why it is a quinardine is antiarismic drug in patient with the which are digitalized grenadine should not be used a myodorant should not be used Verapamil should not be used amiodaron and Verapamil there are multiple reason number one these drugs can reduce the renal clearance specially grenadine so digitalis will accumulate in the body these drugs can reduce the renal clearance of the drug so drug cannot go digital digoxin cannot go out of the body through kidney and it accumulates in the body secondly these drugs can displace the digoxin with the plasma protein binding so if you give these drugs and they rapidly displace the digoxin from the plasma protein then toxin level of digoxin will be free to work on the myocardium and precipitate toxicity right and precipitate toxicity after having said all about you know that what happens in digitalis toxicity why they develop tachythmias and you know what are the special precautions when you are using digoxin now we can do that if you come across a patient who is already having digitalis toxicity or digoxin toxicity how you are going to manage that patient now how you are going to manage that particular patient of course the very one very first step should be stop digoxin don't give any more right management of digitalis toxicity management of digital is toxicity first of all stop digoxin and of course at the same time check the serum electrolytes check serum electrolytes especially potassium magnesium and calcium right and correct the electrolyte balance sometimes simply correcting the electrolyte balance for example if patient has severe hypokalemia and you correct the potassium level right digital toxicity will be under control right if there is mild toxicity then if patient has already developed severe tachy arrhythmia you can use antiarrhythmic drugs you can use antiarrhythmic drugs and drugs which are most commonly used are phenytoin drugs which are most commonly these are sodium channel blockers phenertoin or the you can use lidocaine or lidocaine this is also sodium channel blocker because if you block the sodium channels then Action potentials cannot be produced voltage-gated sodium channels are blocked by so you can say phenotion and Lidocaine are so voltage-gated sodium channels plug they plug the or block the channels so that action potentials cannot be propagated well and generated well so they reduce the generation of action potential as well as propagation of action potentials right and of course you will not use grenadine as antiarismic here no because that will displace the further digestion and put produce a very big trouble right then you need to if there is very severe third degree heart block right then you need to facing for the patient artificial patient piercing for third degree heart block facing for the third degree heart block but before pacing we try atropine sometimes simply given giving 0.6 milligram of atropine ah atropine you know what it is doing what is the function of atropy yeah it blocked The muscarinic receptors and when it blocked the muscarinic receptor then increase with vehicle activity cannot work on acid node and AV node right so you know Vegas is a style choline style choline work through muscarinic receptors so atropion is a musculinity receptor anticholinergic drug muscarinic receptor blocker and when muscarinic receptors are blocked that will end up into what loss of action of Vegas on the evenode and acid node and heart block will be terminated if AV node does is no more internal phase of style choline right if atropy does not solve the problem then you need to go to the Basin and you know look Vegas digital stimulates the Vega and Vegas stimuli stimulated vagus releases too much style choline on acetode and AV node and acetylcholine work on muscarinic receptors and if AV node is too much inhibited cardiac block or heart block will occur is that right now one way is that you block the musculinity receptor so that increased physical activity and increase acetylcholine cannot work on a window is that right to block the muscarinic receptor the drug is atropine am I clear right then we can talk about immunotherapy a very special type you know we have made antibodies this is a structure of antibody uh these are what is antibody antibody has two heavy chains and light two light chains held together by yes disulfide bonds they are held together by disulfide bonds is that right actually uh it is a scientists have developed antibodies against the did you tell us they have developed antibodies against the digitalis now this portion of antibody is called Fab the fragment which bind with the antigen and this is called FC fragment now what we really do that scientists have developed antibodies against the digoxin so that these antibodies can bind the digoxin here and bind the digestion here right and this tail FC portion is digested away so this antibodies available like this right this antibody is called that Digi bind what is the name of this antibody DG digoxin bind Digi bind right what are these these consists of ah Fab portions fragments antigen binders right and what is antigen digoxin so you give injection of this immune material that is Fab antibodies or DG bind to the patient right so that it can go and bind with the digoxin and then the digoxin no more available to act on The myocardium is that right there is one problem the digestion is a long Half-Life and did you find DG bind has a relatively shorter Half-Life because digibind has shorter Half-Life so what really happens that we have to repeat this injection of this Digi bind again and again until digital toxic stays really terminated am I clear so again in a nutshell how you manage the digitalis toxicity first of all stop digitalis number two correct the electrolyte balance number three that if they are taking arrhythmias control them by phenotion or lidocaine if they are Brady arythmia then you control them with atropine or by piercing and if there is you can say too much toxicity then you will go for what thing ah DG bind right and they will neutralize the digoxin which is there right is a brand new card here no some patients may be in sphere some patient may be in cardiac block some patient may have irriterial tachycemia with noodle blocks the classical presentation is the classical and characteristic situation is that patients who come with atrial tachycardia with AV nodal block if patient has atrial fibrillation with evenodle block it is digoxin toxicity until proved otherwise am I clear now we shall talk about other ionotropic agents right other ionotropic agents are basically two classes one class is the other ionotropic agents which work through beta eternergic receptors we call them beta adrenergic Agonist beta adrenergic agonists right uh for example dopamine and dobutamine do butamine dobutamine and dopa mean right and another group which is there is that is called phosphodiesterase inhibitors they are called phospho diets inhibitors right and the drugs in this group are amarenon and milrinone and memory the point which I want to highlight that these two groups energy agents Agonist and phosphor digesters Inhibitors these are used parentally the only orally active ionotropic agent available in USA is digitalis group digoxin right and these drugs are used parentally first I will talk about the mechanism of action and then few important point as you already know the parent row means that by not orally they are given either intravenously or intramuscularly right now let's talk about how the beta energy drugs work you know that here is beta Technologic receptor we have already discussed just a little repetition right that this will stimulate G stimulatory protein G stimulatory will stimulate yes this will stimulate G stimulatory protein especially Alpha stimulatory and Alpha stimulatory will stimulate yes adenylial cycle is that will stimulate adrenaline cyclase and this adenylial cyclase will convert yes ATP into cyclic amp right so whenever there is adrenergic receptor stimulation what is this receptor beta1 adrenergic receptor just one whenever beta1 electronic receptor is stimulated intracellular cyclic MP goes up and this cyclic amp stimulate what is this protein kinase a and this protein can is a will phosphorylate this protein kinase a well phosphorylate with channels this will lead to phosphorylation of calcium channels this will lead to the phosphorylation of calcium channels and phosphorylated calcium channels remain open for longer time and there's increased intracellular loading of calcium and you know anything which load the myocardial cell with calcium will have eventually positive ionotropic action and increases in contract already now the drugs which work through this pathway these are yes these are the two drugs one is dobuta mean another is dopa mean both of them are beta 1 adrenergic receptor stimulant in this way that they stimulate the G stimulatory adrenaline cyclase which increases intracellular cyclic amp Rising Interstellar cyclic amp overdrive protein kinase a which lead to phosphorylation of calcium channels and there is excessive calcium coming into these myocardial cells and you know that excessive calcium will lead to positive contractility uh this this is leading to phosphorylation of calcium channels you know they are leading to phosphate binding calcium channels phosphorylation and when calcium channels are phosphorylated there is increased calcium and flux is it clear now as good doctor you must know what is the difference in use of dobutamine and dopamine right what is the real the butamine and dopamine are different that though butamine has only actually mainly a mainly action on beta1 adrenergic receptors is that right but dopamine has number one action on dopamine receptor less than that action on yes measure action is on the dopamine receptor less than that action on beta 1 receptor and release traction on Alpha 1 receptor this should be very very clear concept let me tell you why dopamine act on dopamineergic receptors as well and dopaminergic receptors are present on renal artery smooth muscle dopaminergic receptors are present on renal artery smooth muscle so this drug stimulate the dopamine receptors and produces renovascular dilatation dopamine can produce Reno vascular dilation and it increases renal blood flow so the very is unique quality of dopamine is that not only by beta1 action attention plays the dopamine not only by its speed of an action stimulates the heart but due to its dopa that it it's not really diuretic uh it it is increasing the blood flow to the kidney right diuretics are increasing the loss of sodium through the nephron now so dopamine has an added advantage over the vitamin that it can act on the dopamine receptors and lead to renal with the dilation and improve the renal blood flow so usually dopamine is a magic drug it's a very useful drug when you have severe cardiac failure with hypotension because someone has severe cardiac failure with falling blood pressure and hypotension he is going into shock you know in shock adrenal vessels construct and renal blood flow become very less and that may lead to acute tubular necrosis necrosis in the kidney again listen let's suppose patient develop cardiogenic heat developed cardiogenic shock and due to cardiogenic shock cardiac output become extremely low it becomes so low that patient has rapidly falling blood pressure if blood pressure is going very much down intense sympathetic activity will be stimulated and this will produce strong renal vasoconstriction if there is strong renal vasoconstriction that will lead to Dangerously reduce blood flow to the kidney and that eventually result into acute tubular necrosis that proximal convulated tubules of the nephrons mandirgo necrosis due to extremely low blood flow and oxygen supply right and that may precipitate a renal failure so again listen any patient who has very severe hypotension has a risk of renal failure you understand it if someone has cardiac failure Plus here's hypotensive episode with that risk of renal failure immediately gave dopamine on one side dopamine dopamine will stimulate heart so dopamine is double action drug number one it is good for heart and number two it is good for the blood flow too right so next time if someone says that your patient is very severe cardiac failure with hypotension and you want to give inotropic sport to the heart which drugs you will give dopamine but if another patient where is your cardiac failure but hypotension is not there the drug is duputamine so these are the minimum you should know about them the most important clinical point it's worth repeating again and again swear card interactable swear cardiac failure without hypotension dobutamine severe intractable cardiac failures systolic cardiac failure with severe hypertension drug of choices dopamine drug of choices dopamine now these vitamin adrenergic drugs they are used in certain special clinical settings for example these drugs are used when there is severe and reversible heart failure for example in patients who are in the cardiac surgery right post cardiac surgery patient post cardiac surgery suppose you have done the cardiac surgery and after the surgery heart is beating very poorly right for a while you can really put the heart on dopamine no it depends on the blood pressure if patient has been under cardiac surgery and heart is having low cardiac output check the blood pressure if blood pressure is not less not falling the butamine if it is falling dopamine other condition is post Mi patient gets severe myocardial infarction and then he goes into shock if a patient after myocardial infarction goes into shock the drug of now what you have to do you have to support the patient is that I know tropically right and again if with the shock he has developed the risk of uh there's too much hypertension then the drug of choices dopamine right yes please if a patient has high blood pressure a postcardic surgery don't use these drugs because increasing the increasing the cardiac output will further increase the blood pressure is that right okay then third situation is another patient who has in where is we are intractable cardiac failure and you have decided for the transplant right so he is waiting for transplant maybe after two weeks during these two weeks you can bridge this time by sporting the patient ionotropically by dobutamine or dopamine depending upon the blood pressure right so third indication is that in refractory heart failure these drugs can be used as a bridge to cardiac transplant these these drugs can be used as a bridge for cardiac transplant is that right now the major problem with these drugs the very major problem with these drugs is that if you are using these drugs for longer time beta1 adrenergic receptors will undergo down regulation look any receptor if you stimulate it too much this may undergo down regulation so if our severe heart failure and you are treating me by dopamine or dobutamine intravenously these drugs are given as intravenous infuriants right sooner or later there will be severe down regulation of adrenological receptors and when receptors undergo down regulation do you think drug will be effective no so problem is the real serious problem with these dopamine and dobutamine is that by using these drugs continuously you lead to the down regulation of beta energy receptors and when these receptors are down regulated that leads to failure of drug action that is why these drugs are mostly used intermittently they cannot be used regularly over the months and years they just enter mitten intermittently intermittently mean they use off and on when patients get into very severe failures use these drugs but you have to wean off the patient from the drug you have to take off the patient from these drugs beta hydrologic receptors and if these receptors are down regulated they disappear from here and they are not functional can these drugs work no so that is why I use this drug for one week then you stop using it then later on whenever patient go into severe cardiac failure again you use it they cannot be used on regular basis the drug which can be used positive anotropic drug which can be used on regular basis and orally that is the digestion clear and again I told you you have to be careful with that drug now phosphodite stress Inhibitors let's talk about this Emery non and melanon they are used only for very short time in very very severe cardiac failure they are never used these days for very long time long term use is absolutely contradicted why they have seen that long term use of memory melanin and Emery non increases the mortality probably it loads the myocardial cell with too much calcium you know the mechanism of action of melanin and emeraldine that cyclic amp is destroyed by an enzyme called into amp the enzyme is phospho ID diastrases these phosphodiesterases are inhibited by these phosphodiesterosis which break down the cyclic MP these phosphor digest traces are inhibited by yes inhibited by melanon and Emery known right yes coffee can also do the same thing that coffee caffeine can also inhibit some of the phosphodite stresses that inhibits very mildly and increase uh slight increase in cyclic amp right when you juice coffee caffeine right but they inhibit phosphorus diastrases strongly increase intracellular cyclic amp which again translate into more phosphorylation of calcium channels and further loading of the calcium which will act as positive anotropic situation right so this was all about the positive inotropic agents all the positive ionotropic agent increase intracellular calcium load in the myocardial cell only orally available is digoxin and others are available parental use right among them these are used intermittently these are used only when patient is intractable failure where dopamine and dobutamine are not working well and we add this drug melanon and amarenon phosphodasteride Inhibitors are always used for short term because long term use increases mortality