Antianginal Drugs Pharmacology | Dr Najeeb

now today we will be discussing about anti-anginal drugs but before I really start the drugs I will briefly review about the pathophysiology of important type of anginais right first of all I will Define that what is angina angina is one of the very common symptom of cardiac ischemia what is angina and genome is a Indian is a symptom of cardiac ischemia how we really Define angina right angina is it may be pain it may not be pain look it is angina is a central chest discomfort or pain which may be just like pressing pain or weight like discomfort or band like discomfort or like a heavy weight on the chest and this uncomfortable feeling in the chest may be radiating to one arm or to the both arm or to the neck or to the jaw or to the epigestion or may not radiate at all or may be felt only in the area of radiation again let me explain what is angina right angina means and China is a clinical syndrome resulting from transient reversible cardiac ischemia it is resulting from transient reversible cardiac myocardial ischemia clinically present as Central chest pain or chest discomfort right and this feeling is less like a pain more like a weight or like pressure on the chest or like a constricting band on the chest or sometimes as a burning sensation right and this chest discomfort or so-called pain meridiate to one r or to the both are or to the neck or to the jaw or to the epigastrium or may not radiate at all or sometimes may be felt only in the area of radiation and why it is there it is due to transient ischemia of The myocardium is that right due to imbalance in oxygen supply and demand when oxygen supply is less to The myocardium and demand is more and oxygen supply needs of myocardium are not met with that may produce the symptom symptom complex but a very very important point is which I have not mentioned yet about angina is the duration about in China typically angina should not last more than 20 minutes this cutoff point is very very important usually angina lasts somewhere between 15 second to 15 minutes usually most of the angina last somewhere between 15 second to 15 minutes foreign which I want to really plant in your mind is that angina should not last or does not last classically by more than 20 minutes why because if severe chest ischemia last more than 20 minutes that will lead to myocardial infarction if we are chest ischemia or myocardial ischemia swear myocardial ischemia last more than 20 minutes then it will lead to myocardial infarction and once there is infarction of course it is not angina because by definition angina is transient reversible scheme of The myocardium which does not lead to death of myocardial cells which does not lead to necrosis of myocardial cells now typically there are three types of anginas right there is classical in China classical angina classical Indiana is also called typical angina and classical Indiana typical angina or another name for the same situation is yes please stable angina stable angina and still another name is exertional angina desertional angina right this type of angina which is classical angina or which is typical engineer or which is called stable and our exertional in China it has a special type of pathophysiology under it right now let me tell you what's wrong with this patient let's suppose this is a left ventricle now here is the coronary artery suppose this is the coronary artery and this has a atherosclerotic plaque the scoring artery has atherosclerotic plaque and this plaque atherosclerotic block is obstructing the Lumen more than 70 percent if atherosclerotic plaque obstruct the Lumen more than 70 percent then it is quite possible that blood flow through the narrow area may be enough during the resting stage when patient is resting the little blood which is coming through the narrow area may be enough for the resting myocardium but as soon as there is increased work of The myocardium for example when patient is doing some exertion or due to some emotional stress or any reason if heart rate goes up right then if there is increased work of The myocardium then this stenotic point cannot dilate and this point does not allow extra blood for The myocardium which is demanding more oxygen due to increased work and then relative ischemia will go up again let me tell you exactly what happens let me make a diagram if I remove this piece of myocardium outside this is a piece of myocardium right this is the vessel coronary vessel now in this coronary vessel let me repeat in case of which angina classical Indiana there is atherosclerotic plaque and this atherosclerotic plaque will produce symptoms of angina when it is obstructing more than 70 percent of the lumen if 70 of the Lumen is blocked by this block right that will that may produce enough blood for the resting myocardium but when myocardium Works extra during tachycardia or emotional upset so when patient is doing exercise or there is any type of increased cardiac work whenever there is increased cardiac work usually the healthy vessel dilate and provide extra blood but this stenotic point cannot dilate so whenever there is more work stress on the heart this narrow Point cannot provide extra blood and this part of The myocardium this is called vulnerable myocardium this part of The myocardium this will become relatively ischemic does that right and this part of The myocardium when it becomes ischemic this is the source of anginal pain or in general discomfort is that right now because this obstruction is stable it does not changes overnight this obstruction is stable so usually the patient's symptoms are also stable for example that patient has really predictable exercise that he can walk so much and then he will get the anginal pain or in general discomfort is that right and this type of angina is always precipitated by exertion or emotional upsides right and usually relieved by taking rest the classical angina is usually relieved by taking rest because just when you when patient who was walking and exalting and myocardium started working more and demanding more oxygen and because this point did not dilate so it could not provide extra oxygen to the extra working myocardium ischemia section start if patients start taking rest right usually within three four minutes or few minutes cardiac work in this area will become so low cardio work in this area after taking rest cardiac work in this area will become so low that it will be able right its demand will be able to meet with the reduced Supply so angina will disappear is that right or other way to reduce this type of anginais by giving the nitrates by giving the nitrates I will explain later how the nitrates work but this in China is very predictably responsive to the nitrates as soon as you take sublingual nitrates right within few minutes your stable angina's pain should disappear is that clear but one point which is very important that if this obstruction become more than 90 percent then even in General Pain may occur at rest because if it is obstructed producing obstruction more than 90 percent of the Lumen only 10 percent of the Lumen is perfusing then this so this this very low perfusion is even not to able to meet the demands of the resting myocardium now this was your classical angina right one more point which is very important about the classical angina is that The myocardium which is more near to the endocardium this is the deepest myocardium is that right and this is a myocardium which is in superficial area this is sub pericardial myocardium and this is sub-endocardial myocardium and this is the middle myocardium now the point which I want to highlight that out of this innermost Zone middle zone of myocardium and outer zone of myocardium first of all ischemia occur to the inner most Zone why because when chest wall is when they sorry this myocardial muscle is Contracting against the blood present in the cavity right this is the innermost layer of The myocardium this layer of The myocardium innermost layer of The myocardium which is compressed by the external myocardium and the blood in the cavity is that right and when this myocardium which is called sub endocardial myocardium is compressed then the micro circulation through this the small vessels through this myocardium is also compressed is that right so whenever heart is Contracting strongly it is the inner myocardium which is most deprived of perfusion right and during even a normal heart the outer myocardium is better perfused and inner myocardium is poorly perfused is that right am I clear to everyone this is few words about classical angina then there is another type of angina and this angina is entirely different than the classical yeah this is Prince Madame jayana I'm going to discuss some of my students are in love with Prince metal right and remember it now look in this case real problem is not the atheroseclerotic layer in this patient atrocyclerotic leaves are not responsible for the symptomatology of angina there may be either very small atherosclerotic lens or there are not actually real problem is that coronary artery has fluctuating tone right now look at it this is the point what has happened there is vasospasticity what is there there is a Vaso coronary artery spasm right and this spasm lead to myocardial ischemia but here the point is very important ischemia will go to the innermost area as well as middle area even outer area is that right because in case of classical angina there were less blood coming and this less blood was preferentially perfusing the outer myocardium and inner myocardium was deprived but when we go to this type of angina which is due to coronary tone fluctuation it is also called Prince Metals angina which is mainly due to coronary arteries plasticity either with a little bit atheroseclerotic lean or with no astrological layer is that right in this case ischemia will occur throughout the wall of The myocardium and this is called transmural ischemia this is called trans mural ischemia is that right the this type of angina is not related with the exertion this type of angina is not related with the blood pressure this type of angina is not related with tachycardia this type of angina May precipitate even with when patient is at rest this type of angina is more common in females I don't know this plastic disease why because spasticity is more common in females but fluctuation coronary artery tone is more common in human females so what really happens that this angina has been called it has two names one is Prince metal angina but there's Metals angina and other is variant angina variant angina now this print metal angina or variant angina this is basically coronary vasospastic angina this is coronary Vaso angina why I am explaining these two so clearly because the treatment of both are slightly different from each other is that right if I draw a big piece of myocardium here here what you will find that coronary artery right it has undergone spasticity so naturally angina is ischemic pain ischemia is present throughout the wall of The myocardium and this ischemical trans Ural ischemia right this was what type of ischemia yeah this is hemia was sub-endo cardial sub endocardial myocardial ischemia is that in only in the deeper part right this is full thickness right now this type of angina is not related with the exertion and it is not relieved by taking rest is that right then we come to third type of angina the third type of angina is called unstable angina and stable angina first let me explain the pathophysiology of unstable angina then I will tell you exactly why it is called unstable angina in patient with unstable angina what is really there there is unstable coronary plaque the astrometers plaque and coronary artery is unstable right let me explain it more clearly suppose this is the piece of myocardium here is coronary artery here is etromatous plaque but the real problem is that this electromatous plaque is unstable unstable mean maybe it has we call such plaques vulnerable plaque vulnerable plaque means which are not stable plaques these are having very thin fibrous cap and lot of inflammatory activity going on within the plaque and such plaque May undergo severe acute changes for example this plaque May undergo fissuring or ulceration or erosion or it may undergo inter-block Hemorrhage any type of acute change may occur in the block and when there's acute change in this plaque then its surface become very irregular and thrombogenic right when this is this plug surface is ulcerated or arrogant or it is fissured or it is ruptured or there is interlock hemorrhages all these things expose highly thrombogenic content from the throma and platelets will stick on that platelets will stick on that let me make it even more clear if I unlike this area like this this is the coronary artery this was the stable plant this was the stable plan here is let's suppose another plaque which is unstable and this plug has very much Disturbed surface right and over this this is the intraplock cholesterol and other things then then superficial layer is Disturbed maybe there is ulceration or erosion or fishing or rupture and then platelet stick on it these are the platelets which are sticking on it just platelet adhesion as well as there is platelet aggregation platelet adhian plus platelet aggregation right and there may be even super super added fibrinogen fibrinogen which is converted into fibrin is that right because of coagulation process the coagulate super added coagulation process converts soluble fibrinogen into insoluble fibrin over the surface of the platelet and when platelet plug is load is having the deposition of fibrin then whole this thing is called thrombus all this thing is called thrombus now look when this Earth thrombus has formed over an unstable plaque this is a right there will be severe ischemia there will be severe ischemia and the severe ischemia right will be initially in deeper part of The myocardium sub-endocardial cardium initially the very sphere ischemia is in deeper part of myocardium but if this thrombus remember if this thrombus occludes the complete Lumen of the vessel then ischemia may become transmural is that right now what you have to remember is that this unstable plaque has led to the formation of little plug and coagulation process over it resulting into thrombo Tech situation so plaque with super added thrombus is a dynamic obstruction this is a dynamic obstruction because platelet and thrombus keep on changing their size right and keep on changing their Mass size so the degree of occlusion is also Dynamic so we can say this clock is not stable because this plaque is not stable at any moment it may develop a thrombos and then thrombos may enlarge and produce severe ischemia this wear ischemia if it lasts more than 20 minutes now listen with open ears if the sphere ischemia lasts more than 20 minutes this will under this my dependent myocardium will undergo infarction and if you treat the patient well within 20 minutes right and due to thrombolysis or there is spontaneous symbolizes or pharmacologically induced thrombolysis within 20 minutes it means infarction will not be there right due to this reason this type of angina is said unstable angina because it is so unstable that if it is not managed well if within if it's a obstruction of the Lumen last more than 20 minutes or 30 minutes it may fall to the category of myocardial infarction is that clear right and this type of angina by definition it is very sphere in China okay write down the definition of unstable antenna unstable angina is severe angina of recent onset or angina with progressively increasing frequency orangana with progressively increasing frequency or angina which is precipitated which is precipitated by progressively reducing exertion or even at rest let me repeat it again what is unstable Indiana unstable in China is a dangerous angina because if it's not manageable it has a high chance to convert into myocardial infarction right it does not remain stable as an angina and what is the underlying pathology of unstable angina it has unstable arithmetal Spark with super added what thrombo's formation and even this platelet May release some vasospastic element and sometimes there is even added vasospastic element as well so how many things are there yeah it may release from books and A2 yes that may produce visual spasticity excellent so it has astrometers plaque which is undergoing acute changes it may develop platelet plug on the platelet plug it may develop deposition of fibrin then there may be local production or vasoconstructor by the Disturbed plaque and the super added thrombus and may lead to visual spasticity is that right and this type of angina if it lasts longer it's very severe pain and well classical you know diagnostic point is write it down this angina does not respond well to nitrates and taking rest because you have to differentiate the patient of stable angina with the unstable angina the classical differences that stable angina patient or classical in general patient as soon as this patient take rest or take nitrates within few minutes pain will disappear but when will go to the unstable angina right unstable angina cannot be relieved by taking rest and cannot be relieved by taking nitrates is that right that is the diagnostic point so whenever you have a patient with very sphere in China and patient is not angina is not disappearing with the taking rest or not disappearing with the sublingual nitrates right the real uh you know diagnostic point is they say when patient has taken sublingual Nitric tablets three times three times within 15 minutes when a patient of angina is taken sublingual nitrates three times within 15 minutes and pain is not relieved and it is unstable angina until proved otherwise it is unstable in China until proved otherwise is it clear now look at the pathophysiology of all these three situations these situations are different because these situations are different their management is going to be different let me tell you very basic clue when you are thinking your strategies pharmacological strategies to manage this patients look attention here classical angina right it is basically precipitated by increased work of the myocardia it is precipitated by increase work of The myocardium so the best therapy should be to reduce the work of The myocardium we have to use those drugs in this case which classically reduce the work of the myocardium right most effective strategy is that angina is due to increased work so we so treatment should have those pharmacological modalities which will reduce the work of myocardium work off Mayo cardium if we reduce the work of myocardium that will of course lead to reduced oxygen demand and if you have reduced the oxygen demand right the management during the acute phases that you should reduce the work of the heart so that there should be reduced oxygen demand and when there is so you have to reduce the oxygen demand so much that reduced oxygen demand become equal to the reduced oxygen supply you have to re-establish the balance between oxygen supply and demand here the art of management is reduce the work of The myocardium so much that reduced oxygen demand becomes equal to the reduced oxygen supply and then symptoms of angina will disappear but when you come to this patient this is due to vasospasticity do you think reducing the work of heart will help this patient no this is the spasm right so art of management the best strategy in this patient is you do coronary weather dilation you have to use the drugs which classically dilate the coronary artery now listen carefully coronary weather do not work very effectively in this case coronary weather dilator work wonderfully for the prince metal angina the best drug presently is foreign but of course nitrates can also dilate the coronary artery if it is pasted but you have to remember here in this case in this case if you use a drug which will only dilate the coronary artery will not be much helpful help will be very little the reason being here arthromatous plaque is a fixed obstruction and atheros metacyclerosis are seclorosis of artery due to anthroma is not amenable to significant dilatation if you give coronary dilator maybe if there is some super added little bits plasticity that may be relieved but because obstruction here is not Dynamic obstruction is fixed so usually by increasing the perfusion of strategies don't work well except either you do big game here for example coronary what is this p t c a that is percutaneous transluminal coronary angioplasty that that may help in this case or you do cabbage that is coronary artery bypass grafting so that you provide the flow around the obstruction right so we can say that because in stable angina atromatous plaque is stable but it is a fixed obstruction so by drugs it cannot be easily dilated during the acute phase is that right but point one thing in the long run these patients should be advised these patients should be advised to reduce the risk factor for atheroseclosure during the acute phase when angina is there right that moment you have to give a drug which will reduce the work of the heart so that reduced work and reduce oxygen demands meet the reduced oxygen supply but in the long long run these patients and rather all of the patients with angina you have to advise for widen the risk factor for atherosclerosis or managing them for example smoking should be stopped diabetes should be managed well hyperlipidemia should be managed well hypertension should be managed well lifestyle should be improved for example stressful lifestyle should be reduced sedentary lifestyle should be reduced exercise should be done so all those advice to prevent the social sclerosis they they are required in all these patients but during the acute phase when patient is really having angina what will help reducing the work of the heart the name of the medication I will go of course the whole lecture will come to this thing and I will tell you how the drugs combinations come and how they interact with each other and what combinations are good in which situations I'm going to make sure good doctor right but first yeah Jamie what's your question yeah yes but if you really want to manage them without drugs then you can do either you pass a catheter into coronary and with balloon angioplasty where you know you stretch out this point and you put a medicated stunt there right that is one treatment which will not discuss today because we are going to discuss the anti and general drugs right uh second is you do coronary bypass graft right when you come to this situation the best do you think in this case we need ptca no now you know by Logic you know that in this situation with a you don't need to do ptca and of course here you don't need to do cabbage there's no bypass there's no fun in doing bypass grafting just give the drugs which keep the coronary artery dilated that's it now we come to this drug this type of situation this this type of patient really tests to your medical you can say knowledge and competence right the test of your medical competences by the patient with unstable angina only good doctors manage them in a good way first you have to understand pathophysiology before we start the management there are four components in this whole game you know Leon is here this is the area which is involving the lion right now what are the points here number one there is a throma stable or unstable which is unstable undergoing acute change this is one problem number two there's platelet aggregation platelet aggregation and plus fibrin deposition leading to thrombus formation plus there may be added component of whether spasm now what should be the strategies to manage this patient first of all first of all you should give the drugs which disperse the platelet from there thrombolytic drugs anti-platelet agents what do you think look here do you think in these two cases you need anti-platelet agents immediately no but remember in the long run we also give them aspirin as antipolated agent because you never know when this plug may become unstable in future but if you put this patient on aspirin right future risk of convert conversion of this stable angina into unstable will be reduced but the point which I want to put in your mind that in this case is that treatment modalities are anti-platelet drugs antithromolytic drugs anti-platelet or anti thrombolytic drugs you understand why you want to dissolve the thrombus as soon as this patient come you ask him to chew aspirin the simple aspirin does Wonder right because it will not allow more platelet to stick on this obstructed point right antiplated drugs should be given of course there's more such serious situation in acute phase you need to give oxygen and more important than that again you have to reduce the work of work off myocardium hard plus you have to give coronary artery dilator in a nutshell look to me in a nutshell an unstable Engineers you have to do everything what you do in stable angina Plus very important point you have to give some drugs which should be able to dissolve the thrombus and the thrombolitical drugs are of course not required in stable angina and they're not required in transmitter am I clear any question here no question now I will discuss into detail that what are the methods to reduce the work of myocardium is that right because this is the work of The myocardium which determines the demand of the oxygen and in these patients ideally we should increase the supply of oxygen and we should decrease the work of the heart now we'll talk about what are the determinants of the work of the heart then we will see how drugs modify the determinants related with the work of the Heart Is there any question no there are many ways to explain the work of the heart but I will explain in a very very simple way right in the terms of preload afterload right so and contractility now I want to know what is your concept of preload what is preload have you heard of the term of freeload when we talk about cardiovascular system what is preload you don't feel what is okay Raul is going to tell us what is after load or preload s okay okay I will tell you first first I will give you an analogy you know your heart is a donkey you don't know it I will tell you our heart is like a donkey like it does donkey work all the time pumping the blood all the time taking from the venous side pumping into arterial side right and we will see what are the problems of an ischemic donkey malnourished donkey and how you can help a malnourished donkey is that right look this is good you have friends as donkeys then you must be protected from lot of nasty things it's good to have donkey friends right now listen listen attention plays here is your heart I don't know how to draw a good donkey right first I'll talk about the normal heart okay let's make it a healthy it's a happy happy donkey it's a healthy myocardium having lot of oxygen supply good nutrition all right now what is the function of this donkey this donkey has to take some preload preload is the load on the donkey which it has to carry upward first you imagine there's a donkey which is having some load on it and with this load it has to go upward is that right and it has to go against this resistance this is the resistance against which this donkey has to perform right and here is the low pressure donkey will work up build a pressure and take some preload here and deposit something here for example here it was 140 ml any deposit here 70 ml and then this donkey will come back right it's 50 percent it has low downloaded there so this was the stroke work of donkey during one stroke and deposited 50 ml there and come back again take 70 ml more and again go back now how much work a donkey is doing listen it's very easy to understand just a minute we're talking about donkey right how much work per minute it is doing it depends on number one how much preload is there if you put more preload work of the donkeys more if you are putting the more load on the donkey work of the donkey more number two if you increase the resistance angle against which it has to work work of the donkey will be more is that thirdly how many times per minute it moves if it moves for example one 30 times per minute work is increased now imagine ischemic myocardium the ischemic myocardium is actually like a donkey which is undernourished like a donkey which is undernourished now it is under nourished donkey very weak and no more smiley this is now what is happening look this donkey has to it has less oxygen supply now due to any reason in classical engine I'm talking about if you take this like this what has what has happened resistance against which it is working is increased if it is to work like this can it work well no and it will start crying the cry is the vaginal pain the donkey is crying The myocardium is crying because it is under angina pain now if this donkey cannot work well how you can help him what are the methods to help the ischemic myocardium ideal ideal thing should be you provide more nutrition to the donkey this is one way give more perfusion this is the ideal thing secondly you can help it by reducing the preload right you can reduce the load on the heart before it works you can reduce the load on The myocardium or load on the donkey before it start working third strategy is you reduce the what is this resistance against which myocardium is Contracting right now this is called preload the load on The myocardium before it work and resistance okay is which it was performing this is called after load myocardium perform against the arterial resistance you know arterial the narrow and myocardium has to pump against that impedance is that right that is after load that is the resistance so if you really want to help the strong key number one increase the perfusion number two reduce the preload number three reduce the afterload the resistance and next point is in strategy be merciful to this donkey and and reduce its number of visits not 140 per minute it should be maybe 65 per minute if this donkey with less preload working against less resistance and total number of stroke per minute or less maybe it's work is so much less that even in ischemic donkey can perform well do you understand it so now I will put the analogy on the truth and real thing but you should not forget your heart is a donkey it needs constant perfusion right and when it is reduced perfusion one way to help this trunk is reduce the work of the Donkey reduce the work of the heart how you can reduce the work of the heart reduce the preload or reduce the afterload and reduce the total heart rate all these things will help the donkey to manage this crisis right what was your question how do I reduce the resistance and the preload yeah I'm going to explain now Mr Abdul has asked that what are the real thing how you reduce the preload and how you reduce the afterload this is your question we are going to do that thing pharmacologically very soon right yes Jamie oh yes he is thinking how we can give nutrition to of course you increase Nutrition By dilating the coronary artery so that it carries more blood to the ischemic area that is so simple you know look to reduce to increase the nutrition to the ischemic myocardium you should dilate the coronary artery or you should do the thrombolysis so that more nutrition come donkey is Happy secondly you reduce the preload pre-load is the end diastolic volume on which myocardium has to contract so you should have reduced the preload what is preload pre-load is the end diastolic volume the volume of the blood at the end of the dastly on which the onset of systole work myocardium has to contract on the end diastolic volume if this volume is less then work of The myocardium is less thirdly Sicily has to generate enough tension to push the blood against the resistance of the arteriolar construction what is afterload this heart is working against this resistance what is this resistance this is the total peripheral resistance arteriola constriction so if your arterioles constrict too much this slope will go up Donkey may fall down you get it and if there's arterial or dilatation the slope will come down you understand it in the same way blood volume is increased preload will increase if venous return is more preload is more venous return is less preload is less are you clear now I will put donkey little bit on the side and talk about your real heart beautiful heart I will just keep our example of donkey here right this is your donkey going up just give me donkey weeping and its legs are really in trouble all right and here is the preload it is carrying and this is the afterload the resistance against which it is working is that right so now will come to the real thing and let me explain it to you this diagram all of you should draw this is the right heart here is your lung here is your left heart now what is really happening now we'll see how the NTN General drugs should work right this is your vascular system in the periphery here is your aorta okay I'll make it more simple diagram this is your arterial tree here are arterials these are the arterials going to the capillary beds is that right these are different tissues right and here is your Venus system it's a very simple diagram this blue light blue system is your venous side this red system is your arterial side is that right and blood from this will go to the lungs their blood gets oxygenated and oxygenated blood comes to left heart is it right and of course we should not forget that here is your oxygenation business now we have to see first the management of for example this may be liver right this is circulation maybe through git this is circulation maybe through the skeletal muscle you understand it and look these are arterioles these are arterolar smooth muscles is that right and this is the venous side now this is right heart of course and there's left heart there now let's see what's happening in angina classical angina I told you in classical in China there is a fixed obstruction there because there's fixed obstruction there whenever hard work more let's suppose this partial person is exerting whenever he does a little bit exertion or whenever there's little tachycardia Demand on oxygen increases but this point cannot dilate further so it cannot provide further oxygen and this part of The myocardium we can say this part of myocardium is vulnerable myocardium right out of this the most vulnerable is a in our most myocardium is that right now we will see how this problem start and how drugs can correct it first lesson what's wrong with this patiently learn is very Advanced maybe 80 percent of the cluvian whenever this person does a little bit exertion or whenever there's little bit tachycardia due to emotional fluctuation a sympathetic overflow heart will increase its cardiac work increase cardiac work will demand more oxygen but this point cannot provide extra oxygen so dependent myocardium become ischemic and that produces the symptomatology of angina and if this point is very severe during one week this patient may develop angina many time now how do you manage this angina this is undernourished donkey we have to help him right now one way is that we give the listen one way is that you reduce the Venus return because this is the end diastolic volume and end diastolic volume is also called end diastolic pressure right and diastolic volume lead to end diastolic pressure in the cavity and that is also called preload now from today onward every doctor should know very clearly what is preload preload is amount of the blood present in The ventricle on which ventricle has to start its squeezing action on which ventricle Astro started successing action or simply preload is the end diastolic volume the volume on which ventricle has to contract right so it is the load on The myocardium before myocardium contract before The myocardium start Contracting this is a load on myocardium now one way is now listen whenever preload is more you know the basic rule Frank starling's law what is the Frank starring law more you stretch the myocardial fiber more it contracts do you know this law it means more you stretch more you contract what does it mean it means more you stretch more it contracts more it demands oxygen now you develop the relationship of oxygen wealth now what is the stretching Factor on The myocardium and astrolic volume if you have more preload or you have more antasolic volume or you have more antioxolic pressure it means there's more stretch in The myocardium it means myocardium has to contract more strongly it means it will demand less oxygen or more oxygen more oxygen now very simple technique if somehow this is one problem that whenever there is more preload this demand more demand for the oxygen you understand it secondly another thing which most of the doctors don't understand that when there is more and diastolic volume there is more pressure in the cavity when there is more pressure in the cavity interventricular intra ventricular cavity pressures are high Whenever there is more and diastolic volume and whenever this pressure is high it will further compress this my inner myocardium and make it more vulnerable to ischemia so it means that whenever there is a high and diastolic volume there is higher pre-stretch on The myocardium there is a higher work of The myocardium and this is higher intra cavity pressure and there is a higher compression on the deeper myocardium and further risk of ischemia now what you do you should do something listen you should give some pharmacological agent which reduces the preload now how do you reduce the preload now we are going to be merciful to this donkey we are reducing this preload how will reduce this brief load how will reduce the cardiac filling very simple from where the blood is coming into heart blood is coming from the Venus side blood is coming to the ventricular cavity from where venous side is maintaining the venous return and filling out the myocardium now very simple technique you give a drug which is vino dilator we dilate all the Wayans if you give Vino dilator drugs very strong Vino dilators do you think blood will now will be pulled into periphery or it will be coming back to the heart paper every so one of the master drug technique should be which we should give such drugs to such patients which are strong Vino dilators so patients veins dilate when veins dilate then blood is pulled over here venous return is reduced when venous return is reduced then cardiac filling is reduced and when cardiac filling is reduced then pre-load is reduced when preload is reduced it means that and now the pre-stretch on The myocardium is reduced so contractility is reduced oxygen demand is reduced and myocardium may be happy even with reduced oxygen supply and ischemia may disappear so this is so simple all those drugs which are Vino dilators are pre-load reducers right all those drugs which are we know that later the preload reducers right they reduce the load from here and of course your donkey should be happy it is carrying less load secondly another thing look donkey with more load will eat well a donkey with less load is going to enjoy his food well less less load so what exactly this is what happened with myocardium Dr diet that when you reduce the preload donkey will eat better how very simple look here when you reduce the preload intra cavity pressures are less when intra cavity pressures are less then compression on the deeper myocardial circulation is less so even with less perfusion better will be better flow will be coming to the deeper myocardial you understand the beauty of this point number one this is undernourished you reduce the load right so that it can work well and whenever you reduce the cavity pressure even the compression on the deeper myocardium become less and even with less flow there will be better perfume to deeper part is that right so this will alleviate or terminate the skinny or reduce the skin yeah so best way one of the way one of the strategy to reduce the work of the heart is you reduce the preload to reduce the end diastolic volume you reduce the end diastolic pressure when all these parameters are reduced then stretch on The myocardium is reduced then according to friends Starling law tension is reduced and work of the heart is reduced oxygen demand is reduced and may be reduced oxygen demand is now able to meet with reduce Supply here let's Supply the laplaces lie as well right what was that that pressure is directly proportional to the tension produced in the pressure in the cavity the pressure which is generated in the cavity is directly proportional to the tension produced in the wall tension produced in the wall and radius right now look at the beauty of it listen listen now it's my turn to explain your turn is in mcqs I'm just developing a logic logical thinking oh my friends you are all of you excited too much without any lady around listen uh what I'm talking about I don't know why my class is a men's show here now listen what is happening that let's suppose this mean arterial pressure is 100 millimeter of mercury so it means that left ventricle has to produce the pressure in the cavity of at least 100 to eject the blood is that right let's listen approximately it is not normal you know ischemic now so what we are talking about that pressure it has to generate this pressure for this pressure right if we reduce the venous return it means we reduce the radius and when we reduce the radius then heart has to produce if same pressure then it will produce more tension in the wall or less tension in the wall look again previously when when and diastolic volume was more radius was more and it was suppose supposed to produce pressure of 100 unit pressure of 100 unit when you give the gave the venodilators blood pulled here less blood coming here radius become less when radius become less than to produce the same pressure it has to build more tension in the wall or less tension in the wall so it has to be more contractility less contact this is the beauty that actually when n diastolic volume is reduced preload is reduced radius is reduced then uh to generate the same pressure myocardium has to develop less tension so it means that myocardium becomes more efficient because when there is less tension When there's less tension then less work is there then less oxygen need is there so we say heart become efficient because hard with look heart with larger radius for producing the pressure given pressure it needs larger tension but when you reduce the preload you reduce the end diastolic volume actually with the Lesser tension buildup it can give the same pressure output so it means myocardium become more efficient what is the efficient myocardium more efficient myocardium is which is with less oxygen giving more pressures generating more pressures and inefficient ventricle is which is with high tensions and high radius giving the pressure so as you keep on increasing the radius of ventricle it becomes inefficient ventricle as you keep on decreasing the radius of the ventricle it become more efficient you understand it so what really happens that when a patient is now you imagine there is a man in his mid 50s heavy smoker hypertensive diabetic recently fought with his own wife and girlfriend is not giving any attention right and he has Financial stress going to the bank will probably money is far less walking against the cold wind right what is happening there is some tachycardia he's exerting against the wind right and maybe uh cold wind is producing arteriola construction hard has to pump against more resistance so he developed ischemic chest pain but he's intelligent man his diagnosis was done one year back and he often on suffered with angina he immediately bring his top is walking sit down on the sidewalk from his pocket he bring out the tablet of glyceride primitrate put it under the tongue within one to two minutes this tablet will start working what it will do don't tell me that it will go to the coronary artery and dilate this patient was a patient of stable angina he was having fixed obstruction so even though nitrates can dilate the coronary artery but dilatation will not be significant at the stenotic point so it may not help much the real help will come that within 2-3 minutes rather than within one to one and a half minute nitrates will dilate most of the veins so while he's sitting veins will dilate or better to standing so the pulling should be better he is standing the sublingual nitrate veins will dilate cardiac filling will be reduced preload will be reduced work of the heart will be reduced intra cavity pressures will be reduced radius will be reduced and eventually the tensions to be generated are less and oxygen demand of myocardium are less and what will happen to him his pain may disappear depends on listen uh now it's very interesting question he is simply taking rest can reduce the pain answer is yes but for example he just rest and keep on remembering his wife and what she said in the morning and why she was not Cooperative yesterday night tachycardia may continue you know you can reduce you can make your body to rest you cannot force your heart to rest hard as its own logic is that right so uh secondly look at the bank where money is less in checks he needs more that's also precipitating tachycardia is that right so do you think that he can make everyone to rest in the world answer is no he can physically rest of course it's Health but still if tachycardia is going on then we have to have more drugs one of them is okay if you take rest and pain disappear it's very wonderful but if it does not disappear he should take sublingual nitrate and even if not take if he has taken 0.3 milligram of the sublingual light rate pain does not disappear in three four minutes what should you do high dose take another dose of sublingual nitrate is that right so that he should make sure somehow pain should disappear and pain should not last more than 20 minutes right he should be rushing to hospital forget about the bank and the girlfriend and the wife right because now he's developing the risk for myocardial infarction now listen this is one way to help his undernourished heart so how do you have helped the Donkey one way to help the donkey was yes please decrease foreign now let me Define what is after load after load is the resistance against which myocardium has to produce the stroke volume after load is the impedement to the outflow of the left ventricle and if aorta is healthy then most of the impedance or the resistance is offered by the most of the resistance is offered by what arteriole degree of arteriolar construction total peripheral resistance is determined by the sum of the resistance of all arteries in the body systemic arterials if arterials are very narrow then heart has to generate has to push the blood against higher pressure and if arterioles are dilated then heart has to generate against low pressure now please listen to me because again laplace's law will come into the play look if this patient has strong arterial Construction if he has strong arterial construction he is again thinking about the unfortunate things in his life or maybe someone pass very beautiful and he become excited again adrenal income and artificial construct right so if the article the constructing too much then to push the blood through the system he need to produce more pressure or less pressure more pressure let's suppose now he has to produce the pressure of 140 millimeter of mercury it means in this patient if there is strong arteriola construction the pressure to be generated or more pressure requirements are more and if there's too much arteriola construction it means donkeys are working against higher slope of course more chances to sleep more chances it should need more energy so if there is arterial construction it has to generate higher pressure if it has to generate higher pressure with the given radius it has to have less tension or it has to produce more tension more it means Whenever there is a significant artery construction then for the left heart to generate the perfusion through most of the body systemic circulation to maintain good pressure right it has to maintain good tension and when it has to increase the tension it means it has to increase its work and when it has to increase its work its oxygen demand is more as I told you whenever there's arterial construction this point moves like this resistance become more now donkey has to travel this it needs more power and energy or less power and energy more so its oxygen demand will be more more right so how you will help this patient another way to help this donkey is that do arteriola dilatation give a drug which will dilate the arterial if you give a drug which can dilate the arterioles then the resistance against which it has to work has gone decrease now look at this donkey how happy is that even though there is back breaking but still he is happy why because preload has been reduced at the top you have given arteriola dilator right so we can say that this was the function of we know dilator and this movement that this has moved into this direction this is a function of arteriolo dilator is that right so when you give arteriolodilator the resistance of blood resistance offered to the blood to move from arterial tree to the capillary system and Venus system has been reduced so pressure will drop in this area and when pressure in arterial tree will drop then it has to generate less pressure and has to generate less tension to maintain the cardiac output is that right so work of the heart will be less and when work of the heart is less then of course oxygen need is less and when oxygen lead is need is less then even with this stenotic plaque little bit oxygen coming may be enough for The myocardium which is working less is that right so what are the best way to help that donkey number one give winodilator and reduce preload number two give arteriola dilator and reduce after load to reduce after load when pre-load and after load is reduced it means that work of the heart is reduced even malnourished heart will not cry much and not much in general cries is that clear so what is the best arteriologer answer is calcium channel blockers calcium Channel blockers is that right calcium channel blockers are wonderful arteriologer and some of them also reduce the activity in the heart I will go into detail later that nifedipine and related drugs are very good arteriola dilator and Verapamil is actually also reducing heart in another way hard work in another way let me tell you how now another way look here yes classical angina yeah right we are still talking about classical angina now you have reduced the preload you have to reduce the afterload now donkey is very heavy happily singing whistling and going up and down you can do more Mercy to the donkey how you should reduce the total number of wizards ups and down you should reduce the heart rate if you reduce the heart rate right right if you reduce if you reduce not digitalis it is it is going to kill him because digitalis will increase contractility and demand will be more now look not digital is forget it now what we are talking about that we have to reduce the total cycles per minute that will also make the donkey happy if you are donkey you will be happy under these circumstances when your total Cycles are reduced so we should give some drug which is negatively chronotropic which is negatively chronotropic and negatively chronotropic drugs should be inhibiting essay node the drug should be inhibiting SA node right let's suppose here is your heart ischemic heart you want to reduce the heart rate and if you want to reduce the heart rate right you can choose two types of drug let's remain focus on this you know as a note produces depolarization which is under calcium dependent this calcium SA node has calcium dependent depolarization so if you give calcium channel blockers what will happen that calcium current in astronaut will decrease total number of action potentials produced by acetode will be reduced is that right and that will produce negative coronopropy that will produce negative chronotropy or other thing is who is the stimulant to as anode is epinephrine or norepinephrine endogenous you know endogenous catacola means epinephrine and norepinephrine stimulate the acinode through beta-1 receptors so another way that don't let the donkey run too much let the donkey walk comfortably right how to reduce the heart rate to reduce the heart rate one way is to give calcium channel blocker other ways you protect the heart from the action of endogenous catecholamines to protect the heart from the action of endogenous catecholamines so these endogenous catecholamine work on the heart through beta1 receptor because they work through beta 1 receptor why don't you give beta blockers another group of drug will be beta blocker beta blocker act on the essay node and reduce heart rate and calcium channel blocker also work on the acetode and reduce heart rate right negative chronotropic action secondly you know myocardial cells their contractility depend on calcium loading you know it or not myocardial cells contractility depends on calcium loading plus this calcium loading may be through voltage-gated calcium channels or this calcium loading may be influenced by beta1 receptors adrenergic receptors you know beta1 adrenaline receptors load the calcium into myocardial cells or calcium is also triggered into myocardium during the plateau phase through the voltage-gated calcium channels l-type calcium channels you know it okay now calcium either goes through the what is this channel calcium channel L Type calcium channel or catecholamine stimulate the beta1 hydrologic receptor and these receptors will activate you must be knowing activate G stimulatory which will stimulate adrenal cyclists that will increase intracellular cyclic amp that will drive protein kinase a which will phosphorylate the calcium channels and further calcium loading do you think just hard we have to reduce the work of the hardening or increase the work of art we want to reduce the work of art one way to reduce the work of the heart is reduce the calcium loading to The myocardium so that it contracts with less tension so it worked less and demand less oxygen so you can give here what should be the drug here my friend calcium channel blocker or what should be the drug here beta blockers you get it now you look at it that those calcium channel blockers which work on the heart like vapormel or dilt Azam they can reduce the heart rate and reduce the contracted stroke volume and reduce the cardiac output and reduce the work of the heart your understanding and that also helps in angina so how many ways to help the angina look now look carefully to me number one we want to help this ischemic donkey reduce the load reduce the preload what is the drug now to reduce the preload what is the name of the drug we know dilators reduce the preload like nitrate or you reduce the afterload what is that calcium channel blockers or ask the donkey please don't run slow down slow down no hurry no worry and don't forget to see the flowers right heart should be slowed down for slowing of the action slowing of the rate and slowing of contractility this is achieved by direct action of beta blockers and calcium channel blockers on the heart is that right any question so this was just basic information the basic strategies used in management of classical angina is that right after the break we'll go into detail of every group of drugs we'll talk first in detail about the nitrates then we'll talk about calcium channel blockers and beta blockers right now you have the concept now I'll teach you what are they done so by the discussion which we have learned that there are three drugs used in classical management of angina these three drug groups are nitrates there are beta blockers there are calcium channel blocker calcium channel blocker these are the three classical drugs right in the management of angina I will explain the advantages and disadvantages of these drugs but there are other things which are also important in the management of angina right for example I told you in the long term management of angina we should modify modify the risk factor risk factor for the development of for development of atherosclerosis is that right for example if someone has stable angina you should stop smoking or if he's hypertensive or diabetic these things should be managed if he has dyslipidemias those should be managed right sedentary lifestyle should be abandoned patients should start Physically Active lifestyle right so that his what should happen the further progression of atherosclerotic disease should be reduced and even by modifying these risk factor ah some some regression in the atherosephology lens has also been seen one thing second thing which is very important we should take the drugs which are plaque stabilizers do you know the group of drugs which can stabilize the plaques atherosclerotic plaques plug stabilizers yes what is that drug stabilizers the most wonderful drug in this group are statins statins so in the for the long run management you have to manage the risk factors as well as you have to use start using the statins which are not only reducing the not only their cholesterol lowering drug right but statins also reduce the progression of the plaque development either under the influence of Statin the unstable plaque right gradually stabilize or the stable plaque has less chance to undergo acute changes is that right so it means if a patient who is having stable angina and he has some atherosical neurotic lens in coronary artery if he is on the long term use of statins then there is less chance that these stable anthromas or plaques may go under acute changes third time that especially those patients who have undergone unstable angina you have to give anti-platelet drugs and T platelet and antithrombotic or thrombolytic drug or anti thrombotic drugs right now these are long-term management is it clear that risk factor management you stabilize the flux by giving the statins and you give long term aspirin juice or other anti-plated drugs so the chances of formation of platelet Aggregates is less right but classical management remains around the nitrates beta blockers and calcium channel blocker in today's discussion we will concentrate more on nitrates beta blockers and calcium channel blockers and we will have a separate full lecture on anti-platelet drugs and fibrinolytic or thrombolytic drugs is that right now let's concentrate on nitrates first of all I will tell you how the nitrates work and what are the nitrate drugs these are also called Nitro vasodilators right one of the term which is coined is Nitro vasodilator so simply nitrates nitrates now the drug which are present in this group of nitrate they are glyceryl trinitrate glyceryl Tri nitrate right then another drug which is present in this group is isosorbide dinitrate ISO sorbide dinitrate and another important drug in this group is isosorbide mononitrate that is isosorbide mono nitrate glyceride Tri nitrate glyceryl with three nitrates Tri nitrate isosorbite mono nitrate now glyceryl trinitrate how it is given to the patient in which forms most commonly it is given sublingual or buccal suppress or oral palettes right why we give it in the oral cavity the reason being that if you take orally glycerol trinitrate through the git when it goes to the liver in the liver this drug is inactivated because glycerol trinitrate is having a very high first pass effect first pass effect mean when a drug is taken orally when this drug is passing first time through the liver most of it is inactivated or destroyed so glycerol trinitrate has a very high very high ratio of very strong first pass effect that is why when you take a tablet off glycerol trinitrate right you just put it in the oral cavity under the tongue from there it will melt and dissolve and this dissolve will go through lingual veins of course into this veins from the head and neck into speed of vena cava so it will go to the systemic circulation without passing through the liver is that right when you take this drug sublingually or in the oral cavity as buccal Supply this will go from the veins of the head and neck drain into superior vena cava going to the right heart pump to the pulmonary circulation drug goes to the left heart and through the left heart drug is pumped into a whole systemic circulation in this way we get the drug reaching to the systemic veins without passing through the liver so that is why within one to two minutes this sublingual dose will start its action that if there's a person who gets intermittent angina right he should keep if a person get intermittent exertional in China this person person should keep a supply of tablets off glyceryl trinitrate and he can use it in two ways number one whenever angina precipitate you can take the table at sublingually or he can juice this tablet's profile actually that whenever he knows there are situations which will provoke angina right prophylactic juice for example he is going two flights of stair so before going those flights of stair he should take nitrates and then go up the right this reduces the on you can say total number of attacks per week is that right so glyceryl trinitrate which is given sublingually tablet or Supply right start action within two minutes and it continues its section for about 30 minutes onset of action is two minutes and it continues its action up to 25 to 30 minutes right duration is that right this is one thing second thing which is important is that there are oral sustained release tablets also oral sustained release tablets also for nitroglycerin nitroglycerin or glyceryl trinitrate they are one and the same thing it is also called Nitro glycerine it is one and the same thing right another is that now there are available oral sustained release tablets they start their action uh within 30 minutes an action continues up to six hours six to eight hours oral sustained release tablets right they start their action within 30 minutes and the continue Direction up to six to eight hours it is minutes of course then you can understand if angina is already starting you have to give sublingual tablets is that right because it will start action within one to two minutes right because if you take oral strained release right it will take 30 minutes to start and of course in acute phase it is not good it is for prophylactic rules here I want to tell one thing attention plays if someone gets angina attack only very occasionally you should keep glyceride tablet with him and use them as required and use them as required but if someone is getting angina more frequently then he should take the nitrates more regularly on daily basis is that right for example yeah again someone who is developing angina very finally he should keep the supply off you can say uh uh sublingual tablets and whenever he needs he can put one tablet either prophylactically or during the acute attack right but he should not take a regular tablets of nitrates but if there is another person who is developing angina of exertion very regularly very very frequently then he must take nitrates on regular bases and when he is taking nitrates for regular bases either he will take the oral sustained release or he can take transdermal application trans thermal application yeah these are transdermal patch or you apply the ointment on the skin you know you take from the tube bring a little bit ointment and apply it on uh you can say one inch to two inch area right from there it will be absorbed and it will be going to the blood right this transdermal application this also start action Within 30 minutes it also starts section within 30 minutes and continue the section from 8 to 12 hours now one thing note here as far as onset of action very fast and termination action also very fast is sublingual applications but when you take it orally or transdermally it takes about half an hour to start the action and it takes many hour of duration for which the drug remain active in the body so this was about the mitroglycerin now few words about isosorbide dinitrate now isosorbide dinitrate can also be taken orally and sublingually it may have some lingual as well as oral preparations right sublingual preparation of the isosorbide nitrate they start action within five minutes and it continues up to start within five minutes and it continues up to one hour so again in emergency preferably you should have nitroglycerin if it is not available and if you are taking the regular drug then you can take the oral slower release tablet and that start of oral slow release tablet and that start action within 30 minutes right and terminates its action within eight hours is it clear and my terminate section within eight hours or around eight hours then there is isosorbide dinitrate right and an isosorbide dinitrate the tablets are taken orally mono nitrate sorry please correct it as now we are going to discuss mononitrate right isosorbite mononitrate and isosorbide mononitrate is the oral extended release tablets and these overall extended release tablets start their action within 30 minutes right but it continues its section for long time sometimes up to 12 hours 12 hours right overall extended release ah look yeah slow release it is releasing the product up to eight hours extended uh release mean it is going beyond that actually they depend on how the drug has been compressed and what are the physical nature of the drug is that right for example a tablet which you can dissolve very rapidly in the git right it will be released into blood for shorter time but another tablet which is present in the git but molecules are too much compressed and they very gradually dissolve they will take longer time and they to dissolve and keep on releasing the product to blood for longer time you get me or not right now here I want to tell you one thing extremely important that is that you cannot continue get the patient protected with nitrates 24 hours because if nitrates are used for longer time the loose Direction you don't know this then you must know what really happens if you give nitrates more than 12 hours or 18 hours continuously after that efficacy of nitrates is lost what is the mechanism they are not very clear but there is something very important for example this is the smooth muscle of a vein or artery how the nitrates work the nitrates go into this smooth muscle nitrate drug and these nitrate drugs release their nitric oxide and later on I will explain how this nitric oxide produces vino dilatation or arteriologation it's a very strong vinodulator and it is slight arteriolo dilator as well you can say we know dilation is like this in compared to arterial dilation at therapeutic doses so why because smooth muscle of winds can release Nitro nitric oxide more effectively from the drug a smooth muscle of artery attention please if drug is going into smooth muscle vein as well as in the smooth muscle of artery drug itself is not active from the drug we have to release the active product what is the active product nitric oxide not nitrous oxide nitrous oxide is you know an aesthetic agent this is nitric oxide so nitric oxide is one of the very important you can say intracellular signaling molecule for the smooth muscle it's so important that the person who discovered its role they were awarded with Nobel Prize is that right just to tell it's so important otherwise let's come back now why this drug is stronger we know dilator and weak arterio later answer is that this drug goes within the venous smooth muscle and artificial smooth muscle in the same amount but venous smooth muscles are more efficient in extracting the nitric oxide from the drug molecule but arterial smooth muscle are poorly extracting the nitric oxide from the parent molecule drug so due to this reason when nitrate concentration in the venous blood and arterial blood is same but still we know dilatation is more an arteriologation is less because there is more release of nitric oxide in the venous smooth muscle less release of nitric oxide and arterial smooth muscle this is one point secondly they believe the enzymes the enzymes which help in release of nitric oxide from nitrates right these enzymes actually develop the phenomenon of these are enzymes of sulfhydrol proteins they show the phenomenon of tolerance what really happens that if you keep on providing the drug right Within 15 to 20 hours around 14 15 hours of regular application of presence of the nitrates then these enzymes stop working and they're unable to release the nitric oxide from nitrates your understanding okay I'll explain it again for example I'm giving you nitrates every eight hourly and I'm covering United with the nitrate for 24 hours nitrate will keep we know dilator very well for about 16 hours after that nitrates mediated Vino dilatation is lost why because the enzyme which was supposed to extract nitric oxide out of the drug these enzymes stop working and these enzymes need a gap of six to eight hours daily to restart their function you understand it that is why the best way to treat the patient badly is give the nitrates regularly every patient who is a nitrate daily should be on six to eight hours or 10 hours nitrate free interval so that tolerance does not develop what is your concept of Tolerance that you should keep on giving the drug regularly right the pharmacological action of the drug is lost after some time right bodies start tolerating the drug right so nitrates show a very high degree of Tolerance Within 12 to 15 hours or 16 hours is that right now why I'm highlighting this thing because whenever you use nitrates for your patients always provide some nitrate free is that right so that tolerance should not develop now you must be thinking that patient may get severe angina during the nitrate free interval and don't forget there's the Other Drug beta blocker that's the beauty of it that you give the nitrate with beta blocker in cases where where angina attacks are very frequent so that when patient is not under nitrate protection patient should be under production of beta blockers I will explain how the beta blockers protect the heart am I clear so Point number one nitrate drug show a strong tendency for the mechanism of Tolerance right every patient who is on regularly nitrates should have at least eight hours of nitrate free interval so that mechanisms which keep the nitrate functional right nitrate mechanisms functional they should not become tolerant is that right and one way to manage the patient during the nitrate free interval is that patient may be put if he is having high frequency of attacks patient may be put on the beta blockers or calcium channel blockers am I clear number two look exertional angina absorptional angina is more in the daytime or at night in the daytime until you are not doing something very special at night right so most of the patient know these are very important if you are going to do something special you have to take special care of yourself so most of the patient most of the patients who have exertional angina right the risk of angina is during the day time when you become emotionally upset so you become physically exerting right so the nitrate interval nitrate free interval in these patients should be provided when at night so you have to remember that patient who display the strong exertional angina or classical in China or stable angina nitrate free interval should be at night for example they should use nitrate patches in the daytime for 12 hours they should use the patch for 12 hour they should remove the patch because when you apply the transdermal application these patches they are constantly releasing the nitrates into blood right but after 12 hours you should remove the patch because if you keep the patches for 24 hour patches will these drug will lose its efficacy am I clear but if you talk about uh variant angina or Prince metal angina Prince metal and Janna has a high chance to be precipitated in morning hours right when adrenaline level in the blood is high catecholamine level so for them nitrate free interval should be in the evening time so you have to intelligently design the treatment for a given patient nitrate treatment am I clear yes we are not talking about unstable right now we are talking about classical angina and in a classical mean stable and transmetal classical in China is related with exertion right so usually patient should be covered with nitrates in the daytime and because most of the people don't exert much during sleep so I must say that nitrate free interval should be provided at the sleeping time yes is that right but when we talk about uh a patient on the prince metal angina Prince metal and China is usually is more frequent in the morning because there is fluctuating coronary artery tone and usually in the morning adrenergic Supply is more is that right and the more chances that patients will precipitate Prince metal in China in the morning hours due to that reason we don't give them ah you can say nitrate free interval at night or early morning we give them nitrate free interval in the evening times they get a tablet before sleeping and they take a tablet just after wake up they miss the tablet in the evening am I clear or noon now listen another thing about these nitrates there is a very interesting phenomenon of historical interest when we talk about nitrates you know nitrates were very commonly used in ammonium nitrates and Other Drugs when you are making explosives and in second world war in those years when people were working in the factories where they were building explosives right workers develop a very special type of syndrome they developed a disease called Monday disease Monday disease Monday disease what was this Monday disease actually what was happening to these patients that after the weekend enjoying a lot when they come on the factory if there are 1000 worker most of them develop severe headaches and flushing and dizziness and after one two days it will be okay right now they came to know what is the mechanism actually uh in those factories in those times uh nitrates were not properly contained in the instruments so the workers who were getting they were also inhaling nitrate many nitrates are volatile like ml nitrate is fully volatile and you can say other nitrates which we are using these days like isosorbide dinitrate the solid at room temperature so those volatile nitrates were going to their circulation so these patient all the week right they were getting good nitrate inadvertently is that right do do during the weekend their enzymes recover and when they come in the Monday morning get the nitrates enzymes will convert the nitrate into nitric oxide and they will develop severe weather dilatation and when vesselton head and neck will undergo weather dilatation they will develop sphere headache and flushing and when most of the veins will dilate venous pooling will occur venous return will reduce cardiac output will drop and they will develop postural hypotension and dizziness but within Monday and Tuesday they will develop tolerance to the drug the rest of the day is there will be no complication you are getting me so every Monday or whenever they come from holidays they develop severe headache and with that they develop flushing and they develop postural hypertension and all the stuff is getting almost right and during as week is advancing these symptoms already used is that clear so this was one problem which was called Monday disease yes the symptoms now I'm going to tell you many of these patients used to get what dependence on nitrates especially some of these workers who are having some degree of atherosclerosis all the weak they don't get angina these workers and on weekends they get in China and they blame it to their family situation is that right so I just wanted to tell you this some something interesting about the nitrates right that there are two concepts related with the nitrates number one was Monday disease number two was nitrate dependence Monday disease mean that when the Monday they will come they will get the nitrates and produce a lot of nitric oxide in the body and develop toxicity of nitrate right but as the weak will go by the enzymes will become uh you can say non-functional and now nitrates will not be converted into nitric oxide and Monday's symptoms will disappear right and some of the patient will even develop nitrate dependence they're all the weak they don't get any in general attack if they are having a tendency from China so they were getting the therapy of angina inadvertently from their uh unknowingly they were getting the therapeutic doses of nitrates and when they go for holidays they develop the ice cream heart disease symptomatology right isn't it interesting yes right now I will come to this fact that how the nitrates exactly work at molecular level right how the nitrate relax the smooth muscles I did not talk about the molecular bases that how the nitrates relax the venous smooth muscle and to some degree arterial smooth muscle now what we will do first we will understand the normal mechanism of smooth muscle contraction and then we will talk about how nitrates alter those smooth muscle contraction it can relax the smooth muscles of veins there will be Vino dilation and if they do relax a little bit smooth muscle of arteries they will produce arterial dilatation let's see at molecular level first physiology and then pharmacology first what is the physiology of smooth muscle contraction and relaxation and how the nitrates modify let's suppose here the smooth muscle it's really very big one right no first I'll talk about how the normal smooth muscle contraction occur you know smooth muscle can also get calcium from outside and this calcium can also release the calcium from yes endoplasmic reticulum of smooth muscle endoplasmic reticulum of smooth muscle is a good store of calcium so calcium is released from the sarcoplasmic reticulum I should call it endoplasmic reticulum because sarcoplasmic reticulum is a term which is used for myocardial endoplasmic reticulum right now when this calcium come out this calcium bind with the protein and this protein is called yeah what is the name of this protein what is it called call Modio Len right so this call Model N is a protein which is modulated by calcium so when calcium bind with curl Model N what call modeling is this complex is going to do I think diagram is a bit dirty but I never made it with this intention so calcium will bind with the cold metal in and calcium carb model and complex it will do a very important thing that this complex will activate an enzyme and that enzyme is called myosin myosin myosin light chain light chain kinase what is the name of this enzyme myosin light chain kinase and what is the function of this ah enzyme myosin light chain kinase right actually calcium carb model in complex activate the myosin light chain kinases and what is the function of myosin light chain kinase actually myosin light chain kinase lead to phosphorylation of myosin light chains let's suppose this is the you can say sarcomere type Arrangement it's not truly a sarcomere in smooth muscle but let's suppose these are actins and what is here myosin this is a heavy chain of myosin and here these are the light change of myosin now you know that when this myosin heads and light chains myosin interact with the actin they will produce contraction of smooth muscle right these are the myosin binding sides these are myosin binding act inside remember there is no troponin here and there is no tropomyosin so don't confuse it with the skeletal muscle R and or myocardial muscle in smooth muscle there is no troponin or tropomyosin smooth muscle the special mechanism of contraction is that myosin light chain kinases will lead to phosphorylation of they will lead to phosphorylation of light chains so phosphates are binding with the light chains and when these phosphates are binding with the light chains then light chains develop these phosphorylated light chains have a capacity to bind with acting now listen carefully that how then actin myosin will start binding and contraction will start is that right this is the normal physiology that calcium level rises into into intracytosol Rising calcium this is also having calcium dependent contraction but different mechanism here is no proponent you know in the heart in myocardial cell calcium bind with proponent here calcium point is called Madeline light chain kinases myosin light chain kinases lead to phosphorylation of yes they will lead to phosphorylation of light chains and when light chains are phosphorylated right what really happens that light chains develop the capability to interact with the with the actin and contraction will start is that right this is normal physiology of contraction now relaxation how the smooth muscle relax how the smooth muscle relax for this purpose there is a monkey-like enzyme here foreign what it is doing it will snatch Veda phosphates from here right what is this enzyme doing it has some transplanted here also right so this monkey enzyme what is the function of this that this enzyme when is activated and this activation will lead to D phosphorylation or removal of phosphate from light chain because it removes the phosphate what should be its name myosin light chain phosphatases it's so simple it is myosin light chain yes phospha phospha is is phosphatase so it means that when you want listen now careful the central concept is the central concept is phosphorylation and D phosphorylation of myosin light chain when we want contraction of smooth muscle then we phosphorylate the light chains when we want relaxation of smooth muscle we dephosphorylate the light chains am I clear now smooth muscles have intrinsically high level of myosin light chain phosphatizes is that right so contraction dependent depends on constant action of myosin light chain kinases as long as now listen carefully as long as smooth muscle has high level of calcium for that much duration myosin light chain Kinesis are activated through calcium carb model and complex as far as as long as myosin light chain kinases are activated they will keep the light chains light chains phosphorylated and phosphorylated light chains will keep on intermittently interacting with the my actin myosin and producing sarcomere as soon as look calcium level become less for example more calcium is not released rather calcium is pumped back into its stores or calcium from here is thrown out so as soon as calcium become low carb model in has dissociation with the calcium car modeling is inactive it does not activate myosin light chain kinases and myosin light chain kinases do not phosphorylate when they stop phosphorylating actually the phosphorylation continues through this phosphatases and smooth muscle relaxers now look one way to relax the smooth muscle is kill this thing if you want to relax the smooth muscle you actually inhibit what is this myosin yes light chain kinases if you inhibit the myosin light chain kinases what will happen right that it's a light chains will be no more light chains will be no more phosphorylated is that right yes now the thing is that How We Do It the drugs answer is nitrates how the nitrates inhibit this enzyme you get me because this enzyme is going to produce what thing light chain kinases and precipitate contraction now let's see how it is working let's suppose the nitrates come nitrate drug come into the smooth muscle nitrates nitrates release which enzyme which Subs active substance nitric oxide right you remember there was some enzyme here which was responsible sulphideal containing proteins which are responsible to release the nitrate from night release the nitric oxide from nitrate and these are the enzyme which display the phenomenon of Tolerance but anyway if patient has these enzymes active nitrates will release the nitric oxide nitric oxide will bind with a special type of enzyme here and that enzyme is present into cytosol what is the name of this enzyme yes nitric oxide will bind to the what is this enzyme what is the name of this enzyme yes please this is cytosolic governale cyclase what is the name of this enzyme cytosolic guanalis cyclist right when nitrates bind with cytosolic guanalyl cycle is what this is going to do it will convert yes it will convert what is the function of this enzyme yes it will convert GTP into cyclic GMP it is not adrenal cyclist it is going allyl cyclists you know adrenal alcohol cycle is convert 80 if it is adrenal cyclase it will convert 80 P into cycle amp but this is not adenylial cyclase what is this go on allyl cyclist so this goanalyl cycle is convert GTP into cyclic GMP when cyclic GMP levels are high right this will bind whether a special type of enzyme and this enzyme is called what is the name of this enzyme this is protein kinase G what is the name of this protein kinase G why we call it protein kinase G because this enzyme is a protein right and it has a kinase activity kinase mean phosphorylating activity and its phosphorylating activity depend on GMP cyclic GMP so this is called protein kinase G and what is the function of protein kinase G foreign it is going to inhibit the action of light chain right this is going to inhibit the action of foreign light chain and how it does by phosphorylating the light chain look at it it has Port what it has port phosphates in the mouth of light chain kinases when light chain kinas is itself phosphorylated it is inhabited remember most of the protein on phosphorylation are activated some of the proteins on phosphorylation are inhibited myosin light chain is one of the protein that when this protein is phosphorylated it becomes inhabited now you recap it nitrates come into smooth muscle release nitric oxide nitrix oxide stimulates cytosolic when Ally cyclists that converts GTP into cyclic GMP when intracellular cyclic GMP become High it activate protein kinase G protein kinase G thus phosphorylation of phosphorylation of myosin light chain and when myosin light chain gets phosphorylated right then myosin light chain is non-functional and inhibited and then myosin light chain is inhibited there is no more phosphorylation of myosin light chains and phosphatase will lead to D phosphorylation and when ah phosphatase mediated myosin light chain phosphate is mediated dephosphorylation is not compensated by phosphorylation by this then D phosphorylated light chains fail to interact with actin and smooth muscle relax this is a molecular basis of action of nitrate and after that we'll recap a little bit what is the physiological basis of nitrate we've already discussed a little bit how nitrate basically did you manage the angina okay I will just repeat it in few words that once smooth muscles of veins are relaxed what will happen we know Venus pooling and Venus return to heart is reduced preload in the heart is reduced and preload on the heart is reduced please stretch on myocardium is reduced contractility of myocardium is reduced and oxygen command is reduced number one number two when Venus return is reduced pre and diastolic volume is reduced intra cavity pressures are less so the less compression on sub endocardial myocardium so slightly increase blood flow third nitrates do produce direct arteriola dilatation to some degree in the coronary arteries but when there is fixed nautical iron right there is only slight Improvement because when there is fixed nauticalane if it has a little bit associated with a spasm that may be relieved but there's a very special mechanism how in the heart it helps look here this is ischemic myocardium now look at this carefully this is the major Cardinal trunk coming and this is divided into two branches here let's suppose this branch has atherosclerotic lens let's concentrate on it this branches atherosclerotic ions now what will happen that this area will become ischemic this is the dependent area is that right but outer area has a good perfusion outer area has a now these three vessels these are called collateral Supply because main Supply was coming from this was the main Supply to this myocardial piece and if there were chronic ischemia the ischemic area keep on releasing the angiogenic growth factor so what really happens that from repeated ischemia ischemic area releases endogenic growth factor and over the time there will be development of collateral to the ischemic Zone collateral Supply now look here when you will give nitrates the stenotic point may not dilate significantly but actually the collateral Pathways May dilate and there may be extra blood coming from the collateral as well so that may also help in termination of angina so how then Jenna is terminated by nitrates I've discussed three mechanisms rather I will discuss four let's recap do you remember four or not most important single most important point you should mention strong window validation strong reduction in and diastolic volume and preload and and reduce cardiac work this is one mechanism second reduction in intra cavity pressures so there is less extra vascular compression on the deeper myocardial vessels so better perfusion third uh nitrates can dilate the collateral Pathways and provide additional blood to the ischemic area fourth nitrate at higher doses can do at least to some arterial or dilatation and if there is even little arteriola dilatation that helps in reduction of afterload that health and reduction of the resistance against which myocardium is Contracting that further reduces the work of the heart and reduces further helps and reduction of ischemia is that right so these were molecular mechanisms of how nitrates work and when we talk about preload mechanisms and we talk about how that is that is physiological mechanisms how the nitrates work let's have a break now we are going to discuss the side effects or adverse effects of nitrates right now the side effects of nitrate mainly stem from exaggerated pharmacological actions nitrates and side effects of nitrates right or adversifiers number one thing that nitrates produce severe headache and this is the most common side effect of nitrates that they produce headache and they also produce facial Flushing now why let me tell you why they produce headache remember all the drugs which are strong vasodilators can do have a capacity to produce headache now tell you this headache is a very special type of headache we call it probing headache now let me tell you the mechanism of probing headache let's suppose this is your cranial cavity and these are the vessels which are going through foramina to the cranial cavity these are the artery meningeal arteries or other arteries which are passing through the foramina to the central nervous system and you know the internal side of the cavity cranial cavity is lined by Dura matter and this dura mater makes a sleeve around these arteries write this durometer makes a sleeve around these arteries and this Dural sleeve which extend along these arteries now actually listen very carefully this point durometer point these are very very rich in pain receptors these are very rich in pain receptor these Dural sleeves they are having lot of pain receptors now when you produce arterial or dilatation arteries are dilating constructing dilating with every pulse during every systolic pulse now listen carefully with every systolic expansion arteries Hammer the pain receptors against the bone and that produces severe throbbing headache what really happens that all those arteries where all those drugs which produce strong arterial dilatation right if they produce arterial dilatation of the vessels which are passing through meninges these vessels are surrounded by meningeal Dural sleeves and these Dural sleeves are very very rich in pain receptors so when Our arteries are significantly dilated during every systolic expansion arteries hit the Dural sleeve with the pain receptors against the bone and that produces severe throbing headache headache with every pulse is that right this is the basic mechanism how headache is produced with nitrates one of my teachers used to say if a patient is taking nitrates and develop headache tell the patient we are sure drug is original drug has started its function right so as drug reached to the meningeal artery meningo arteries start dilating or vessels passing through the foramina cranial foramina dilate and beat the dura metal pain receptors against the bone with that arteries of the face and skin are more sensitive to the action of the nitrates due to that reason many people when they take nitrates not only they develop severe headache but with that they also develop dilatation of facial arteries and facial blood flow and they develop facial Flushing is that right then another extremely important sideways most common side effect was headache and most important side effect is postural hypo tension now let me tell you what is postural hypotension postural hypo tension now first I have to explain the normal physiology right that how blood pressure changes and cardiac output changes with change in posture and what happens when patient is on nitrates most important side effect is postural hypotension now how the side effect occur first let me explain the basics that let's suppose here is your heart and you know that from here there is venous side and this is the venous blood return to the right heart and you know it that from here it will go to the lungs and through the lungs it will come to the left heart is that right now and here is your let's pose just a minute if we draw the aorta on the aorta there are what is this rotate sinus what is it they rotate sinus now listen carefully what really happens first about the normal person and then about the now in a normal person from lying down position from the lying down position if normal person suddenly stand up what happened in the body when he is suddenly stand up the venous blood pulls into lower part of the body this point number one normal person from lying down position with suddenly stand up Venus blood pool into lower part of the body so Venus return is reduced so cardiac filling is reduced and of course and diastolic volume is reduced so that will lead to reduced cardiac output you understand when a lying down position person suddenly stand up initially for a very brief time this reduction in venous return due to pooling into lower part of the body the reduced cardiac reduced venous return reduced cardiac filling reduced cardiac output reduced stroke volume this reduced stroke volume produces less blood pressure and there are baroreceptors in the Carotid sinus immediately as soon as cardiac output is reduced through the barrel receptor information goes to the central nervous system right information goes to the central nervous system to the medulla right and from the medulla Vaso motor centers are stimulated which centers are stimulated Vaso motor centers are stimulated and sympathetic outflow occurs what occurs sympathetic outflow occurs this sympathetic outflow look here the sympathetic fibers will lead to we know they will lead to we know construction right they will act on venous smooth muscle and release on the venous smooth muscle what thing not epinephrine so what really happens that sympathetic outflow has two functions number one it will fire on the sympathetic outflow on the veins and squeeze the vein so the normal person as soon as you stand up and there is reduced cardiac output it activate the compensatory mechanisms and reflects compensatory mechanism produces Vino construction so that cardiac venous return should be maintained so that cardiac output should be maintained and cardiac output should not drop significantly and for prolong time am I clear in this way if you you are young healthy people from lying down position when you stand up you don't get any problem because the reflex neuronal reflexes so squeeze the veins so that venous return should be maintained am I right now you imagine patient of nitrates on the nitrates what happens that from lying down position if you suddenly it's okay this patient is going to run away now from the lying down position this patient is on the nitrates as soon as you stand up of course Venus pooling will occur of course cardiac output will initially drop of course baroreceptors will be activated and these Barrel receptor you can say sensory nerves will stimulate and form the medulla that there is reduced cardiac output of course sympathetic nervous system will fire but if nitrates are working on these smooth muscles can sympathetic nervous system induce significant contraction answer is no so if sympathetic reflex mechanism can not stimulate what contraction right it means venous return will not be maintained so there will be prolonged reduction in Venus return and there will be prolonged reduction in cardiac output and in this person from lying down position when he will stand up he will develop significant significant fall in blood pressure systolic blood pressure is that right and we say with the posture from lying down poster to suddenly standing posture he has developed High poor tension his blood pressure has dropped because compensatory mechanism could not maintain the blood pressure right because veins was dilated and they did not respond to a sympathetic overflow am I right so we say this patient will develop postural yes hypotension this type of hypotension is also called orthostatic hypotension so postal hypertension or orthostatic hypotension is a condition in which neurovascular mechanism cannot uh you can say constrict the veins on standing and cannot maintain the Venus return and they cannot maintain the cardiac output and swear and prolonged drop in cardiac output right on standing will lead to postural hypotension or orthostatic hypertension am I clear right now due to this thing the blood flow to the brain is increased or decreased decrease this prolonged reduction in blood flow to the central nervous system will produce light-headedness and that prolonged reduction perfusion to the central nervous system will produce vertigo that will produce dizziness or vertigo and with that if it becomes really too much then blood flow to the whole cerebral cortex becomes so low the cerebral cortex does not work and you know cerebral cortex is responsible to maintain your Consciousness when cerebral cortex does not work you become transiently unconscious a syncopal attack occur so many patients when you give them antihypertensive drugs those anti-hypertensive drugs which interfere either with the output of sympathetic nervous system or interfere with the we know Construction such drugs have a risk of producing postural hypotension and such patient will come back to you Doctor I had the hypertension hypertension did not do anything to me because most of the time mild to moderate hypertension is asymptomatic right but doctor you give me the drug and after taking your table ads when I wake up in the morning I develop severe dizziness headache and sometimes you know two days back I fell in the washroom because I got unconscious so you have to be careful when you are prescribing these drugs right that how how you can alleviate these side effects am I clear so one of the very important side effect is postural hypotension there is systolic drop significant systolic drops on standing up position with that number two position is there is lightheadedness and dizziness and sometimes even transient loss of consciousness due to global cerebral hypoperfusion am I clear right so this is something we have to take care about these patients that nitrates do should be adjusted in such a way that patients should not undergo postural hypertension and another thing which is very important look when Venus return is reduced attention plays any drug which significantly reduces the venous return you know that reduces cardiac output and of course venous return reduced and diastolic volume reduce cardiac output reduced and there's strong stimulation to vasomotor centers and their strong sympathetic outflow please listen very carefully this is I told you already that this sympathetic outflow will fail to squeeze the vein but this sympathetic outflow will be able to stimulate heart and if there is essay node here then this will stimulate the SNR so this patient with hypotension will develop severe reflex tachycardia do you think this is good for a general patient no no that is why we have to give the other friend of this drug who is the friend of nitrates beta blockers so when we give beta blocker they prevent The Reflex tachycardia which may be precipitated by nitrates again let me repeat it that when you are giving nitrates right this significant we know dilatation in a way it is good for us and sometimes it is not good for us why it is good and therapeutically useful because winners pooling reduces winners return reduces and diastolic volume and that reduces the work of the heart and reduces the oxygen demand and angina is terminated terminated is that right but sometimes if Venus return is too much reduced and endospholic volume is too much reduced then cardiac output is too much reduced that may lead to severe sympathetic outflow especially from when patients undergo postural change from lying down position to standing up and when patients stand up is that right this sympathetic outflow will fail to construct the vein but it will be very successful in stimulating the and the sympathetic stimulation will also produce positive inotropic sorry positive chronotropic action and positive ionotropic action of course these two things increase the work of the heart right so we should give some other drug along with nitrate to prevent the side effects so we should block the beta receptors in the heart so that sympathetic nervous system does not drive the heart wild is that right and the drug in combination should come as beta blocks is that clear right so these were some side effects with the nitrates I have talked about that this headache there is flesh and facial flushing there can be hypotension there can be reflex tachycardia which may precipitate patient will not come and say doctor I have reflex tachycardia patient will complain about palpitations how Jamie how do you define the palpitations what are palpitations or palpitations hello okay he says this is something like feeling like something coming out of chest yes this is one of the expression for palpitation but palpitation in medical term is different you say palpitation is in medical terms palpitation is unpleasant awareness of cardiac activity either you think something is coming out of chest or you feel something is coming out of throat but actually what is palpitation that patient becomes unpleasantly aware of cardiac heartbeat because because so many of these patients due to reflex tachycardia May complain about palpitations is that right but remember sometimes you are pleasantly aware about the cardiac activity sometimes when you are with your certain circumstances especially after exercise or some special company you are and you feel palpitation pleasantly that is not to be treated medically is that right so medically we talk about palpitation is unpleasant awareness about the cardiac activity is that right unpleasant word is very important we will be talking about beta blockers and their role in patient with angina right first of all few words about the beta blockers beta blockers are the drugs which block reversibly or competitively reversibly or competitively competitive lay beta adrenergic receptors you know adrenergic receptors are classified like this receptors for epinephrine norepinephrine and dupe right receptors for catecholamine they are classified like Alpha receptors and beta receptors right we will not talk about Alpha receptor today because beta blocker do not act on Alpha adrenergic receptors they mainly work on the beta adrenergic receptors and beta adrenergic receptors are divided into two categories that is beta 1 adrenergic receptors and beta to adrenergic receptor right beta1 adrenergic receptors are present mainly on the heart beta1 adrenergic receptors are present mainly on the heart let me show you the beta1 adrenergic receptor distribution of the heart here is your essay node here is your yes AV node very good bundle of fails and bundle branches now beta1 adrenergic receptors are present on essay node they are present on Atria they are present on AV node they are present or percentage of fiber and specialized conduction pathway and they are present on ventricular myocardium so it means that beta 100 energy receptors are present on specialized myocardium as well as general myocardium specialized myocardium is acetode Av node and conduction pathway and general myocardium is real myocardium and ventricular myocardium which does the function of contractility so we can say beta1 receptors are present throughout the heart and here I would like to mention that now there is release of norepinephrine from the nerve endings and through the circulation you know Adrenal medulla releases epinephrine into circulation so through the circulation epinephrine reaches to all heart epinephrine goes to all myocardium and through the nerves there is arrival of norepinephrine epinephrine and norepinephrine they work on this point number one as a node when they work on the essay node this is star one action I can write it that when the work on essay node okay I will write star one action star one action is the action on the S note and that will produce positive chronotropic activity Chrono tropic effect positive chronotropic effect mean increase in heart rate this is the normal function of beta 1 receptor stimulation then when beta 1 receptors are stimulating the AV node there is star two action and beta 1 receptors are stimulating the AV node then conduction through the AV node become fast and that produces positive dromo tropic effect or action that is increase conduction yeah through the AV node right by action on the SN word it produces positive chronotropic action by action on the even ordered produces positive Tropic action remember AV node is like a drum between the artery and ventricle every node is like a drum between the Eritrean ventricle so things which increase the activity of Av node reduction they are positive dromotropic and things or drugs which reduce the conduction through V node the negative dromotropyl then star three action is that epinephrine or norepinephrine stimulate the beta's one receptor on contractile myocardium and that produces increased contractility called positive inotropic action so star three action is positive inotropic action that is action of by stimulation of beta 1 receptors on the myocardial contractility when those receptors are estimated there is increase when epinephrine stimulates the beta-1 receptors on myocardium myocardial contractility is increase and we say that is a positive I know tropic action or effect am I clear so this is the main action of beta 1 receptors on the heart moreover beta 1 receptors have their receptors or in the bronchial smooth muscle normally beta 1 beta 2 receptors now we are talking about beta two receptors which are two receptors act on the bronchial smooth muscle and normally produce Broncho dilation bronchiole dilation normally number one number two beta2 receptors they work on the liver hepatocytes have beta2 receptors and when this beta2 receptors are stimulated on the hepatocytes there is increase glyco Geno license it means when epinephrine is more in the blood epinephrine will act on the hepatic which are two receptors and produces the breakdown of glycogen and when there's breakdown of glycogen there is increased glycogenolysis and that lead to the release of glucose from the liver thirdly beta2 receptors act on the pancreas and which are two receptor stimulation when it act on the pancreas really releases glucose gone and this glucagon also act on the liver and when glucagon act on the liver okay again let me repeat that Peter 2 receptor stimulation produces glucagon and this glucagon will act on the liver and increase glucose Neo Genesis gluconeogenesis mean production of glucose from known carbohydrate sources is that right so it means that beta2 receptors can directly release the glucose from the liver beta 2 receptor activation on the liver can directly release the glucose by breakdown of glycogen plus beta2 activation can release glucagon so it can act on the liver and increase gluconeogenesis and further release the glucose into blood is that right and beta2 has many other functions also right now they are not relevant with us now we are going to discuss about the beta blockers beta blocker drugs are the drugs which will block The beta-1 receptors and if they are non-selective drug they will also block the beta to receptor now let's talk about those drugs into detail I've told you very briefly few actions of beta 1 and beta2 receptors when these receptors are activated now we go to that these beta blocker drugs they reversibly are competitively bind with the beta receptors and block them and these beta blockers are non-selective drugs non-selective beta blockers which will block the beta 1 as well as they will block the beta2 receptors they will block the beta 1 receptor as well as beta2 receptors the classical example of the drug in this category is propranolol Pro Prana wall and there are others also but the minimum you have to remember that the classical example of non-selective beta blocker is propranolar but there are some other drugs write the beta blockers and at low doses the specially block beta 1 receptor receptor they work more on the beta 1 receptors so they are called selective beta1 blockers and the classical drug in this category are selective beta 1 receptors blockers these are Atenolol Atenolol acidolol right the drugs which are present in this and atenolol occipitalol and metoprolol Vito Pro law again listen one category is non-selective beta blocker which block beta1 and beta 2 both then there is selective category which block mainly beta one receptor at low doses but remember this selective action is lost at higher doses for example Atenolol at lower doses will block mainly beta 1 receptor right but as you keep on increasing the dose beta2 blocking will also start again beta 1 selectivity is only relative term because these drugs block more beta 1 and the block less beta2 right but they do block beta 2 to some extent and if the dose is increased then the selectivity is lost and while blocking beta 1 at higher doses they also block the beta 2 am I clear once you have made this concept you know beta 1 receptors are present on the heart that is why beta 1 blockers are also called cardio selective beta blocker cardio selective because they specially work on the heart oh cardio selective beta blockers so what are cardio selective beta blockers these are the group of beta blockers which are beta1 blocker at load hoses am I clear now once we have talked a little bit about these drugs beta blocker let's see what is their role in angina what are the advantages of beta blockers in angina right let's suppose here is your heart okay let's make a smaller heart okay I need to clean it again right so we have a heart over here again what is here essay node and what's here even all right and park Angel system right and then now I told you beta1 is suppressor on essay node right they are on AV node as well as an atria and they're present on now these are all beta1 receptors so heart is well decorated with beta 1 receptor let's suppose we give a beta blocker drug when we give a beta blocker drug what this drug is doing it will bind with the adrenergic receptors on acinode on AV node as well as on The atriant ventricle so it means that sympathetic action will be lost on heart so when snored beta1 receptors are blocked then Epson nodal stimulation by catecholamine is reduced by endogenous catecholamine is reduced so heart rate will go up or down it will go down so actually it produces negative chronotropic action this positive chronotropic effect of endogenous endogenous when snode is blocked that will lead to Point number one is when SA node is blocked by the beta blocker there will be negative chronotropic action and heart rate will reduce and when you can say AV node is blocked having its beta receptor blocked then conduction through every node will become slow and that that will become negative dromotropic action and when beta 1 receptors are blocked on contract contractile ventricular myocardium ventricular myocardium is no more driven by endogenous catecholamines and conductivity of ventricle is reduced and that produces negative chronotropic action in a nutshell what can we say that beta blockers reduce the electrical activity of the heart as well as reduce the mechanical activity of the heart so simple to state that beta blockers reduce the beta1 blocker especially they reduce the electrical activity of the heart as well as mechanical activity of heart when electrical activity in the heart is reduced this reduced normal automaticity and negative chronotropic action heart rate will reduce conductivity through the AV node is reduced and mechanical activity is reduced it means contractile it is reduced now listen when beta blockers reduce heart rate as well as the reduce the contractility it means they reduce the stroke volume so if they are reducing the heart rate and stroke volume it means they are reducing the cardiac output it means they are reducing cardiac work if heart rate is slow you know donkey is moving less cycle I think you should not forget the donkey so the donkey is moving less cycles and this is Contracting slowly is that right and with less tension so what really happens the cardiac work is reduced and when cardiac work is reduced there's reduced need of oxygen this is how beta blockers help that primarily they lead to reduction in heart rate and reduction in heart rate due to negative chronotropic action and reduction in stroke volume due to negative ionotropic action and both things lead to reduced cardiac output to reduce work of the heart reduce need of oxygen am I clear yes no positive chronotropic increase the heart rate negative chronotropic decrease the heart rate listen catecholamine stimulate the beta-1 receptor and positive chronotropic action problematenolol block the beta-1 receptor and reduce the heart rate Amic layer look of course we have to negative chronotropic well reduce the heart rate and reduce the conductivity and of course reduce the contract a that is of course you are right I need it yeah again listen first was physiology that normally we are physiological some sympathetic tone and some epinephrine in our blood right this physiological epinephrine keeps it's a node somewhat stimulated AV node somewhat simulated and contractility is someone stimulated somewhat stimulated am I clear now what is the advantage of beta blockers now beta blockers reduce the heart rate reduce the contractility eventually reduce the cardiac work and reduce the need for oxygen so beta blockers reduce the work of the heart reduce the need of oxygen so do you think when your heart is well protected by beta blockers is work is less do you think rational engineer will easily precipitate no no secondly extremely important thing not only at resting situation it is good you know when this patient is resting right with the classical angina this patient is resting and without his on beta blocker so the heart rate is less than normal maybe heart rate is 65 not 85. right so even resting heart rate is less so we can say resting work of the heart is reduced less chance of vagina during rest and even if this person starts from some exertion person with beta blocker starts from exertion or he undergoes some emotional turmoil right beta blockers when you are on the beta blockers and you undergo some emotional excitement or emotional tension epinephrine is released if your beta receptors are blocked can appear different really drive your heart rate up no or when you start a version of physical activity you know sympathetic tone goes up and your heart rate should go up but do you think if you are on beta blockers your heart rate go up no so the beauty of beta blocker is that not only it protect the heart when person is emotionally and physically comfortable but it also protect against the cardio acceleration during the emotional stresses and during physical aversion right so these patient of angina if they are protected with the beta blocker if they are on the beta blocker when they do physical exertion heart rate will increase only slightly a work of the heart will not be increasing too much right that is why that total episodes of angina will be reduced is that right so this patient with angina can have beta blocker and then he can afford to go under some excitements or emotional fluctuations because beta blockers will keep the heart well protected from the internal flooding of epinephrine is that right so no risk of angina or less risk of angina or even Mi am I clear yes the point which I want to tell another that nitrates and beta blockers make a very good couple nighters and beta blockers make a very wonderful couple they help each other you know very good couple very good man and a lady what they are doing you I know you know what they are doing but the good thing which they are doing is both of them are good for each other and they try to compensate for the shortcomings of each other if husband has some you can say shortcomings or adverse action maybe wife will compensate if there's a good wife and if wife has some adverse effect on community on the Family Life husband will try to compensate now we will see when you combine the nitrates and beta blockers they make a very wonderful couple very happy and beautiful couple they try to increase the advantages of each other and try to cancel the side effects of each other let's see how they do it now we discuss the combination of nitrates with beta blockers you know that nitrates produce Vino dilatation should I make a diagram or without diagram we discuss without diagram okay what really happens nitrates are strong what we know dilators right let's suppose here is your heart I will make a very simple diagram and here is your Venus input to the heart and here is your arterial system very simple diagram right here is your central nervous system right this is the baroreceptor system from where from arterial tree from aortic body they produce input to central nervous system is that right and this is the sympathetic outflow this is sympathetic outflow now sympathetic outflow is going to the heart right sympathetic outflow is going to the veins and of course sympathetic outflow is going to the arteries right so these are beta 1 receptor in the heart this is the beta1 receptor on the veins or veins sorry it has Alpha One receptors and arteries these are alpha one receptors now as you imagine listen please carefully what is happening when you give nitrates we know dilatation occur when there's significant Vino dilatation venous return is reduced cardiac filling is reduced is that right cardiac output is reduced and cardiac work is reduced all this thing is good for angina but there is one problem with nitrate when they work too much there's too much we know dilatation cardiac out filling is too much reduced cardiac output may be dangerously reduced and when there's two might decrease in cardiac output nitrates by reducing the cardiac output right stimulate the reflex tachycardia the stimulate the reflex we know construction the stimulus that reflects arteriola construction but because nitrates keep the veins dilated so this reflects we know construction will not be there but there's a problem when nitrates dilate the winds too much sympathetic overflow will stimulate the heart and there may be reflex tachycardia so there in nitrates there's increased risk of heart rate increase and the risk of increase stroke volume because beta 1 receptors are also here is that right so it means nitrate giving nitrate is good in one way but in some patient by producing reflex sympathetic activity right there may be increased risk of heart rate and increased stroke volume and that may increase the work of the heart so in this way the work of heart which was reduced by reducing the preload has been canceled if we give beta blocker listen carefully if we give beta blocker here then nitrate induced reflects sympathetic activity will not write will not be successful because beta blockers do not allow the sympathetic nervous system to work on the heart and secondly beta blocker do not allow uh right in this way nitrate and used reflex tachycardia is reduced by beta blockers so in this way beta blocker help the patient to cancel some of the side effects of nitrates am I clear now we come of course nitrate is good in return it should also help the action of beta blocker now let's come to the beta blocker and what it is doing I told you beta blocker slow the heart rate and slow the contractility and when beta blockers are slowing the heart rate and slowing the contractility and reducing the contractility it means total Venus fill in time if your heart rate is less then diastolic time is more if your heart rate is less it means that totals cardiac cycle the more or less per minute less if cardiac cycle the less then naturally diastolic time will increase and it means that any drug which reduces the heart rate increases the diastolic filling time so it means beta blocker favor the ventricular filling so beta blockers increase and diastolic volume secondly another bad thing which beta blockers do is contractility is reduced and when contractility is reduced then less stroke volume is ejected and more is retained and again and diastolic volume will increase it means one of the disadvantage of beta blocker is that they increase the end diastolic volume do you think it is good for a Jana patient or bad it is bad for a Janna patient here the nitrates will help how by keeping the veins so much dilated that in spite of there is more diastolic duration still Venus feeling will be less is that right in this way again in a short in a nutshell advantage of beta blocker is that it reduces the heart rate reduces the contractility and reduces the work of the heart and by doing these things it is good for anjana patient but unfortunately by the same thing it increases and diastolic volume which is bad for the patient of angina patient of angina but if you are giving with the beta blocker nitrates nitrate will take care of this unwanted action of the beta blocker that beta blocker should reduce the heart rate should reduce the contractility but there should not be increased and diastolic volume but beta blockers do increase and diastolic volume if given alone so if nitrates are given with them they will keep the veins enough dilated that in spite of prolonged diastolic filling and in spite of slow contractility still and diastolic volume is not increased right so in this way both drugs help each other again because it's so important to understand this combination I will repeat it in now one sentence listen what is the advantages of combination of nitrates and beta blockers in a patient with angina classical angina listen side effect of the nitrates are partially compensated by the beta blockers side effects of the beta blockers are partially compensated by nitrate how when we give nitrate alone they may precipitate reflex tachycardia and and that may lead to again increase in cardiac work so whenever with the nitrate beta blockers are there nitrates will not be able to precipitate reflex tachycardia because beta sub 1 receptors are blocked and in this way this unwanted action of nitrate is abolished then when beta blockers are given alone if beta blockers are given alone they do reduce the heart rate they do reduce the contractility in this way they do reduce initially cardiac work but unfortunately when heart rate is reduced too much and when contractility is reduced too much then end diastolic volume increases with low heart rate and with reduced contractility and diastolic volume increases because at low heart rate there's longer diastolic duration so this is longer time to fill the ventricle and if there's low contractility then less amount of the blood is ejected and total pooling become more so it means beta blockers are good and bad how they are good by protecting the hard against tachycardia and protecting the heart against contractility they are good by reducing the heart rate by reducing the contractility by reducing the work of the Heart by reducing the oxygen demand they are good but by increasing the industrial equal volume they are bad but when nitrates are given along with beta blockers then beta blocker tend to increase and astolic volume but nitrate tend to reduced and diastolic volume so this unwanted action of beta blocker is canceled in the presence of nitrates is that right that is why combination of nitrates and beta blocker make a wonderful combination is that clear now we come to one more thing some important side effects of beta blockers some extremely important side effects of beta blocker every doctor should know what are the contraindications for the beta blocker before I really go for contraindication for beta blocker or special precautions and use of beta blocker I tell you one thing very important side effects of beta blockers in detail I will discuss when I discuss the beta blockers with autonomic nervous system right but first thing which I'm going to tell those side effects as well as contraindication together is that right no no I will give it more clearly now hold on first first lesson lesson plays be a tentative what I was saying I think you are getting tired maybe my we are about to finish but most important part of the lecture come now because if you give beta blocker to a wrong person you may kill her right and you should not do that then while trying to reduce uh you know beat up in China of a asthmatic patient you give beta blocker and kill him with asthma yeah so this this mistake should not be done so let's talk about what are the special precautions with use of beta blocker the most important precaution is never stop the drug abruptly if you have been given given it for long time when you are using beta blocker for a long time never ever stop the beta blockers abruptly why can you tell me why why we should not stop the drug abruptly the reason being beta 1 receptors has been blocked by the drug for a long time and when the scepters are blocked for very long time when receptors are blocked for very long time receptor undergo up regulation for example you are the patient with angina and you are using beta blocker from last three years in these three years you have been keeping the receptor blocked so receptors will undergo down regulation or up regulation up regulation receptor concentration will decrease or increase on the heart increase look at the diagram hold the heart is overloaded and overly decorated with the receptors whenever you block a receptor for long time receptor goes up regulation whenever you stimulate a receptor strongly for long time receptor go down regulation is that right so patient on the beta blockers for long time have upregulated beta receptors now if patient has higher concentration of receptor then you are keeping these receptors well blocked with beta blockers no problem to the patient but if you suddenly stop the drug unfortunately certainly this heart with upregulated beta1 receptor become exposed to the endogenous epinephrine and norepinephrine and they will be very strong stimulation of endogenous catecholamine to this heart suddenly heart rate will go up Suddenly what is this cardiac stimulate contractility will go up and that may enormously increase the heart rate and contractility and that may enormously increase the work of the heart and that may dangerously increase oxygen demand and if your narrow vessel cannot meet their demand very dangerous what angina's or even four myocardial infarction May precipitate I hope you'll remember it in your lifetime right that if you are giving beta blockers for a long time then bitter one receptors in the heart are up regulated and when beta1 receptors are upregulated what really happens what really happens right that as soon as you abruptly stop the beta blockers by mistake right endogenous catecholamine will drive the heart Wild suddenly heart rate will go up contractility will go up and cardiac work will go up oxygen demand will go up and if narrow vessels cannot meet that oxygen demand where is sphere ischemia may lead to even precipitation of myocardial infarction is that right now we will we shall be discussing about the side effects and contraindications of beta blockers uh disrespect of beta blocker is very heavily tested in all the medical exams the reason being that beta blockers are very important drugs they are very widely used drugs but they have to be used with lot of precautions already we have discussed that if you are using beta blockers on the long term basis for your patient never stop them abruptly because that may precipitate ischemic heart disease episodes is that right so whenever you are going to stop beta blockers after after a long term use you should taper off the doors over 7 to 14 days so over one to two weeks you should reduce the dose of beta blockers gradually then there are some side effects related with the use of beta blockers very important side effect is fatigue patient feels fatigue now this fatigue may be due to some Central mechanism That central nervous system is slightly inhibited and this fatigue may be due to peripheral mechanisms as well you know that uh beta 2 receptors are responsible for certain degree of vasodilatation and skeletal muscles did you know that or not right their blood vessels look here the blood vessels which are going to the muscles must write these blood vessels have less alpha 1 receptors and these blood vessels are having more beta2 receptors you must be knowing that when epinephrine act on Alpha 1 receptor rate produce arterioloconstriction but when epinephrine work on beta2 receptors it produces Vaso dilation right so we can say in the peripheral circulation there is Alpha One mediated Vaso construction normally Construction in a normal person and in the peripheral circulation in normal person there is beta 2 mediated yes mediated Vaso dilation naturally the blood vessels which are rich in Alpha One receptors they undergo there is a construction on epinephrine right and blood vessels like blood vessels or the muscles which are rich in beta2 you know receptor as the undergo base of dilatation while keeping this in mind now you imagine if you put the patient on beta blockers right and if beta blocker drugs are blocking the peripheral again if you are putting the patient on beta blockers and if beta blockers are blocking The beta2 receptors of peripheral vasculature beta2 receptors will not work because they're blocked by the drug what will happen beta-2 mediated vasodilation will be lost right so the concept is when you give the beta blockers especially non-selective beta blockers when they block the peripheral vasculature beta2 receptors then beta2 receptor mediated visual dilatation is lost and plus blood vessel become slightly constructed in this patient if they do exercise do you think their vessels can dilate well how they will dilate beta 2 mediated visual validation is lost you know during exercise when sympathetic flow is there is the right increased sympathetic outflow is there during exercise that lead to beta2 mediated visual validation of the blood vessels especially to the muscles and if patient is already on beta blockers then if you do some exertion or patient is doing some exercise even though sympathetic outflow will be there but sympathetic outflow will not be able to stimulate the peripheral beta-2 receptor to mediate wizard validation so there will be loss of beta 2 mediated wizard allocation in the patients who are on the beta blockers and of course if your blood vessels are not dilating during your exercise can you have exercise for longer time you cannot and you will get fatigued too early and you will develop some degree of exercise intolerance you get it so this is one of the common problem that patients who are on the beta blockers they develop a resting fatigue and especially they develop fatigue during physical assertion right too early right one of the mechanism may be that there is loss of beta 2 mediated vasodilation right so there is no incremental increase in the blood flow to the muscles am I clear then another important thing is that beta blockers which go to the central nervous system they produce sleep disturbances right they produce sleep disturbances many patients develop insomnia and some of the beta blockers which go to the central level system they also produce nightmares red sleep disturbance and night nightmares are another problem related with the use of beta blockers right then as you know adrenergic nervous system stimulates the as you know adrenergic Drive stimulates the central nervous system of course beta blockers are anterior energy drugs so what happened they suppress the central nervous system very little but sometimes it may precipitate in some patients depression it may precipitate in some patients depression right and last but not but not the least important side effects especially in the mail there's yes importance you know males talk about immediately yes importance right failure to maintain enough erection right that is also seen with the patient on the beta blockers so now we'll come to the special contraindication and special precautions which must be used for the patient with beta patients on the beta blockers right now for this regard we will talk about thank you foreign there are five situations which you should remember very well right I will explain them the five conditions at least where beta blockers should not be used or you should be very very careful right now what are those five conditions first I'll tell you what are those five conditions and then I will tell you that why beta blockers are contraindicated in those five conditions you know this is a death star this is a death star and death even may occur uh in some of these conditions and beta blockers are used it must be Black Star this five conditions number one is asthma asthma or other copds what are copds chronic obstructive pulmonary diseases right here this is the beta blockers should not be used I will explain why second condition is diabetes mellitus especially those diabetic patients who are insulin dependent were insulin dependent beta blockers should are contraindicated or should not be used I will explain of course why then peripheral vasospastic diseases like Raynaud's phenomenon Reynolds disease or in arts phenomenon right the patient in which there is peripheral vasospastic situation beta blockers should not be used then patient with Brady eurythmias right patients who are already having right Brady arrhythmias ready Mayans right in these patients beta blockers should not be used and of course if someone has already depression will you use the beta blockers yeah he will get more depressed so these are the five conditions in which beta blockers should not be used or very carefully I will deal these conditions one by one first of all why beta blockers are contraindicated in corn chronic obstructive pulmonary diseases right why first I will talk about normal what normally is going on in your lungs and what happens when you give the beta blockers listen carefully actually normally you know smooth muscles of bronchial broncular smooth muscles they're very rich Let's suppose this is bronchial system right and bronchial smooth muscles they're very rich in uh these are two receptors this is bronchial's post Booth muscle I just showed you one bronchial smooth muscle and it is very very rich in beta2 adrenergic receptors what are these beta2 heteronergic receptors normally what happens that your endogenous category means endogenous category means stimulate beta2 receptors on bronchial smooth muscle and normally you know there is beta2 mediated yes bronchodilatation Bronco dilation so normally you have a slight degree of bronchodilatation maintained by the beta2 activity right by the endogenous catecholamines now when you give up beta blockers to normal person there may be slight loss of this which are two mediated bronchodilatation and in a normal person it may not be a big problem but those patient who have coronary pulmonary chronic obstructive pulmonary diseases they have a tendency to develop they are already having a tendency to have obstruction to the Airways is that right these patient may be asthma patients as stomach patient COPD these patients may be yes chronic bronchitis patient chronic bronchitis patient these patients may be emphysema emphysema patients and of course the patient with bronchiatases he act says so these patients patients with asthma patient with chronic bronchitis patients with emphysema where there's loss of elasticity in the lung and bronchial cannot be kept open properly and patient with bronchitis is in all these conditions there's always some degree of Airway obstruction patient come to you and due to some hypertension or due to some cardiac indication you inadvertently by mistake put these patients on the beta blocker especially non-selective beta blockers like Propranolol there will be certain laws of beta2 mediatase bronchodilidation and because they have already a degree of Broncho obstruction so what happened this loss of beta 2 bronchodilation May precipitate very severe bronchoconstruction and sometimes this may be fatal right so you have to be very careful that whenever you are going to administer to a patient beta blockers right and right you must be sure that patient does not have any disease like chronic obstructive pulmonary disease am I clear why because there's loss of beta2 mediated bronchodilatation which is very important in the patient with coronary chronic obstructive lung diseases right this is one condition and here you have to remember that in these diseases even it is better to avoid the selective beta blockers because selective beta blocker like Atenolol even though they are having more action to block the beta1 and uh they have less section on the beta2 but still to some degree they do block The beta2 receptors so why to take the risk am I clear then we come to the very important concept that why patient with severe diabetes are labile diabetes or the patient with insulin dependent diabetes why this patients should not be given beta blockers patient of diabetes mellitus especially who are insulin dependent let me tell you the main problem with the patient on the insulin dependent diabetic patient is that sometimes they develop severe hypoglycemic attack you know why for example if I'm a severely diabetic patient and you are managing Me by in injections of insulin then I have a risk of developing hypoglycemia what could be the reason no actually insulin is given in a standardized ways you will measure my requirements of insulin and give me but what really happens for example patient has taken insulin injection but has not taken food what are the conditions in which insulin dependent diabetics can develop hypoglycemia write it down the conditions in which insulin dependent diabetics May develop severe hypoglycemia right so hypoglycemia May develop when patients are taken insulin but not food he may develop or patient has taken insulin and after that he has taken food but he has vomited out vomiting so you lost the food and Insulin which has gone and will precipitates we are hypoglycemia or patient has taken insulin and even he has taken food but that day he has done specially more physical activity excessive excessive physical activity and of course this patient has entered advertently taken extra amount of insulin is taken insulin more than what he really needed right so under all these circumstances and many other circumstances patients who are insulin dependent they develop hypoglycemia now listen carefully I'm going to explain that when insulin dependent patients develop hypoglycemia when insulin dependent patient develop hypoglycemia how the body responds is that right then I will explain how the beta blocker interfere with the body responses right first I will tell you that if you are if I'm insulin independent diabetic and I'm undergoing hypoglycemia how my bodily mechanisms are activated right later on I will tell you how beta blockers interfere with those bodily mechanisms listen for example this is my circulatory system this is my circulatory system what is happening the primary problem is Hypoglycemia hypoglycemia means that glucose level is dangerously low is that right now whenever glucose level is low there are some physiological responses activated some neuronal responses are activated and some endocrine responses are activated number one that whenever glucose level is low what really happens that your central nervous system is activated low glucose will stimulate the central nervous system and that will lead to very strong sympathetic outflow that will lead to very strong sympathetic outflow now this sympathetic outflow is good for the patient the patient who is having what is the patient problem hypoglycemia as hypoglycemia gets more and more severe there is stronger sympathetic outflow from central nervous system now what are the advantages of these sympathetic outflow number one these sympathetic outflow will produce warning signs warning symptoms for the patient right for example that this patient May undergo tachycardia turkey and many patients right or this patient with tachycardia May develop tremors is that right so and even patient may develop sweating now listen These Warnings symptoms are very important for the patient why they are important the reason being that if I am insulin dependent diabetic and if my glucose level is going down with the experience I will learn that whenever I develop palpitations tachycardia leading to palpitations and whenever I develop Tremors and sweating probably my glucose level is low and I should abort hypoglycemia by taking a lump of sugar immediately actually all the patient whom you put on insulin it's always wise that expose them purposefully to hypoglycemia and then educate them how they these are the for example if your first time putting a patient on insulin so why is that tell him that you're going to expose him to the hypo and then really give a little more amount of insulin and when you go hypo then he will develop this warning signs and tell him how to recognize this warning sign and tell them that these warning signs are the signs are due to hypoglycemia then offer him some sugary drink or lump of sugar and educate him that how he will take it and how he the symptoms of hypoglycemia will disappear is that right so thank God that patient when they undergo sphere hypoglycemia nature provides the patient nature provides the patient with warning symptoms is that right now when you put the patient on beta blocker listen carefully when you put the patient on beta blocker drugs right there is beta 1 mediated tachycardia and this beta-2 mediated primers so patient who is on beta blockers will he be aware he will develop the warning sign on hypoglycemia no so this is one problem that patients who are diabetic and insulin independent and unfortunately you have put them on beta blockers so whenever they develop hypoglycemia right they will not develop the warning signs of hypoglycemia so patient will not be aware of that he is going into progressively deeper hypoglycemia which are two receptors when they are stimulated you know beta2 receptors are present on the muscle spindles and when beta2 receptors are stimulated that leads to Tremors is that right so which are two mediated primers beta2 adrenergic receptors lead to Tremors and of course beta 1 hydrologic receptor lead to tachycardia so there's loss of tachycardia there's loss of Tremors so we can see that this drug leads to one problem which this drug is doing one dangerous thing that there's loss of warning symptoms of warning yes symptoms of hypo glycemia this is one problem so patient is handicapped that patient never gets aware that he is undergoing hypoglycemia and he does not take exogenous sugars am I flat now what is the next step next step is that liver should provide the glucose liver should provide the extra let's suppose here is a hepatocyte here is a hepato side now what really happens that when your glucose level is going down two humoral actions will occur two humoral actions will occur number one of course a lot of adrenaline is released by adrenal gland due to sympathetic overflow so there's a lot of epinephrine in the blood and normally this epinephrine Act through beta2 receptors these are beta2 receptors where on hepatocytes so normally what happens when your blood glucose level is down due to increased sympathetic activity not only there are warning symptoms but increased sympathetic activity also increases epinephrine in the blood and this epinephrine will act on adrenergic receptors on hepatocytes and when this epinephrine will act on the hepatocytes what will happen that intracellular signaling eventually lead to breakdown of yes glycogen there is glycogen so glycogen will be broken down under these signals into glucose and this glucose will be provided to the blood from the hepatocytes is that right what a beautiful normal mechanism that whenever you develop hypoglycemia not only body is giving given warning about that at the patient's conscious level but endogenously increase epinephrine stimulate the beta-2 adrenergic receptors on hepatocytes and they give intracellular signal which order the glycogen break down into glucose and liver start hepatocytes start releasing glucose into blood to counteract the hypo glycemia is that right it's good news the bad news so good news unfortunately when you give the beta blockers they block the receptor here so endogenous mechanism to compensate for hypoglycemia by glycogenol lysis is lost this is the action of propranolol propron and LOL block The beta2 receptors on the hepatocytes and then epinephrine induced glycogenolysis is lost so glycogenolysis cannot be done and hepatic glucose cannot be released to compensate for the decreasing glucose level in the blood am I clear so now it's a good news or bad news it's a bad news is that right now not only this another help normally come and that help come from pancreas you know what pancreas produces under sphere hypoglycemia pancreas produces glucagon it produces glucagon and this glucocon also has the receptors right on what hepatocytes glucagon has also receptors on the hepatocytes and when glucagon activates the hepatocytes and gives signals to the hepatocytes these Master metabolic cells what they will do they will start converting the fatty acids and amino acids into glucose right what will be the result the conversion of fatty acids and amino acid to Watson to glucose right and this process is called gluconeogenesis let's define what is gluconeogenesis gluconeogenesis is the metabolic process in which we make glucose from non-carbohydrate sources right and in the liver the process of gluconeogenesis is activated by glucagon right so it means that there are two mechanisms right that one mechanism is look from the liver we can get glucose by two mechanism number one we can get glucose by breakdown of glycogen number two we can get glucose by breaking the fatty acids and amino acids and using their carbon skeletal skeletons using the fatty acids and amino acids carbon skeletons to build new glucose is that right the first process breakdown of glycogen is called glycogen lysis and the second process is called gluconeogenesis now look at it here's again beta blockers make a trouble actually beta receptors are present beta 2 Beta receptors are present on glucagon release in South you know this is a glucagon releasing cell and what really happens that during hypoglycemia glucagon releasing cells release glucagon which will do gluconeogenesis unfortunately beta blockers also block these receptors so it means data blockers reduce their release of glucagon beta blockers reduce the release of glucagon and when glucagon release is impaired then liver is unable to do gluconeogenesis now let's sum up what's happening look here attention that when a patient is on beta blockers and patient is diabetic patient and Insulin dependent this patient may undergo extremely severe hypoglycemia right and why these patients undergo very severe hypoglycemia one reason is that when such patient is on beta blockers right whenever hypoglycemia occur patient does not develop warning symptoms so patient is never knowing that how or that patient is suffering with hypoglycemia and patient does not take external glucose is that right this is problem number one problem number two beta blockers also impair the internal hepatic glucose release in hypoglycemia how do they impair in a normal person epinephrine stimulates the hepatocytes to produce glucose from glycogenolysis and normally epinephrine also stimulates the glucagon producing cells so that glucagon should act on the hepatocyte and produce new glucose from gluconeogenesis these are the two main hepatic mechanisms which provide the glucose to the blood Whenever there is hyper glycemia unfortunately patient who is on the beta blockers a hepatic beta2 receptors are blocked so epinephrine induced glycogenolysis cannot be induced so this source of hepatic glucose Supply is lost so secondly when patient is on beta are two blockers right then glucagon releases also impaired so gluconegone glucagon mediated gluconeogenesis cannot be done and further a loss of internal supply of compensatory glucose from the liver so patient is not taking the glucose from outside and hepatic gluconeogenesis and glycogenolysis is impaired an internal glucose is also not released from the liver so patient goes into where is severe hypoglycemia and patient may develop even is very severe irritation and patient may develop fats or even we're going to Coma right so of course you don't want this for your patient if you don't want for this patient so next time you have to be careful for what that when a patient has insulin dependent diabetes mellitus don't put them on beta blockers look for alternative drugs am I clear okay now we come to the third thing here Alto it's wise not to use beta blockers patients who have peripheral patients who have peripheral vasospastic tendency what is Reynolds disease or Reynolds phenomenon actually in the north phenomenon peripheral vessels of the limbs specially vessels of the hands the undergoes severe with the spasticity sometimes again what happens in the north disease or the North phenomenon that patient has a tendency to develop severe vesospasticity of the peripheral vessels is that clear and that may make you know a hands cold and pale and you know the first they will become very pale and cold and then later on they may undergo reactive cyanotic and then reactive hyperemia right these whenever this is cities precipitated that will lead to cold extremities and painful extremities and if patient who has such tendency if unfortunately you put such patient on beta blockers due to some indication what will happen the beta2 mediated peripheral vascular visual dilatation is lost what really happens that if such patient is put on the beta blockers then endogenous epinephrine cannot keep a small degree of dilatation in the peripheral vessels and patient is already a tendency for viso spasticity so beta 2 mediated loss of visual dilatation will lead to intense business possibility and severe problem in the patient with peripheral vascular disease am I clear then we come to the patient with Brady arrhythmia this is the most easy to explain of course if there's a patient even if he is having angina or Mi or congestive cardiac failure but along with these problems he has breadierythmiasmia mean that any patient who is having let's suppose one example of bloody urhmias sinus bradycardation right if someone has his SA node too much suppressed if SN note is working very less we say there is sinus bradycardia if heart rate is less than 60 per minute in the daytime or heart rate is less than 60 per minute 50 per minute in the sleeping in the waking state if your heart rate is less than 60 per minute this is sinus bradycardia or during the sleep if heart rate is less than 50 per minute that is also sinus bradycardia or due to some reason AV node is not working well maybe if you notice patient is on some drug or there's some pathology with the AV nerd and there is some degree of heart block heart block mean that impulses from The Atrium are not transmitted to the ventricles in a normal fashion there's undue delay for the actual impulses to go to The ventricle or maybe if initial impulses are all together not able to go to the ventricular such conditions are called heart blocks right now in such patients uh epinephrine Through The beta2 receptors is normally responsible to stimulate acinod and evenode is that right epinephrine normally stimulate essay node and AV node is that right normally epinephrine even norepinephrine norepinephrine comes from sympathetic nerve endings write it down norepinephrine is mainly released from sympathetic nerve endings an epinephrine is mainly released from Adrenal medulla so epinephrine and norepinephrine through activation of beta-1 receptors on SA node and AV node they act as stimulated reagents is that right now if a patient has already bready arrhythmia either patient is having sinus bradycardia or nodal blocks and at the top you supply the patient with beta blockers you block these receptors so in a patient who has already Brady arrhythmia if you abolish the catecholamine mediated stimulation to asinode and AV node simple mild to moderate radial will immediately convert into very severe degree of yeah that's the right and due to that reason if you have a patient with a tendency of Brady arrhythmias please don't try beta blockers there am I clear for example if the partial Block in the AV node and some of the impulses from HD are going down to ventricle and some impulses are not going but once you give the beta blocker maybe none of them Pulses from Atria go to The ventricle is it clear right another important thing with bloodier in acute in acute congestive cardiac failure now this is a very important point to understand you have to be really very sharp to understand this point because these days we use beta blockers as a treatment in patient with congestive cardiac failure but if someone has very acute congestive cardiac failure then we should not give the beta blockers because that may worsen the symptom you know beta blockers are negative inotropic agents right they reduce the contractility do you know that or not right and if patient has already mechanical impairment of the heart and very severe mechanical impairment right would you like to give the patient some negative anotropic agent answer is no but here you have to remember these days beta blockers have become one of the standard drug use in patient with congestive cardiac failure why they are used in congestive cardiac failure I will explain in lecture on congestive cardiac failure management but the point which you have to remember that if a patient is severely under very severe mechanical failure of the heart right of course beta blocker should not be done that's the right because beta blocker and heart failure have a long term benefit but if a patient is in such a sphere failure and you give the beta blocker maybe patient does not live for long-term benefit patient dies with complete failure am I clear so use of beta blockers and cardiac failure has to be very very judicious is that clear and now in the end I told you beta blocker should not be given in patient with depression I think there's no fun in explaining that I told you one of the important side effect of beta blocker is mental depression of course patient if patient is already having mental depression and at the top right you give him beta blocker for hypertension or as antiarismic drugs or as antine general drug she will go into very deep depression and maybe this person commits suicide it's also very bad news isn't it so I hope my very good students will remember that beta blockers should be used in these conditions better not to be used or to be used with lot of care or best is that that you should consult your seniors if you have to use them Emma glare other and depression is so simple let me tell you when your adrenergic activity is more you are excited or you are depressed excited so it means person who is depressed already he has reduced adrenergic activities in his brain when you will study the pathology of depression one of the reason of depression is the monoamines in central of a system are reduced the action of epinephrine norepinephrine dupe and dopamine and certain especially these are reduced in depression already patient has reduced adrenergic activity in the brain and due to that reason he has depression at the top you give some beta blocker and block the remaining activity of the sympathetic nervous system what do you think patient will be excited he will go into deeper depression some of them become so depressed even they don't have energy to commit suicide why I'm telling you this because those patients who are extremely depressed and they don't have energy to commit suicide when you give them antidepressant drug this sometimes a little little get better and get energy to commit suicide so you have to be careful when you patient manage the patients of depression right let's have a break now today we are going to talk about the calcium channel blockers and their role in patients with angina right so our major discussion is calcium channel blockers and their role in yes please Roland angina first of all I will tell you that what a what calcium channel blockers are going to do for example if you give a patient calcium channel blockers calcium channel blockers are group of the drugs which will bind with the calcium channels which calcium channel voltage grated calcium channel you must know the many types of calcium channels right and our drugs use a selected special group of calcium channels and which calcium channels voltage grated calcium channels and which type of voltage-gated L Type so what we say that they are competitive Blocker of L Type calcium Channel block you may be thinking that why I am stressing that they are blocking a specific type of calcium channel why it is so important to know it the reason being that calcium influx in the cell operates many biological functions right for example calcium influx in the neurons releases neurotransmitter calcium influx in the Endocrine cells releases the hormones calcium and flux and smooth muscles and skeletal muscles that can lead to contractility in the same way calcium and flux and the myocardial cells also produces contractility now when we want a particular drug which should be used use useful in the patient with cardiovascular diseases we want that drug should block the calcium channels only in The myocardium and smooth muscles so that vascular diameter should be altered and myocardial activity should be altered but we do not want any drug which will also block the calcium channels which are involved in neurotransmitter release and we do not want any type of calcium channel blocker which will block the Endocrine cells calcium influx so that endocrine release should be disturbed so what I was saying that there are many types of calcium channel blockers some are controlling the neurotransmitter release others are controlling exocytosis of the Endocrine cells now these two types of channels should not be blocked if we have a drug which can block all the calcium channels that will go into trash basket right so what I wanted to put that when we are using calcium channel blocker in cardiovascular diseases we need such drugs which will specifically block the calcium channels which are present in the myocardial cells and the smooth cells of the blood vessels is that right now the calcium channels which are calcium channel blocker which are presently available to us they are basically I will mention three classical runs three classical drug even though there are now many new drugs but all of them are compared and contrasted with these three classical calcium channel blockers one calcium channel blocker is called nephedepine the fed the pain very commonly used and you should be able to compare and contrast the actions of nifida pain with the actions of Delta as m deltaia them and third important classical drug and calcium channel blocker is Verapamil now just knowing the name of these drugs here is not enough you must know how they are different from each other because even though all of them work on the cardiovascular system but the way they work is significantly different now what is the difference let's talk about this is your heart right let's suppose here is your heart and this is atrial myocardium and here is ventricular myocardial right first I will tell you in the heart which tissue is dependent on calcium right then we'll talk about how the drugs block it basically as a node depolarization is calcium dependent Point number one is that SA node depolarization is calcium dependent number two AV nodal depolarization is also AV nodal depolarization is also calcium dependent now let me stress first depolarization in snode is calcium dependent depolarization in atrial muscle is sodium dependent this is a very big difference you must write it down that in the myocardial tissue in the whole myocardium right some of the myocardial tissue is having depolarization which is calcium dependent and some of the myocardial tissue has depolarization which is sodium dependent and let's make it like this depolarization myocardial depolarization Mayo cardial depolarization right which can divide it into calcium dependent depolarization and sodium influx dependent depolarization now which are the calcium dependent essay node and AV node as a node and even Oda calcium dependent depolarization and sodium dependent depolarization are irritial myocardium atrial General myocardium and ventricular General myocardium remember acetone and AV nod are also myocardial tissue but it is specialized in myocardial tissue myocardial tissue law it is specialized it has lost the capacity the myocardial cell in snode has lost the capacity for contractility but acquired the capacity of automaticity automaticity mean increased tendency to produce automatic depolarization in the same way AV node is also specialized to myocardium it's a general myocardium specialized myocardium modified myocardium what is special thing about AV node the myocardial cells which are present in AV node have again lost the capacity to contract and they have acquired the capacity to for slow conduction my friend no so that current from Atrium will be passing through EV nodes so slowly that Atria should complete their contraction fill the ventricle only then current will come to The ventricle and ventricles will contract is that right so what I wanted to say that The myocardium in the heart has two types of myocardium there is General myocardium and there is specialized myocardium General myocardium is General atrial contact and myocardium General ventricular myo contractile myocardium right but specialized myocardium is acinode and AV node plus per conjure system you know system that is also specialized modified myocardial fibers the bundle branches and turkanja fibers but remember that this fibers their depolarization is sodium dependent right so now today onward you have to remember that specialized myocardium is acinode Av node and prochanger system General myocardium is atrial contraction and ventricular contraction is that right calcium dependent electrical activity is seen in depolarization is calcium dependent and sodium dependent depolarization is atrial and ventricular myocardium plus one specialized tissue which is also sodium dependent not calcium dependent so you may be thinking why I'm stressing it the reason being that there are some drugs which act as calcium channel blocker so they will reduce electrical activity in this tissue and the other drugs which are sodium channel blocker they will mainly act the electrical activity of Atria ventricular and per congest system is that clear Amorite this is one thing right that there is calcium dependent automaticity here this calcium dependent conductivity here because this is a function of automaticity this is a function of conductivity slow conduction but one more thing even though listen carefully even though the atrial and ventricular myocardium has depolarization which is due to sodium but contraction of Atria and ventricle depends on oh again listen carefully atrial and ventricular depolarization is sodium dependent but contractility of atrial ventricular is calcium dependent is that right now in a nutshell we can say calcium dependent activities in the heart so that then we'll know that when calcium channel blockers are given what really happens physiology linked with pharmacology now we can say what are the calcium dependent cardiac activities cardiac activities calcium dependent this is the right which can be modified by calcium channel blockers one thing we already know yes SA node Plus AV node depolarization second thing should be clear plus ventricular not depolarization but contraction but contraction it means when we will give calcium channel blockers to reduce the activity of as a node electrical activity of as anode will reduce the electrical activity of Av node plus will reduce the calcium channel blocker will reduce the mechanical activity of Eritrea and ventricle you know heart has basically electrical activity and vent and mechanical activity is that right so we can say now we go that if you give a calcium channel blocker what will happen to heart if there is a calcium channel blocker which can block the calcium channels in the heart what really happens again what will happen to us a node it cannot depolarized it's very easy to understand if s a node is exposed to the calcium channel blocker it cannot go under depolarization easily the rate of depolarization will be slow right it means tendency of SL node to produce automatic impulses slow so there we say that there is reduced automaticity calcium channel blocker when they act on SA node they reduce the automaticity and reduced automaticity is technically called we say that there is negative yes chronotropic action Chrono Tropi so calcium channel blocker when they act on as a node they'd slow down the rate of depolarization of Sno they inhibit the automaticity of as a node total number of cardiac impulses generated per minute by asinode has been reduced of course that will lead to reduced heart rate that will lead to yes reduce heart right and this phenomenon is called negative chronotropic action right so one action of the calcium blocker is negative chronotropy secondly when calcium channel blockers will work on what is this AV node what will happen here it was acid nodal activity now AV node it's very easy when essay node is under the calcium channel blocker and you know AV node is calcium dependent depolarization so again electrical activity in asinode is suppressed major function of acetone was AV node was that it was transferring the impulses from atr2 ventricle when every node is suppressed then transfer of impulses from Atria to The ventricle is further reduced or suppressed is that right so we can say that there's pathological depression of conductivity there is pathological dependent of the depression of conductivity through the AV node is that right and that is called negative yes please dromo is that right and that will lead to if this action become excessive that will lead to what problem if the section become excessive yeah bradycardia noodle bradycardia simply we call it heart blocks what are heart blocks hard blocks are conditions in which impulsives from the Atria right impulses from the Eritrea are going to The ventricle either with undue delay or they are not going at all what is the heart block the term is also called heart block the same thing is also called there is another term for this we call it nodal block there can be heart block there can be nodal block and some people call it junctional block all these are the same thing heart block or noodle block or a junctional block these terms are used that whenever normally what happen attention plays every atrial impulse will conduct from ATR Atrium to The ventricle with normal delay delay of 0.1 second it means when atrial impulse reaches even node it is held there for how much time 0.1 second so that Atria completes their contraction and fill the ventricles only then current is released but let's suppose you have given some calcium channel blocker now rather than 0.81 second maybe this delay is taking 0.2 second so it is normal due delay or undue delay it is undue delay and if every impulse listen now carefully if every impulse from Atrium is going to The ventricle but with undue delay we say first degree heart block what is that first degree heart block when every impulse from Atrium eventually goes to the ventricle but within due delay and in second degree heart block probably AV node is further suppressed probably we notice further suppressed then second degree heart block occur what is second degree heart block some of the impulses from Atrium go down and some are aborted they are not allowed to go down is that right in first degree heart block every impulse from here was going down but with undue delay and second degree heart block some of them pulses will be allowed to go down and others not for example snode is firing at the rate of 80 but AV not allow only 14 buses down so irritial activity will be 80 per minute and ventricular activity will be 40 per minute so we call it second degree heart block and if really there is much toxicity due to calcium channel blocker then there will be very big problem that if there's too much toxicity of calcium channel blockers and suppress the evenode so much that AV node cannot conduct any atrial impulse to The ventricle we say this complete heart block what is that complete heart block or we simply called it third degree heart block so this is partial heart block this is also first degree and second degree both are partial heart block because and in this case none of the actual impulses is able to pass through the AV node to ventricle we call it complete hard block is that clear now why I'm explaining it because we have to relate the physiology with the pharmacology and blocker and toxic actions of calcium channel blocker so this is one thing can happen and here I should also mention as I have told you that AV node is normally suppressed by calcium channel blocker and if it is too much suppressed it will produce heart blocks but if snode is suppressed first snode will reduce its automaticity for example your heart rate is 90 per minute I give you calcium channel blocker which specially work on essay node your heart rate may become 60 per minute 50 per minute and if there's too much right we say that when heart rate is suppressed less than 60 per minute we say the problem is sinus what is that bradycardia so it is one of the side effect of calcium channel blockers sinus Brady cardia and when we say there is sinus bradycardia one heart rate is less than 60 due to reduced automaticity of as a node and heart rate is less than 60 due to reduced automaticity of as a node and if you are really giving very heavy dose of calcium channel blocker very toxic dose and as a node stop working what term we use it there is what term is used we say there is sinus there is sinus arrest it is completely arrested no function of s a node if there's a very heavy dose of calcium channel blocker right for example very heavy dose of calcium channel blocker here will produce sinus arrest no automaticity displayed by SA node and very heavy dose here will produce complete heart block is that right so we'll say that there is sinus rest look look just a minute when you give calcium channel blocker asynode and AV node electrical activity reduce as a some reduced electrical activities are said to be bready arrhythmias what are they called Brady eurythmia heart has gone out of rhythm on the bradycardia side slow side Brady arrhythmias may be related to acetone or they may be related to AV node or to the both when Brady arrhythmias are here these are called sinus bloody arrhythmias when they are here we call it nodal Brady arrhythmias sinus are simple sinus bradycardias or if sinus activity totally stop we say that there is sinus rest noodles are first degree heart block second degree heart block and third degree heart block is that Claire right now this was the action of calcium channel blockers on snod and AV node right which are calcium dependent depolarizing tissues now we come to the action of the calcium channel blockers on contractile myocardium especially ventricular myocardium what happens in The ventricle normally you know in the plateau phase some calcium goes in when there's depolarization of The ventricle during Plateau phase there is calcium going on that calcium trigger the release of calcium from sarcoplasmic reticulum and that total calcium act on proponent and pull the tropomyosin away so that actor myosin can contract so we can say that calcium in flux during the plateau phase of action potential triggers the release of intracellular stores of calcium within the myocardial cell a lot of calcium which is present in the myocardial cell that is that is going to lead to contractility is that right now listen if you give calcium channel blockers right then uh calcium channels which are throwing the calcium during the plateau phase they are blocked with the drug so it means Ruger calcium to The myocardium is increased or decreased decrease then intracellular release of calcium is also decreased then of course contractility is decrease and the term which will be used is yes please the term which is used again listen on calcium channel the block on these cells calcium is not going in and ultimately there is suppression of calcium dependent contractility this reduced calcium dependent conductility when contractility is reduced the term which is used is yes Jamie what is the term then culture negative inotropic effect negative I know trophy actually negative inotropy means there is yes there is reduced strength strength of contraction is that right negative inotropy mean that there is reduced contraction reduced strength of contraction but while not only strength of contraction is reduced even velocity of contraction is also reduced by blocking the calcium channel channels for example let me explain that let's suppose this is a graph showing the contractility is that right normal contractility is that during the systole pressure will go up contraction tension will go up and then tension will come down and then there is dastly is that right this is the normal dynamics of systolic contraction is that right now this is the total what strength of contraction this is the strength of contraction and here's the time frame y-axis you have time on x axis you have strength of contraction is that right this is normal now let me draw the graph when calcium channel blocker is given and calcium channel blocker is given number one there is reduced total contraction this process the total contraction has been reduced this is called negative inotropy total contraction has been reduced and relaxation is also reduced now look at the phenomenon normally this is a High Velocity with which it will go to the peak contraction and with high velocity it will relax but after calcium channel blocker the velocity with which with weight the tension will develop and tension will be lost that velocity has been reduced as well as strength has been reduced for example normally to go to the peak tension this was the time taken but after the calcium channel blockers the time taken for Peak tension is prolonged now so we can say when calcium channels block the myocardial calcium calcium channel blockers block the calcium channels in the contractile myocardium there is reduced contraction as well as this reduced velocity right because when you reduce the contraction oxygen demand of the heart is reduced and when you reduce the contractility velocity that also further reduces the oxygen demands so what is the term used when velocity of contraction is reduced you have already told me the term when there is reduced strength of contraction the reduced strength of contraction we say there's negative inotropy when there is reduced velocity of contraction what is the term used when there is gas reduced velocity of contraction T of contraction and relaxation it slowly contract and slowly relaxes because this thing will reduce the oxygen demand when you reduce the strength of contraction oxygen demand is reduced when you reduce the velocity of contraction oxygen demand is further reduced what is the terms used okay 10 dollar price for this no one needs ten dollar all of you are very rich now he asked what is the question no I'm just telling you that don't concentrate on ten dollars concentrate on the topic what I'm saying yeah uh I'm cons I'm just telling that by giving the calcium channel blocker and please add it even by giving the beta blockers both have the same action they reduce the total strength of contraction they also reduce the velocity of contractile mechanism both of them calcium channel blockers and beta blocker reduction in strength of conduction is called a negative inotropy reduction in velocity of contraction is called yes ten dollars question I think ten dollar is fine to you negative dromotropy is reduced conduction remember reduced normal automaticities negative chronotropy reduced normal conduction is negative dromotropy reduced strength of contraction is called negative inotropy and reduced velocity of contraction is called yeah Sean is going to tell what is that negative clinotropin kalino tropia excellent so someone will get 10 dollars later right reduced clinotropy so today when you talk to your friends you can say calcium channel blocker reduce the heart rate reduce the conduction through every node reduce the contractility reduce the work of the heart and reduce oxygen demand so they are good in angina but when you talk to a Cardiologist then you should talk in a better term calcium metal blockers are negative chronotropic drugs their negative dromotropic drugs their negative inotropic drugs as well as their negative planotropic drugs right and then you mentioned because heart rate is reduced and contraction Dynamics are reduced so what happens total oxygen work of the heart is reduced per minute work is reduced and oxygen demand is reduced and when oxygen demand is reduced you remember in the beginning of the lecture I told you on stable angina what was the problem there was astrological erotic plaque which was given small amount of blood flow to myocardium right so whenever you develop tachycardia or whenever you develop extra work of the heart whenever you develop the extra work of the heart what really happens that atherocyclerotic obstruction cannot be dilated that is fibrous tissue and plaque right so whenever your heart oxygen demand is more let's suppose this is myocardium piece and this was your coronary Supply and let's suppose this coronary Supply here is obstructed more than suppose 80 percent obstructed or seventy percent obstructed now the little blood which is coming due during the with little blood which is coming through the obstruction that may be enough for the resting myocardium but whenever myocardium undergoes increase work during tachycardia or when patient is exerting right this point cannot dilate so the dependent myocardium will become ischemic and that will precipitate classical angina and China and China of exertion rangina with excitement or emotional tension you are understanding you remember that what was the trick to manage this in China One of the trick was that reduce reduce the work of the heart so much and reduce the demand of oxygen of the heart so much that reduced demand of oxygen is now matching with the reduced supply of oxygen do you get it and this function can be achieved with calcium channel blockers because calcium channel blocker reduce the heart rate reduce the contractility of course when heart rate is reduced when there's reduced heart rate and there is reduced contractility and when there is reduced contractility it means reduced stroke volume so that will lead to reduced cardiac output and of course reduced cardiac work that will lead to reduced cardiac oxygen demand is that right so by reducing the heart rate and reducing the contractility and stroke volume we reduce the cardiac work and reduce the oxygen demand and in a typical angina what we really wanted we wanted to reduce the amount of oxygen so much that reduced demand of oxygen by The myocardium is matching now with the reduced supply of oxygen and patient does not feel ischemic pain am I clear this is how uh calcium channel blockers work on the heart and help in termination of symptoms of angina but there's still more to be said the very special thing which I would love to mention is that nifedipine okay that I will mention later when I go into detail of their differences what's your question I will explain this I've just mentioned calcium channel blockers can be used in classical in China right now I've just told that but in classical in China first you should try nitrates and beta blockers if both of them are not effective then you add the calcium channel blockers is that right am I clear but I will explain some further functions of calcium channel blocker then we'll integrate the information that how it is beneficial some other types of angina as well right now we have just concentrated only the action of calcium channel blockers on The myocardium that is electrical how the calcium channel blockers alter the electrical activity of heart and how calcium channel blockers alter the mechanical activity of the heart mechanical and electrical activity of heart now we'll make a diagram and you must remember this in a good way okay here is again our hard back already you know how much we have discussed about it remember when I will draw diagram you see I'm very careful that atrial myocardium should not touch the ventricular myocardium why because between the atrial myocardium and ventricular myocardium there's fibrous partition ring the only connection between the atrial myocardium and ventricular myocardium is normally AV node this is the only electrical window between the Itchy and The ventricle in a normal subject right this is what we have seen that what are the now you see here is what was this arterial side and what was thing on this side Venus side right and you must be knowing already that what are here these are the capability beds in different tissues right and you know blood is coming through arterials to the tissues and leaving through veins now now you will see the integrated function of calcium channel blockers where cardiac function and Vascular functions are correlated we have only discussed about that it produces X here reduces heart rate X here and reduces yes reduces conductivity right and X here and reduces contractility and stroke volume this is what we have already discussed in a nutshell with all the mechanism but we have to remember one more thing that calcium channel blockers also act on the smooth muscles calcium channel blockers also act on the smooth muscles of arterials right you know here are the arterials is that right this is arteries and arteries now you know articles are the major resistance vessel when blood flow is moving from the arterial tree to the venous side the major resistance to the flow is offered by arterial all of you know that now actually calcium channel blockers also work on the arterial right because arteriola smooth muscle is also dependent on calcium influx through the calcium channel system and Drug also block here so it means when arterial or smooth muscles are not getting enough calcium in the presence of calcium channel blockers what will happen will the contract strongly or weekly when calcium is unable to enter in smooth muscles of arterioles then arterioles will construct strongly or weekly weekly if they constrict Weekly right when you give calcium channel blockers which work on the artery roller smooth muscle and calcium is not going into entering into arteriola smooth muscle well then articular smooth muscle relax and when arterial smooth muscle relax diameter of Articles is more then the blood flow from the arterial site to venous side it will have more resistance or less resistance again when you are giving calcium channel blockers calcium channel blocker relax these filters so now the resistance to the blood flow from arterial side to the venous side is more or less less blood will vary reduced vasoconstriction Jamie let me explain it again to you listen when you give calcium channel blockers calcium cannot enter into these smooth muscles so they cannot contract well so they will relax so there will be production of visual dilatation but but the right term should be that in the presence of calcium channel blockers smooth muscles of Articles cannot constrict well so of course physiologically what is there Vaso arteriola dilation and when these arteriolar system is dilated blood can move from arterial side to window side easily is that right it means resistance to the flow from arterial side to venous side is reduced or we can say total total peripheral resistances reduced is it right total peripheral resistance is reduced it means that when you give calcium channel blockers if it produces arterial or dilatation it means now left heart is working against more resistance or less resistance you know function of the left heart is that it should contract push the blood through arterial side into the venous side now once you if some calcium channel blocker work on the arterial then relax the arterioles then left heart is working against less resistance now listen carefully how do you define after load we say ventricles have preload and after load preload is the amount of blood which is present in The ventricle at the end of diastole is that right so preload is the amount of the blood which is in The ventricle on which ventricle has to produce its squeezing action Contracting action is that right that is preload what is after load have you heard of this term what is afternoon what's after load after load is the resistance against which left ventricle has to perform I think I should repeat them about the donkey a little bit hard is like a donkey look this is your heart right now this donkey has to go 70 times per minute up take some load here and come back it carries normally heart is filled with how much blood 140 ml this is a load on the donkey before its start function so we call it pre-load what is it preload and once donkeys start moving up systole start it is moving against the slope slope is acting as a resistance right now donkey is moving against the resistance and when donkey is moving against the resistance right this resistance against which donkey has to perform right that is called after load what is it called after load is that right so preloaders the amount on the donkey before it starts performing after Lotus the resistance against which it has to perform is that right of course is very stupid donkey you know what it does it goes at the top out of normally what it does during one cycle it takes 140 ml there through there only 70 ML and Carries back 70 ml down right so amount which originally it had it is called and diastolic volume and the resistance against which it has to pump the blood that is after load and whatever it leaves here is stroke volume and whatever it brings on the back is called end systolic volume the volume in the heart at the end of the system is that right I told you that what what is angina angina is a myocardium which is crying due to ischemia producing pain is that right angina is a crying donkey right if you want to reduce the cries of donkey you must reduce the ischemia right very simple thing number one you reduce the load we discussed in previous lectures that we should reduce the preload donkey will be happy is that right number two why don't you reduce the yes after load if you reduce it like this donkey will be happy or sad I think you know donkey is very well that's right he knows donkeys will be very happy so what really happens when you give vinodilators and it relax listen now an angina treatment when you give nitrates what are nitrates nitrates are we know dilators when you give the Vino dilators veins dilate blood pool over here and less blood is going to the ventricles so it means when you give nitrates this reduced filling of the ventricle and this reduced and diastolic volume and nitrates are all the drugs which are Vino dilator they are actually the drug which reduce the preloads and in angina you have to reduce the preload as well as you have to reduce afterloads so that heart should act on less amount of volume and should act against less amount of resistance so the work of the donkey should be reduced so that donkey performed well with the reduced Supply reduced nutrition so how do you reduce the resistance against which the donkey has to perform how you can what are the drugs which can bring this slope down yeah all the drugs which are strong arteriolodilator that's the basic concept all the drugs which dilate the artery holes they reduce the resistance against which the myocardial donkey has to perform so it means that all the drugs which are arteriola dilators are primarily after load reducers from today onward please never forget we know that later that pre-load reducers artery after load reducers right am I clear so some calcium channel blocker okay let me tell you what is that some the classical independent and related drugs in the Philippine classically relaxes arterial when it I take the tablet of nifedipine it will classically more act on the arterial and less act on the heart right so in the Philippine is special type of calcium channel blocker we also call them dihydropyridine group die Hydro pyridine derivative now in the Philippine and some related calcium channel blockers like amlodipine nifedipine amlodipine philodipine is that right these are the calcium channel blocker which work more on the calcium channel the smooth muscle and work Less on the calcium channels of hard so they are primarily arteriolo dilators so when you give drug like nifida pain it will relax the arterioles and heart will be pumping against less resistance so this oxygen requirement is less Emma clear so yeah yeah now listen again back there were multiple ways to manage the angina one way was reduce the load on the Donkey pre-load here we use the drugs which are we know dilators like nitrates and if you want to reduce the slope what what group of drugs should be used in angina yes arterial dilators and if you further want to help this crying donkey what can you do lose you reduce the load you are donkey lover now you reduce the load you reduce the slope after that do a favor to donkey ask the donkey to make a favor to the donkey that if it is making 90 cycles per minute let it make only 60 Cycle per minute the uncle will be sad or happy very happy is that right reduce the heart rate and even don't ask the donkey to run with the load let it walk it comfortably what is that negative not only heart rate but negative climotropy with less velocity it is moving is that right so not only you reduce the preload not only you reduce the afterload but help the Donkey by reducing the by reducing the number of Cycles and the velocity of cycle it means we have to produce negative chronotropy as well as negative inotropy that will also reduce the work of the donkey you get it or not so now listen carefully here we put which drug which group three loader reducers nitrates pre-load reducers are nitrates right we know dilator we know dilators and by reducing this slope we are giving arterial law dilator and in which arterial dilator classically it is nepheidipine and related drug calcium channel blockers which are nifedipine amlodipine philodipine and related drugs is that right once you have now you have reduced the preload you have reduced after load then lets the donkey reduce its work during the cycle the drugs which will reduce heart rate and which will reduce contractility that will also help the donkey here the drugs are number one beta blockers if the drugs are beta blockers you know beta blockers reduce the what is that they reduce the essay node activity and reduce the heart rate if your heart rate is 90 you give beta blocker it may become 60. so donkey is happier that it has per minute it has to produce less Cycles number two beta blocker is also reduced contractility beta blocker is also reduce contractility so further so donkey will not only produce less Cycles but it will produce the Cycles comfortably these are right Amma clear and now please concentrate on calcium channel blockers in the Philippine mainly work on the arterios and Verapamil mainly work on the heart because listen carefully please concentrate the calcium channels in smooth muscles are slightly different than the calcium channel on myocardium calcium channels on smooth articulous smooth muscles are slightly different than the calcium channels in the heart some calcium channel blockers work more on arterial arterial side some calcium channels work more on heart and some calcium channels work on both of sides if you know this group you can really combine the drugs as they should be listen the food opinion is mainly what mainly working working on arterial Arty roller dilator and this is working mainly on heart so we can say and this is going to work on both now listen carefully let me draw this thing that Delta exam look at it just work on the heart as well as work on the arterial it has work on the heart as well as arterioles and this is the action of Delta enzyme which has a balanced action it is arteriolo dilator as well as negative chronotroper as well as negative dromotroper as well as negative inotroper as well as negative clino dropper do you get it so Delta enzyme reduces artery construction so it is reducing pre after load sorry Delta Azam reduces afterload as well as reduces the cycling of the heart and reduces heart rate as well as contractility but when you come to the vapormel look here vapormel this is the Verapamil on the heart it has strong action there's stronger action on the heart but weaker action on arterial only this so we can say rapamyl is more cardio selective and the feeder pin is more arteriola selective both of them are calcium channel blocker but this is more selective or arterial or selective and Verapamil is more cardio selective and deltaism work on both sides now why I'm so much stressing this thing let me tell you when you give a person a feeder pain it mainly produces arteriola dilatation and reduces diastolic blood pressure and reduces the afterload reduces the resistance against which heart has to perform this is a function of nephedipine now very important concern extremely important concept there's one type of angina in which ischemia to the heart is due to coronary vasospasticity there is one type of angina special type of angina in which the real pathology is not astrology and the real pathology is the coronary arteries undergo repeated spasticity the coronary spasticity what is the name of that engineer Prince metal engine excellent it is not classical engineer it is Prince medal in Jannah what is Prince metal and Janna it's a special type of anjana in which car there is coronary visual spasticity in this type of angina amount out of these calcium channel blockers attention plays in Prince metal angina coronary vessels plastic coronary arterial tree is in Prince medal in China which drug will be the best nephedipine a diltazam or Verapamil which is the best you want to dilate the arteries coronary is an artery the filter pain so you have to remember it it's a classical drug for Prince metal angina it's a classical drug for vasospastic angina now you understand it that when a patient has angina due to coronary artists spasticity then you need a drug which will dilate the arterials we need what nifedipine but in case of classical angina this partial obstruction due to astral signalotic plaque in that case all of them can be used why because if there is partial obstruction I told you in the last diagram if there's partial obstruction this small amount of blood prickling to The myocardium and whenever myocardium has increased demand ischemiah is the right classical angina and classical angina in the Philippine can also help because in classical angiana the Philippine dilates peripheral arterioles reduces the afterload and even in classical angina Verapamil can also be helpful because in classical in China we need to reduce the work of the heart and Grappa milk can reduce the work of the Heart by reducing heart rate and contractility now please listen special aspect you know an angina patient this is reducing the vascular Construction so it is somewhat like nitrates the feeder pain is somewhat like nitrates even though nitrates are mainly we know dilator and the vitamin is mainly arteriola dilator but both of them bring the blood pressure down please listen carefully what happens if you give nitrate to the patient what will happen we know validation and if you give calcium channel blocker of variety with the nifedipine artesial load annotation of course both of them will bring the blood pressure down and Ice told you told you previously that whenever blood pressure goes down this reflex tachycardia because whenever blood pressure will go down Barrow receptors will fire from the carotid sinus and activate the sympathetic outflow from central nervous system you know that right so whenever blood pressure goes down sympathetic outflow will occur powerful sympathetic outflow so when you give the patient nitrates or you give the patient nifedipine or you give the combination of these drugs patient has a tendency to develop hypotension and that hypotension has a tendency to precipitate reflex tachycardia and that reflects tachycardia may increase the work of the heart do you understand it that tachycardia sympathetic overflow may increase the work of the heart that is why a wise doctor will combine these drugs with beta blocker so that arterial dilatation or we know dilator system when it produces strong sympathetic outflow let the sympathetic system fire but you put a block there what is that block beta blockers which do not allow the sympathetic nervous system to increase the heart rate that is why classically it's good to combine these drugs because in angina we know the letters in our digital dilator are very good we know the letter reduce the preload after dilator reduce the sorry arterial or later reduce the afterload but if these two things are too much reduced there's a risk of reflex tachycardia and reflects tachycardia can be blocked by beta blocker is that right but another way to control the reflex tachycardia there's another way let me tell you rather than using this calcium channel blocker why don't you use this one or that one because if you use Verapamil with nitrates what will happen nitrates will do vinodalator and precipitate reflex tachycardia system nitrates will do vinodilator and may precipitate The increased sympathetic outflow this increased sympathetic outflow will try to increase the activity in AC node AV node and contract LED it is bad but with nitrates if you have combined the varapamil it is strongly inhibiting acinode and evenode and this so action of sympathetic stimulatory action of sympathetic nervous system is canceled by inhibitory action of the Verapamil you could not understand yeah no what I was trying to say what I was trying to tell you was that those drugs which produce reflex tachycardia reflex tachycardia is dangerous you should have some way to prevent The Reflex tachycardia right listen one way the best way to prevent The Reflex tachycardia is that somehow you keep the essay node and myocardium somewhat inhibited the Keep The myocardium inhibited one way is give the beta blockers other way to inhibit The myocardium is give those calcium channel blockers which are cardio selective do you get it Jamie now what are the implications of this listen carefully all calcium channel blockers are not same primarily I have divided them into three groups when you give injection of nifedipine to someone but usually it is given orally if someone is on nifedipine what is the risk reflects tachycardia but when someone is on heavy rapamyl what is the rift risk Direct bradycardias nitrates are risk for tachycardia as well as nifedipine is also risk for tachycardia because nitrates dilate the veins reduce the blood pressure the phytovin dilates the arteries again blood pressure goes down again tachycardia this is what I'm trying to put in your mind that all the drugs which reduce the blood pressure significantly has a tendency to produce reflex activation of the heart they have a tendency to produce reflex sympathetic activation of the heart is in angina such activation is good or bad it's bad we don't want it is that right is it clear yes so what can we do we can do number one with the nitrates or with the nifedipine when you add the beta blockers so let them stimulate the sympathetic outflow but beta blocker keep the sympathetic receptors blocked so sympathetic system powerfully activated but unable to drive the heart wild is that right then their second strategy also if you don't want to give beta blocker for example someone has asthma he has angina and with that asthma asthma chronic obstructive airway disease will you give beta blockers no in previous lecture I have mentioned that beta blocker May precipitate strong Bronco construction or someone has very severe diabetes can you give beta blocker you have to be very cautious now you have to give nitrate and you don't want to give beta blocker but nitrous you are giving giving in heavy dose so if you have are worried about that nitrates may not precipitate calcium channel blocker but you should be wise don't add the filter pin to these drugs you will add so that what what's the beautiful combination that nitrates dilate the winds right even if some reflex tachycardiosympathetic activation is there but Verapamil is keeping SA node AV node and myocardium inhibited so that it is not responsive to sympathetic over stimulation plus whenever we will of course by reducing heart rate and contractility will also reduce the oxygen demand but there is one thing wrapper milk can produce sinus arrest can produce noodle arrest heart blocks wrapper milk and precipitate cardiac failure if there's too much negative inotropy did you get it but can the Philippine can precipitate such things no so these were the important delicate differences within the group that even though these drugs are grouped as one group calcium channel blockers but as a good doctor you must know that this is mainly arterial director it is mainly cardio inhibitor and it works on the both parameters am I clear to all of you right so under what circumstances we use calcium channel blocker the special uses of calcium channel blockers are number one the uses of calcium channel blockers number one calcium channel blockers are used in angina but again you should talk about this classical angina and there is Prince metal angina In classical in China right with nitrates plus beta blocker if you want to add calcium channel blocker is the Right In classical angina you can use any one of them right any one of them depending upon which parameter you want to change but in case of what is this what is the battle angina the best drug is nifedipine because it is coronary artery dilator the Philippine is coronary artery dilator is that right here I will mention one more calcium channel block occur this is called depredile a new calcium channel blocker they pray there actually this is a very special of culture type of calcium channel blocker number one it produces coronary arteriologation number two it blocks the cardiac sodium and potassium channels now listen careers unusual drug like the nifedipine it can do coronary articular dilatation like other calcium channel blocker it can inhibit acetode Avi node and contractility but it has additional function it can block some of the sodium and the passion channels I will explain into detail during a rhythmias that when sodium channels and potassium channels are dysfunctional when sodium channels and potassium channels are dysfunctional a very special type of unique type of arrhythmias are produced these are called torsa D pointas have you heard of them okay I will explain it there but I just mentioned here there's a very special type of twisting points actually Q are as complex goes like this for few QRS complexer having points upward then for few beats they are having downward then again they have upward so this type of special type of tachycardia is called tachycardias with twisting points now this type of tachycardia I will explain in the lecture with arrhythmia it is due to defective sodium or potassium channels so this type of you can say disease can be managed by depoidal which is calcium channel blocker sodium channel blocker potassium channel blocker as well as coronary dilator so when a patient comes to you with angina plus a tendency for parsati pointers what is the best drug is it right the best drug is The Prado okay and I will mention that nifedipine has a very special group what is the name of that group dihydro pyridine derivatives these derivatives are more arteriolodilator and less cardio suppressor is that right but reflexively they can stimulate the cardiac activity is that right and now let's go to the side effects of calcium channel blockers there's a good news very easy to understand side effects of nifedipine are like nitrate side effect and side effects of vipamila like beta blockers because this is cardio inhibitor and beta blockers are a cardio inhibitor and nitrates are Wizard or later and nifedipine is also vasov dilator but let me tell you what are the major side effects related with these drugs the Philippines especially because it is arteriola dilator right if article the two might dilated especially in the head and neck that may produce severe throbing headache I told you the mechanism of headache in the lecture and previous lecture right again so what happens in the Philippine nifedipine right when it produces strong arteriolodilator and if arteries passing through the meninges when they dilate too much right you can how the arteriola dilated drug produce the headache these are the vessels which are passing through foramina this is intracranial cavity it is extracranial area these are the blood vessels which are passing through this area and I told you that these blood vessels which are passing through the foramina they are having sleeves off they're having sleeves off what is this Dura matter and this part of the durometer which is making a sleeve around the blood vessels when they are passing through foramina cranial blood vessels this part of the sleeve has unique very very sensitive pain receptors what are these pain receptors so what really happens any drug which produces strong vasodilatation has a tendency to produce severe headache how this headache is produced let's remain focused let's suppose you take any strong arterial dilator it may be the Philippine it may be hydralazine or any other drug it when these are

Channel: Dr. Najeeb Lectures

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Keywords: medical lecture, dr najeeb, dr najeeb lectures, usmle step 1, medical video, neet pg, whiteboard lectures, education, medicine, antianginal drugs, antianginal drugs pharmacology, pharmacology, angina pectoris, pharmacology for nursing students, dr najeeb pharmacology lectures, cardiac medicine, cardiology, beta blockers, myocardial infarction, introduction to angina, angina, pharmacology lecture, heart attack, anti anginal drugs, antianginal drugs mnemonics, angina treatment

Id: nEWvcIG51ZE

Length: 271min 14sec (16274 seconds)

Published: Sun Feb 26 2023