Adrenergic Drugs Part 2 | Pharmacology | Dr Najeeb

so dear student now we will talk about the characteristic physiological actions of adrenergic receptors in previous videos we talked about that how that energy receptors alpha 1 Alpha 2 receptors beta 1 beta 2 and beta 3 receptors how these receptors are logically distributed on our body tissues is that right that is what we discussed in last video now we will be talking about that if there is some drug which only stimulate alpha 1 receptor what will be the physiological changes in our body or there is another drug which specifically stimulates pose only Alpha 2 or only beta 1 receptor or some drug is specifically stimulating only beta2 receptor what will be the typical changes in our biological system so let's start about the characteristics physiological changes in our body when a specific group of adrenergic receptor is stimulated right so we start with this characteristic thank you rustic physiological actions physiological and of course pharmacological the physiological action when it is endogenous epinephrine and norepinephrine but if you are giving some drugs right which are sympathoma metric drugs the same actions will be said to be pharmacological actions so characteristics physiological and pharmacological actions right by the stimulation of right physiological and pharmacological action by stimulation of relation of specific adrenergic receptors right suppose if we have a drug which can stimulate alpha 1 receptors what will be the changes Alpha One adrenergic receptor after this then we'll talk about that if there is another drug which specifically stimulate Alpha 2 adrenergic receptors then what are the changes in the body and then we will be talking about that if we come across one more drug which can specifically stimulate beta 1 adrenergic receptors right what will be the changes in our biological system and in the end we'll talk about if we have some other drug which can stimulate specifically beta2 hydrologic receptors what are the changes in our biological system right let's start with the Alpha One receptors already we have discussed that alpha 1 adrenergic receptors are basically stimulatory receptors right when alpha 1 receptors are stimulated on any tissue usually that tissues activity is increased right now characteristically alpha 1 receptors are present number one on the vascular smooth muscle right number one there are many sites where Alpha One had energy receptors are present one is vascular smooth muscle right and when alpha 1 receptors stimulate the vascular smooth muscle let's suppose this is a smooth muscle on a blood vessel right and this is Alpha One adrenergic receptor and when sympathomagnetic agent stimulate and sympathomimetic agent stimulate Alpha One adrenergic receptors on the vascular smooth muscle vascular smooth muscle that stimulated and when vascular smooth muscles are stimulated it produces Vaso construction so primarily Alpha One actions Alpha One stimulation on the vascular smooth muscle leads to vasor yes Construction but this Alpha One mediated vasoconstriction on vascular smooth muscle will change the cardiovascular parameters how let's talk about that let's suppose here is your beautiful left heart right and from the left heart this is aorta and major vessels and let's pose from here our trees are coming out and arteries are going down into yes arterioles right I will just draw the cardiovascular system and we'll talk about that Alpha One stimulation how it changes different parameters of cardiovascular system so this is arterial tree coming to the yes capillary Network coming to venules right and then going to yes veins and this venous drainage is of course going to be chart right harder left hard yes right heart and from the right heart you know blood is pumped to the lungs and from there right it will eventually come to the yes that will get oxygenated and come to the left hand now let's see that when Alpha One stimulation occurs Alpha One hydrologic stimulation occur how the cardiovascular parameters are directly altered as you know that arterioles right our arterioles have lot of smooth muscles right and these smooth muscles on arterioles they are having adrenergic receptors let's suppose this smooth muscle right I bring it out this is having Alpha One adrenergic receptors now when Alpha One Agonist will stimulate it this smooth muscles will be stimulated and constricted when these smooth muscles will constrict what will be the result that these vessels will become narrow and blood flow from the arterial side moving to the capillaries and venous system will find more resistance again when there is arterioloconstriction and arterial construct right then when blood moves from arterial tree to the capillary side it is facing more resistance so it means when Alpha One stimulation is there many articles in the body especially the arterioles and sublank neck circulation which is gastrointestinal circulation arterioles and the cutaneous circulation and arterioles in the Renal Circulation all these arterial will construct and total peripheral resistance will be increased the resistance offered by the arteriole for movement of the blood from arterial side towards the venous side will be increased so what will be the result right result will be increase total peripheral resistance on Alpha One adrenergic receptor stimulation right so we can say arteriolo constriction that will translate into yes increase total peripheral resistance now when total peripheral resistance will increase then as blood will have more difficulty to move from arterial site to the venous side so amount of blood in the arterial side will be slightly increased and pressure on the arterial side will be also increase and actually you know blood pressure you know arterial blood pressure systemic arterial blood pressure is having two parameters systemic arterial blood pressure is equal to yes systolic by systolic blood pressure by diastolic stolic blood pressure now you must be knowing that systolic blood pressure is the pressure in the major systemic arteries when heart is Contracting then left ventricle is Contracting and diastolic blood pressure is the pressure maintained in the major arterial systemic arterial tree when heart is relaxing let me make a very simple diagram to explain this phenomenon let's suppose this is your left heart and this is arterial tree and here are suppose your arterioles right now listen these are the arterial of smooth muscles and which are very very sensitive to sympathomemetic action and these arterioles construct when there is Alpha One adrenergic activity now when you take blood pressure here right if left heart is Contracting the pressure which is present over here that is called systolic blood pressure and when left heart start relaxing when left heart undergoes directly naturally blood try to go back but this valve is aortic valve is closed and when aortic valve is closed as left ventricle is relaxing it means that connection of arterial tree with the left ventricular chamber is lost right during the densely aortic valve closes is that right so there is during diastole no blood is coming from The ventricle to arterial system right now what will be the pressure maintained in arterial system during dazzling the blood pressure which is maintained in the arterial tree during the dastly does not depend mainly on cardiac output because at that very moment there is no cardiac right now the pressure of blood here depends on which factor it depends on yes arterio motor tone right for example if arterioles relax if arterials totally relax during dastly most of the blood will move forward and there will be less blood in major arterial tree and blood pressure will drop which blood pressure will drop diastolic blood pressure Amorite so during the diaphase if arteries are open or there is arteriola dilation blood will very rapidly move forward from the major arterial tree to the venous side right and pressure diastolic blood pressure will fall opposite to that if you constrict arterioles stimulation if you constrict arterioles then during the dastly blood cannot move easily forward because for the movement of the blood total peripheral resistance is increased so whenever total peripheral resistance is increased right it becomes difficult for the blood to move forward from arterial tree towards the venous side so blood is retained retained here and pressure here is maintained at high level so it means whenever you will open the arterioles pressure in the pressure in the major systemic circulation will drop pressure during the dash lay and if you constrict the arterioles during the dash leave blood will be trapped here even though there is no blood coming here during ghastly but if during dastly arterial the constructed significant amount of blood is trapped here and we say diastolic blood pressure is elevated the whole purpose of this talk is to tell you that blood pressure maintained in systemic arterial arterial tree during the diastole mainly depend on total peripheral resistance these arterioles are like Taps you know tap you open the tab pressure in the main pipe is low you close the tap pressure in the main pipe is high so today onward whenever we talk about there is any drug which is producing arterial construction that is taking total peripheral resistance up that is still taking diastolic blood pressure up and again what we infer out of it the next time someone say that this is a drug which is mainly arterial or dilator it means next time when you give a person arteriodilator drug as soon as arterioles will dilate blood from systemic arteries will run this way and diastolic blood pressure will drop is that right so let's come back after this Basics that whenever you give Alpha One adrenergic Agonist arteriola construction will occur and most of the Alpha One Associated vascular beds and total peripheral resistance will increase and that will result into yes increased diastolic blood pressure am I clear this is the direct result of alpha 1 receptor stimulation on arteriola smooth muscle any question after this there's no question okay but there is one more thing that alpha 1 adrenergic receptors are also present on the veins on the venules and veins so it means whenever you give Alpha One Agonist drug it means there will be Vino constriction as well is that right whenever you give Alpha One Agonist drug there is yes we know construction as well and you know 70 percent of your blood volume is normally present in venous side again listen right now you are sitting comfortably and you have about five liters of blood in your body I suppose if you have five little blood in your body 70 percent of that five liter blood is right now present on your venous side it means Venus vessels Venus channels have the maximum capacity which is a logically to hold the volume of the blood that is why Venus venous vessels are also called capacitance vessel and that is why I told you that arterial vessels are not capacitance they are resistant vessels when you change the diameter of arterios you change the resistance and vascular system when you change the diameter of veins you change the capacity of the system very important point now lesson when you give Alpha One stimulant not only they produce arterioloconstriction they also produce yes we know construction and because in the veins lot of blood is there a little Vino construction will push squeeze you know little Vino construction Alpha One mediated Vino construction will squeeze the blood to the right heart so what how we should say this then Alpha One midi Alpha One receptor stimulation produces Veno construction and we know construction squeezes the blood volume towards the heart and when there's a lot of blood is moving towards the heart we say there is increased venous return what is that there is increased venous return so all Alpha One stimulant right they produce yes please we know construction and when there is systemic we know construction that result into increase yes Venus return return to where of course to the Heart Right heart and right heart will receive more blood Frank Sterling's law when Alpha One Drug stimulate the venous smooth muscle right we know construction occur it's the quizzes the blood from the veins to the heart when right heart is over failed it is over stretched Frank Starling lies more you stretch The myocardium more strongly IT contract within physiological limit Within physiological limit so when there is increased mean of return there is yes increased Venus return that will lead to increased and diastolic volume at the end of the day actually there will be more blood filling here and that will lead to increased yes stretch on The myocardium and Frank Sterling law there will be increase myocardial contraction and there will be increased stroke volume and there will be increase cardiac output and of course when right heart cardiac output will increase there will be increase venous return to the left ventricle and left ventricle will have increased Venus return it will also have increase yes and diastolic volume and Frank Starling law operate to the left ventricle also so as they were more increased venous return it will go stretch the right ventricle it increases its cardiac output then venous blood going to the left ventricle increases left ventricle gets stretched and then it more you stretch more it contracts within their logical limit so it will contract strongly and that will lead to yes please increase yes stroke volume which will eventually end up into yes increase cardiac output is that right so whenever there is there is Alpha One mediated we know construction increased venous return lead to increase and diastolic volume increase stroke volume increase cardiac output when there is increased cardiac output let's go to this example when there is increased cardiac output it means that during the systole of course cardiac output is during the left ventricular cystole so during the left ventricular systole Whenever there is increased left ventricular filling there is increased cardiac output Whenever there is increased cardiac output the volume here is less than normal or more than normal more than normal when so during the systole more than normal amount of blood will come to the systemic arterial side and during the syst play these will be stretched and having higher pressure and we say that's systolic blood pressure will be increased so what is systolic blood pressure now I will work into return fashion what is systolic blood pressure systolic blood pressure is the blood pressure maintained in major systemic arteries during the left ventricular systole is that right it means that systolic blood pressure is the blood pressure you are measuring and major arterial tree when left ventricle is filling the arterial tree it's very logical that if cardiac output is more then systolic blood pressure will be more and if cardiac output is less so strongly blood pressure will be yes less it's so easy to understand so what we'll say increase venous return will lead to yes please increase venous return will lead to increase and diastolic volumes in the ventricles and that will lead to increase stroke volumes will eventually lead to increase cardiac output and that will translate into yes increase systolic yes blood pressure so all the stock what did we learn we learn that systolic blood pressure depends mainly on cardiac output because when systolic blood pressure is the blood pressure in our major artery during systole diastolic blood pressure is the blood pressure in major artery during Dias Lake during the systole the pressure here mainly depends on how much blood is coming from the heart right so it means systolic blood pressure depends mainly on cardiac output and during diastole aortic valve closes so no blood is coming during that actually no blood coming from The ventricle to here now during the dastly how much will be pressure here it depends on how fast blood can go from major arterial system to the capillaries and veins if arterioles are open total peripheral resistance to blood movement is less blood during the diastole will move very fast forward and pressure will be less here but if there is arterioloconstriction these Tabs are closed and during the densely blood cannot move forward rapidly and pressure here will be high right so in a nutshell next time when you say that blood pressure is blood pressure is it's a strongly cover yes okay I must say that someone has a blood pressure of 120 by 80 millimeter of mercury right of course you know 120 is systolic and of course you know that it is that solid blood pressure and then you know systolic blood pressure mainly depend on cardiac output mainly there are other factors also but mainly cardiac output and we know diastolic blood pressure depends mainly on total peripheral resistance is that right now it is so logical and so easy to understand that whenever you will change the cardiac output which component of blood pressure will change systolic whenever you will change the total peripheral resistance which component of blood pressure will change is that right let me do a little uh threat with you just a very simple understanding of this fact very Elementary graph let's suppose this is blood pressure of a thorough gentleman it's 120 millimeter mercury systolic and 80 millimeter mercury diastolic right and so it means right now this is his blood pressure right I give a drug here I give a drug here and blood pressure become like this right systolic is not changed systolic is not changed but diastolic come down so his blood pressure is here blood pressure was 120 by 80. here blood pressure is 120 by suppose 60. what do you think what the drug has done yes it has done arteriolo dilation this drug is arteriolo dilator because arterials dilated and during the day sleep blood ran away from the major vessels and pressure drop do you need to have a diagram or you really understand okay now I give another drug here suppose this for drug a let's suppose I give a drug B and now so strollers remain the same but now his blood pressure has changed his blood pressure after the drug B is 120 by 100. yes what is this drug doing is that right so you see the drugs which are arteriola the later they bring the diastolic blood pressure down right okay I will make the same diagram so here the drug opened up these points during that aslay right when they open up the astralic fall here the drug has constricted these points so blood was maintained here during Gastly and pressure went up now let's talk about one more drug we have given another drug and now suppose drug C here and we see that blood pressure has altered in this way then what is the change in the blood pressure is now it is okay we yeah this is normal you know this is normal but this has elevated so it is 1 40 by 80. so what has happened that slowly blood pressure is normal as in the beginning right systolic blood pressure has increased it means when you took the blood pressure here during the systole it was more than usual during that sleep it was normal so what is the change what drug has done increased increased cardiac output here the drug has increased cardiac output because there is increased cardiac output during systole this was overfilled and pressure during the sleep was high so systrology blood pressure went up am I clear or not all of you are clear now we do another graph we give another drug it is still going 120 by 80 now right 120 by 80 and now we have given a drug and this is the change now blood pressure is 100 by 80. and this was the drugs d yes what we have done we have given a drug which are significantly dropped reduced the cardiac output and when reduce the cardiac output systolic blood pressure dropped am I clear so next time when I say a drug is mainly increasing change drug is mainly changing the total peripheral resistance it is changing the dash solid blood pressure when we say drug is mainly changing the yeah cardiac output it means it is modifying the stralabular pressure okay let's do another drug here I give another drug here it is f f stands for f only here right and you see what happened here it is um one 80 by 40. what has happened the drug has significantly increased cardiac output and dilated the arterials so when cardiac output increased too much during split stretch out pressure is very high but as soon as it blocks because arterials are very much relaxed rapidly blast goes forward and very little pressure is maintained here am I clear if you want to continue we can do one more experiment continue from there 120 by 80. we do another experiment and this is the action of the drug blood pressure is now 100 by 90. what drug has done it has brought the systolic blood pressure down it means cardiac output is less and diastolic blood pressure has gone up it means yeah arterioloconstriction you are so intelligent people it's pleasure to teach you is there any question about this so now we come back we were talking about that vascular smooth muscle is constructed by Alpha One adrenergic actions and arteriola construction increases diastolic blood pressure and we know construction increases cardiac output and systolic blood pressure right then any any other action of the Alpha One receptors when we give a drug it will stimulate alpha 1 receptors number one it will produce vasoconstration number two from previous lecture what happens to pupil pupil will construct or dilate on Alpha One stimulation occur you forget remember there were some beautiful eyes like this and this is your dilator pupili this is your dilator pupili and dilator people I have which receptors Alpha One adrenergic receptors when Alpha One adrenergic receptors are stimulated here dilator people I will construct and when dilator people have a construct right and dilateral people I will construct then naturally people will dilate so there is pupilo dilation which is also called materials right sulfur One Drug Alpha One stimulant especially if they are instilled in the conjunctiva they can stimulate the dilateral pupili and produce midrases right then we can come to you remember there was some muscles attached with the very tiny muscle that act with the hair follicle right and which were the receptor there Alpha One receptors you remember when dog was after you and your hair stand up right the COS alpha 1 receptors are there so that will produce pilo increase pilo erector activity then alpha 1 receptors are very importantly present on urogenital system somewhere yes alpha 1 receptors alpha 1 receptors they are present in especially about the male that's very important erection of the penis oh my God no no no no no look look let me tell you one thing erection of the penis is parasympathetic activity you know males cannot achieve good erection if they are not mentally relaxed as females cannot get wet if they are not mentally relaxed a female who is very anxious and effort and worry about many things she finds difficult to have wetness same is true about males they cannot get erection if they are under Financial burdens or office problems or they have to give some exams narcity exams and medical Sciences right things like that if they're really worried about that so don't tell me next time that direction depends on Alpha 1 receptors uh election is mainly there are sympathetic activity we will talk about that later I'm talking about a male urogenital system what is the role of Alpha One receptors ejaculation ejaculation is sympathetic activity a male who has a full erection for a long time the sympathy of his biological system that he is capable of ejaculating getting relieved is that right and that depends on which activity Alpha One stimulation is that right you may be thinking I'm just telling is it having some medical importance or not it is a big big medical importance the advantages and disadvantages let me tell you first of all prostate gland prostate gland is smooth muscles or not probably that's the only gland which has well defined smooth muscles right so prostate gland has smooth muscle and smooth muscles of the prostate gland have Alpha One adrenergic receptors right so this is your urethra passing through the prostate tissue right and in the prostate tissue there are Alpha One adrenergic receptors right and when these Alpha hydrologic receptors are stimulated smooth muscle contract right they help in ejaculation but ah there is some pharmacological importance you know the men as they get senior citizens and elderly and more powerful they prostrate also grow right and when their prostate grow powerful means they financially may become more freshly become more powerful but prostrate unfortunately also grow and prostate me press the urethra and person may have a condition called benign prostatic hypertrophy right BPH right right BPH benign prosthetic hypertrophy now there are so many ways there are so many Surgical and Medical ways to treat benign prostatic hypertrophy one way to manage these patients symptomatically is the patient with BPH we should give some drug we should relax the prostate smooth muscle if prostate smooth muscle relax prostate will not clamp the urethra will not compress the urethra so what you what type of drugs you will give Alpha One stimulant R and agonists or antagonist yes antagonists very good so what we do that you have to remember that Alpha One receptors are present in the smooth muscle the prostate as well and this has clinical relevance that there are drugs which are Alpha One receptor blocker right and specifically on the prostate and they can relax the prostate and reduce the symptoms of benign prostatic hypertrophy and hyperpasia is that right but there is another thing as I told you that males ejaculation is dependent on sympathetic activity and that sympathetic activity is mediated true or for one adrenergic receptors Nails will be very very unhappy when they are giving what kind of drug Alpha One blockers right that produces sexual dysfunction and males is that right so that is another relevant point that you have to remember male urogenital system has Alpha One adrenergic receptors and it has two clinical relevance number one you can give Alpha One receptor blocker to relax the prostate and it will and relieve the urethral urine urine flow and symptomatically relieve this problem related with the nine prosthetic hypertrophy and secondly whenever you are giving Alpha One receptor blockers those males may be very very unhappy with you some of them because they have ejaculatory problems why we use Alpha One receptor blocker very frequently we want to create a jaculatory problems in males yeah yeah hypertension Alpha One blockers are excellent antihypertensive drugs I told you in last lecture there is something called prazocene and trazosin Alpha One blockers precision and resistant drag block the alpha 1 receptors and produce arteriolo dilatation a little bit little bit we know dilatation an arterial load dilatation and we know dilatation will bring the blood pressure down but some males after taking presence you know Precision or related drugs may experience ejaculatory problems is that right no problem okay so then Alpha One receptors are also present on internal surfinger sulfur 1 stimulant will increase the tone of internal urethral sphincter right then so these were some important Alpha One action next time whenever we I say there's a drug which is having Alpha One stimulatory action it is arteriola constricted drug it is we know constricted drug it is if it is stimulant it will construct even the smooth muscle then prostrates and if insufficient amount present on the pile uh dilator PPI it can produce material cells right that is why Alpha One stimulant sometimes can produce urinary retention because internal sphincter may be your cell sphincter may be stimulated too much is that right no problem up to here right after the Alpha One mediated Alpha One actions now we go to Alpha two actions right what are the alpha two actions in the last lecture I told you a lot about Alpha two receptors number one alpha II receptors were present free synaptically in the neurons if it is adrenergic neuron suppose it is releasing norepinephrine on the Target tissue right a part of the norepinephrine yes part of the norepinephrine act as a negative feedback on The presynaptic receptors this presynaptic receptor is yes please Alpha 2 adrenergic receptors right and when norepinephrine stimulate Alpha 2 presynaptic Alpha II receptors they inhibit the nerve ending function and further release of norepinephrine is inhabited further release of so Alpha 2 receptors which are present pre-synaptically are release inhibitor for sympathetic nerve and dance right so Alpha 2 receptors which are presynaptically pre synaptic right Alpha two original receptor will lead to yes it will lead to reduced norepinephrine release from the nerve ending of course this is one action of alpha two adrenergic receptor what is the another action of alpha two adrenergic receptors yes Alpha two hydrologic receptors are also present on insulin producing cells insulin is produced by which cells I think you must be remembering there is something called pancreas and in the pancreas there are eyelets of langerhans in the islets of langerhans the beta cells and beta cells of highlights of langerhans have Alpha recipients beta cells of islets of langerhans have Alpha two receptors suppose this is the beta cell right which is normally responsible to produce yes insulin but this cell is loaded with Alpha 2 adrenergic receptors so whenever these Alpha two receptors are stimulated they are again linked with Gene inhibitory protein intracellularly and the inhibit the function of beta cells of pancreas and Insulin releases inhibited so they reduce the release of norepinephrine they also reduce the release of yes release off insulin right there reduce the release of insulin then any other function of alpha two receptors you know on the liposite adipocytes this is a deposite and adipocytes you may be remembering their beta 3 receptors beta three hydrologic receptors which are modified beta 1 receptors right but actually only very good students know that liposites also have Alpha 2 adrenergic receptors right actually when you stimulate the beta2 adrenergic receptors right it increases lipolysis it increases lipolysis but when you stimulate Alpha two hydrologic receptors it will decrease lipolysis so it means on the deeper sides right there are alpha two adrenergic receptors as well as beta3 hydrologic receptors beta three hydrologic receptors are stimulatory for lipolysis and Alpha 2 receptors are inhibitory to lipolysis so naturally if you cannot remember both type of receptors forget about Alpha 2 but please remember beta3 hydrology receptors which are more important right but if you are really too good you must remember that on the deeper side or liposite there are adrenergic stimulatory receptors beta 3 and adrenergic inhibitory receptors Alpha 2. so it releases reduces yes lipolysis of lipolysis from adipocyte then any other function of Alpha 2 receptor if Alpha 2 receptors are stimulated again an alpha two receptors are stimulated nerve endings release less norepinephrine beta cells release less insulin adipocytes release less free fatty acid and when Alpha 2 receptors are stimulated right she's saying blood pressure Alpha two stimulant which drugs you are talking about clonidine I think clonidine actin Central number system stimulate Alpha 2 receptor and reduce sympathetic outflow that is by reducing the norepinephrine release right we'll talk about that later uh Alpha two receptors are also present at one some part of the body or some components of the body where nerve endings are not releasing or open a frame Alpha two receptors are present okay I will give you a hint Alpha two receptors are present on some components of the blood yeah platelets yes very good excellent so Alpha two receptors are also present on the platelets right this there are alpha two adrenergic receptors and when they are stimulated yes when Alpha two receptors are stimulated on the platelets platelets get activated and you know activated platelets undergo clumping aggregation right so Alpha two receptor stimulation can lead to platelets aggregation they can lead to platelets aggregation right so what can we do you know pharmacologically we have drugs which can block the Alpha 2 receptors right and reduce the platelet aggregation they are still working to make some more efficient drugs to reduce the platelet aggregation right so again let's compare fastly if someone asks what are the alpha one action arteriola construction we know Construction stimulation of yes prostate smooth muscle and internal internal urethral Sprinter plus materials Plus filey erection right that's good Alpha two action Alpha two actions are reduced nor epinephrine released from the sympathetic nervendence reduce release of insulin Reduce lipolysis by beta cells and increased aggregation of the platelets let's have a break right so we have already discussed what are alpha one action and what are alpha two action right now talk about beta 1 action and beta2 action beta 1 action mean the typical action produced in our body when beta1 adrenergic receptors are stimulated when I mention in future that there are beta2 action actually I mean that what are the typical actions produced in our body the stimulation of beta2 adrenergic receptors so let's first talk about typical beta 1 action you must be knowing that beta 1 receptors are distributed and three types three important tissues what are those tissues on which beta1 receptors are present yes please number one is your heart your heart has beta 1 receptors the heart you know there is a note there is Av node here bundle of phase and purkinje system now beta1 adrenergic receptors are present on yes as a note they are present on atrial myocardium they are present on ventricular myocardium as well as beta 1 receptors are present on AV node and they are also present on special conduction system right it means beta 1 receptors in the heart are distributed most of the areas why I am specially stressing that there is a good beta1 hydrologic receptor distribution because when we talk about cholinergic muscarinic receptor distribution that is different you know as vagus nerve releases a style choline on the heart and muscarinic cholinergic muscarinic receptors are not distributed on all the heart receptors are distributed mainly on AC node and AV node little on Atria and not on ventricles so cholinergic action mainly affect the acinodal activity and AV nodal activity but adrenergic activity adrenergic action effect acinodal activity Avi nodal activity also if at the atrial and ventricular contraction is that right now let's suppose if you have a drug which can stimulate beta1 receptors can you tell me a drug which can stimulate beta 1 receptors yes please there are so many intelligent doctors sitting here yes this any drug single drug which can stimulate beta1 receptor let me tell you this drug is going to be important because in failing hard it can stimulate the heart and increase cardiac output now yes was somewhere like Angiotensin converting enzyme inhibitors right it is still Yes digoxin remember this answer is wrong digoxin is not adrenergic drug digoxin basically stimulate Vegas nerve to release more style choline plus digoxin can block the sodium potassium 80 pages in The myocardium so that less sodium goes out of the myocardial cell and then sodium accumulate into myocardial cell intracellular sodium is exchanged with extracellular calcium and then calcium comes in and increase myocardial contractility that is the mechanism of fraction of digoxin that has nothing to do with the beta1 adrenergic receptor stimulation any drug which can stimulate beta1 adrenergic receptors yes Gavin okay he comes with a perfectly wrong answer he says beta1 blocker my friend I'm asking about beta1 stimulant yeah dopamine and dobutamine dopamine and dobutamine not they have a beta one stimulant action we'll talk in detail later then we'll talk these drugs into detail but for a while you must know dopamine and dobutamine these are beta1 stimulant right especially dopamine is cardio stimulant with renovascular dilator dopamine stimulate the heart and dilate the renal vessels and in improved renal blood flow dobutamine mainly stimulate the heart okay it's a little out of the way but it's worth talking about if you come across a patient where heart kinetic activity is slow heart is pumping very poorly cardiac output is very low and due to low cardiac output renal blood flow is also less for example a patient who is undergoing shock is someone a patient who is undergoing shock circulatory shock due to cardiac failure and heart is not pumping well right and of course when heart is not pumping well cardiac output to brain is also less than sympathetic overflow occur and renal vessels construct and if renal vessels construct intensely that may produce the risk for acute tubular necrosis so when you have a patient with a combination problem a patient with reduced cardiac output with renal vasoconstriction and threat of acute tubular necrosis the drug of choice to stimulate the heart is dopamine because dopamine has beta1 stimulant action plus it stimulate dopamine receptor on renal vasculature to dilate the renal vasculature so dopamine is a wonderful drug even though it has to be given by intravenous infusion that it can by beta one action it can stimulate the heart and increase cardiac output and simultaneously it can dilate the renal vessels reduce the risk of acute tubular necrosis but if you come across another patient his main problem is reduce cardiac output due to reduced contractility of the heart but renal blood flow is not significantly reduced that patient should not be given dopamine because you don't need renal dilation there again the patient second patient which are the main problem with the reduced cardiac output due to hypokinetic heart which is poorly Contracting right but renal blood flow is acceptable you want a drug which specifically stimulate the beta-1 receptors then drug is not dopamine drug is dobutamine this is the real basic difference in these two trials other than the spell ends right the butamine is cardio selective stimulation and dopamine is cardio stimulant plus Reno dilator okay let's come back we were talking about the beta1 adrenergic actions in your body the typical beta1 action if you forget everything please remember cardio stimulation whenever we say beta1 stimulation cardio stimulation whenever we say beta1 blocker cardio inhibition is that right no problem and of course you know that when adrenergic drugs will stimulate the SA node adrenergic Agonist beta1 stimulant when they'll stimulate the Earth as a node there will be increased increase chronotropy Chrono Tropi and if beta one drug beta1 stimulant stimulate the AV node yes what is that when AV node is stimulated yes there is when there is Av node stimulation by beta 1 heterogative drugs and conduction through AV node become more positive dromo Trophy and when uh beta1 receptors on yes specialized conduction system was stimulated and excitability yes excitability electrical excitability of system increases and specialized conduction system has increased excitability when there is more epinephrine or epinephrine stimulation on beta-1 receptor what we call it positive don't tell me positive ionotropy it is positive bathymetropic positive bathroom tropical has nothing to do with bathroom yes I must remind because once I ask a student what is positive bathymetropy you say when in the washroom you release lot of adrenaline and your heart rate become fast right there are people like that don't worry so remember positive that's more trophy means there is increased excitability of specialized conduction system that's the right and when SA node is excited that is positive chronotropy basement trophy it is important to know because over excitation of specialized conduction system by the epinephrine and norepinephrine produces a rhythmia risk tachythmia risk when there's overstimulation of specialized conduction system by adrenergic beta-1 stimulation that may increase the risk of tachy arrhythmias then beta 1 receptors are of course present on The myocontile myocardium so when Peta 1 receptors are stimulated on the yes atrial myocardium and ventricular myocardium and degree of myocardial contractility is increase degree of myocardial contractility is increased this is called positive positive ionotropic I know tropic now I think there is something here I need to explain more clearly look let's suppose on this there is contraction contraction and on this this is the time right let's suppose before getting beta 1 stimulation patient has contraction myocardial contraction which goes to the peak and then come to the relaxation right you know during the sisterly left ventricle contract so this is systole electronical start Contracting pressure goes to the peak myocardial contraction has gone to the peak and then myocardium relaxes is that right this is without exogenous beta1 stimulation now let's suppose you give injection of a drug which is beta1 stimulant after the injection this profile will change after the injection after the beta-1 stimulation look at it contraction will go like this and this now what are the real alteration number one the total degree of contraction has increased because before the beta1 stimulation degree of contraction was up to this you know this after the drug total strength so strength of contraction has been increased this increase in the strength of contraction yes this increase in the strength of contraction is called positive I know Tropi right that strength of contraction as significantly increased before strength of contraction was here now strength of contraction is there right but there is another thing which has increased you know velocity of contraction and relaxation let me show you how look contraction started from here and to reach to the peak it took this much time without Beta 1 stimulation right contraction took so much time to reach to the peak but after the beta1 stimulation you see contraction went very rapidly to the peak now P could be achieved only in this time so it means the without Beta 1 heart was Contracting slowly and for lesser strength with beta1 stimulation hard contact with high velocity and with higher strength this increase in velocity that to reach to the strength it is taking shorter time are you understanding me or not right this is called positive kalinotropy what is that positive this is this thing that heart previously was taken so much time to reach its peak contraction but in the presence of beta1 stimulant it took a much less time to reach to the peak this effect of beta 1 stimulation is called positive enotropy yes positive I know trophy so let me repeat it if I say beta1 stimulation produces positive chronotropy it means the stimulate when I say that beta 1 stimulant produce positive dromotropy it means the increased conduction through AV node when I say that beta 1 stimulation produce positive bathymetropic it means it increased increase excitability electrical excitability of myocardial cells right especially specialized conduction system when I say this positive inotropy it means there's increased strength of contraction in myocardium when I say there is positive clinotropy it I mean there is increased velocity of contraction of The myocardium so actually uh beta1 stimulant are positive ionotropic positive chronotropic positive dromotropic positive bathymetropic positive ionotropic and positive clinotropy this has clinical significance because when there is positive chronotropy there is increased heart rate is that right and when there is positive inotropy and clinotropy there is increased stroke volume so it means due to positive chronotropy and due to positive ionotropy and clinotropy right there is increased heart rate plus there is increased stroke volume it means there is increased cardiac output it means there is increased systolic blood pressure so all the drugs which are direct cardio stimulant which are positive chronotropic and positive inotropic they increase the cardiac output and increase the systolic blood pressure and it's very easy to understand that if there's a drug which is beta1 blocker can you tell me any drug which is beta1 blocker like Atenolol metoprolol so if you give up your patient beta1 blocker that will be acting as negative chronotropic negative dromotropic negative basmotropic negative inotropic negative clenotropy and this patient when heart rate will decrease with beta1 receptor blocking and there is decrease in contractility and stroke volume there will be decrease in cardiac output and the aerobic equation systolic blood pressure is that right so one of the typical action of beta 1 Agonist is cardio stimulation is that right and one of the typical action of beta1 blocker is cardio inhibition fine so this was one thing that beta 1 receptors are present on myocardium then we come to the second tissue on which beta1 receptors are present abundantly if you remember previous lecture you remember that there was yes juxta glomerular operators in the kidney and juxtapur operators also has lot of beta 1 receptors you must be remembering that juxta glomerular operators right this is macular densa here are your arterial affront and different arterioles right all of this is just a glomerular operators right and juxtaglomerular operators have is having beta1 this adrenaline receptors so whenever beta1 stimulant are present in your body they stimulate the juxtaglomerular operators and increase the release of stimulated and then angiotensin two mediated of course when renin is more angiotensinogen is converted into Angiotensin 1 then in the lungs Angiotensin one is converted into angiotensin two and then Angiotensin to produce arterioloc okay before I tell you these things I want to know man Angiotensin 2 is a stronger vasoconstructor or epinephrine is a stronger vasoconstructor yes ma'am I'm about to be impressed by you yes okay yes sir epinephrine is a stronger vasoconstructor or Angiotensin 2 is stronger with a Constructor I don't know you have to decide yes you think angiotensity is more powerful than epinephrine okay Dr Sergio Mauri says Angiotensin 2 is more powerful than epinephrine and norepinephrine anyone who does not agree with him raise your hand yes many people raise hand all of you are wrong Angiotensin II as 1000 time more powerful than epinephrine and norepinephrine on weight basis as a vasoconstructor why yes he knew it that's good yes he knew it yes and then he must know one more thing the drugs is slightly reduce Angiotensin 2 level significantly controlled blood pressure that's the point to be made right so what is happening anyone who is beta1 stimulant it is increased rain in Angiotensin aldosterone excess right but let's suppose if we give a drug which is beta1 blocker vitamin blocker will not only act as cardio inhibitor but beta1 blocker drug will block beta 1 receptors on in juxtaglomerular operators and renin production in your body will be less and when raining will become less then angiotensinogen into Angiotensin one will be less and Angiotensin one converted into angiotensin two will be less then Angiotensin II mediated arteriola construction will be less than diastolic blood pressure will be less then angiotensin two mediated we know construction will be less Venus return will be less cardi and diastolic volume will be less cardiac output will be less and systolic blood pressure will be less E1 aldosterone will be also less you know in your tension 2 not only construct arteriole not only construct veins ingotensin to also stimulate Zona glomerulosa to produce aldosterone so when Angiotensin 2 is less less than aldosterone mediated salt and water retention is less then blood volume is less venous filling is venous filling is the blood volume is less then venous filling is less than Venus return is less than cardiac filling is less than cardiac output is less than soluble pressure is less that is why those drugs which reduce Angiotensin 2 level in the body are very very good antihypertensive drugs but here we should make a point that beta1 blocker drugs reduce the blood pressure where cardio inhibition and also reduce the blood pressure by inhibiting the renin Angiotensin aldosterone system am I clear then any other beta1 actions of course on the liposites adipocytes you know your friends the deposites keep on accumulating in your body so frankly right they also have modified beta-1 receptors which are called beta3 adrenergic receptors and if there is a drug which can stimulate these heterological receptors on liposite or adipocyte that will produce lipolysis and if you have a drug which can stimulate beta-1 receptors that will produce lipolysis is that right and if there's a drug which block beta three receptors of course that will prevent lipolysis am I clear so next time if I say there's a drug which beta one action you know it it's cardio stimulant and it is stimulate amplifying production of renin and producing renin Angiotensin aldosterone system stimulation and disrupting some liposite defunction right now we come to beta2 action is that right now we come to Beta 2 actions what are the typical beta2 adrenergic receptor mediated actions in your body yes beta 2 receptors number one you know in the lungs there are beta2 receptors present on yes please yeah where they are present on bronchial smooth muscle and bronchial smooth muscle there are beta2 receptors these are bronchial smooth muscles it's a very simple diagram and on this smooth muscle I bring it out there are beta2 adrenergic receptors right and beta2 receptors are inhibitory receptors here so when there is beta2 stimulant right this will inhibit the contraction of bronchial smooth muscles right and that will end up into what beta2 mediated bronchodilation and this is clinically a very important concept there when beta2 receptors on bronchial smooth muscles are stimulated that leads to these are two mediated bronchodilation ah yes pharmacologically we take advantage of this mechanism in patients with asthma patients who have generalized tendency patients who have a tendency for generalized bronchoconstriction like patient with asthma in patient with asthma we give beta2 stimulant like albuterol albuterol or terbutaline these are beta2 stimulant drugs and which are two stimulant drugs can lead to Broncho dilation am I clear so this is one action of beta2 stimulation on the bronchial smooth muscle do you think in bronchial tree or in the lungs there is any other action of beta2 stimulation I will be impressed again is there any other part of any other component of the lung where there are beta2 receptors of course there are beta2 receptors present on bronchial smooth muscles right and whenever you stimulate them there is beta2 mediated Broncho dilation and clinical point is they have beta2 stimulant are used as bronchodilators like turbital in Albuterol they have Broncho dilators and you must also know better two blockers like Propranolol which are beta1 and beta2 blocker when you take propranolol beta 1 and beta 2 receptor the block and when pulmonary beta2 receptors are blocked then beta two mediated bronchod dilatation is lost and this tendency of bronco construction that is why Propranolol is contraindicated in patients with asthma because an asthma patient the Propranolol will block The beta2 receptors and normal which are two mediated bronchodilation is lost you know normally our body does have some circulating epinephrine and some norepinephrine which comes from the nerve endings and this endogenous normal usual amount of adrenergic Drive keep bronchi a little bit dilated so as soon as you take propanolol beta2 mediated bronchodilation will be lost in normal person it may not be significant problem but a person who has tendency for asthma he may receive precipitate severe bronchoconstriction I was asking that is there any other component of the lung which has beta2 receptors which may help in allergic asthma yes masked cells you know there's something called mast cells which play a big role in allergic asthma mast cells have many types of receptors including the beta2 receptors mast cells they also have beta-2 adrenergic receptors and when these receptors are stimulated mast cell membranes are inhibited and membranes of mast cells and granules of Marcellus stabilized so tendency of mast cell membrane to produce prostaglandins and leukotrienes is reduced and tendency of Mast Cell granule to release histamine is reduced is it good for patient with allergy customer bag my God it is good if I have allergic asthma do you think my Mast Cell should be stimulated and release prostaglandin in the liquid tree in the histamines you don't want let mast cells sleep like dogs we want them to be inhibited is that right so this is the added advantage of beta to drugs which are better to stimulant that not only they produce bronchodilation which is the major action of beta2 drugs in asthma but beta2 receptors on the mast cells are also stimulated and beta2 receptor when they are stimulated on the Mast Cell they inhibit the activity of mast cells so mast cell chemical mediators are naturalized so we can say the beta2 stimulant drugs like turbital in Albuterol such drugs not only produce bronchodilation but they also stabilize the mast cells in the bronchial mucosa Amorite clear okay so this was beta2 action on the bronchial smooth muscle then there are beta2 action on the yes vascular smooth muscles I told you in previous lectures that the blood vessels which go to the skin they are having alpha 1 receptors blood vessels which are going to git they are also having mainly Alpha One hydrologic receptors and blood vessels which are going to the kidney they are also having alpha 1 receptors but blood vessels which are going to the muscles they are having yes more beta2 receptors and less sulfur 1 receptors blood vessels which are going to the skeletal muscle they are those blood vessels suppose they remove one smooth muscle here this is smooth muscle from the blood vessel of skeletal muscle it has more beta2 receptors these are all beta2 receptors and very little Alpha One receptors right so when you give a drug which is mainly beta2 stimulant then beta2 receptors will be stimulated and there will be beta2 mediated relaxation of vascular smooth muscle in the blood vessels going to skeletal muscle specially so skeletal muscles blood vessels will arterial as well relax right and resistance peripheral resistance to skeletal muscle will be reduced now listen carefully a drug which is purely Alpha One stimulant right that will act on these alpha 1 receptors and produce vasoconstriction and another drug which is mainly beta2 stimulant will produce beta2 yes that will produce beta2 stimulation on this smooth muscles and relax so it means that drugs which are alpha one stimulant they produce arteriola construction and which are beta2 stimulant drugs they produce here articulo dilation it means that Alpha One stimulant produce increased total peripheral resistance and beta2 stimulant decrease total peripheral resistance reserved right or you may be thinking what is the clinical importance of this let me tell you right now I was telling you that endogenously normally there is some degree of epinephrine circulating in our blood that epinephrine endogenous normal epinephrine produces a slight vasoconstruction in Alpha One mediated vasoconstrate arteriola construction and cutaneous Splunk neck and Renal Circulation and normally endogenously circulating epinephrine normally produces beta 2 mediated vasodilation and skeletal muscles is that right and let me tell you something interesting now even though when we read literary medical literature we say cutaneous blood vessels have which receptor alpha one but to be very critical cutaneous blood vessels smooth muscle has lot of Alpha One lot of Alpha One Alpha One Alpha One Alpha One Alpha One receptor little beta 2 walls to be very critical you know there are some people who are really nasty and very critical to be very critical most of the places in our bodies have alpha 1 and beta to both but when I say that this area has alpha 1 receptors mainly I mean Alpha One or abundant far more in concentration than beta2 right not a lesson there is some clinical importance when you give a drug which is beta2 blocker you know beta1 and beta2 blocker drug is propranolol Propranolol is beta 1 and beta 2 blocker when you give proper and a law that will block the beta 2 mediated weather or dilation to skeletal muscles are you understanding me when these beta2 receptors are blocked here do you think when you do exercise and produce epinephrine and not epinephrine and this epinephrine goes and through beta 2 mediated action exercise induced epinephrine through beta 2 mediated action dilate the blood vessels to skeletal muscle but if you are on propranolol during physical assertion beta 2 mediated vasodilation of blood vessels going to skeletal muscles is lost if you are taken propranolol which are two receptors here are blocked then when you do physical exertion which are two mediated vasodilation or skeletal muscles is blocked lost so there is reduced tolerance to physical exertion when you are on proper and Allah there's reduced tolerance to physical exertion patient complains of fatigue ability it has a little activity and feels more fatigued due to some Central action of the drug and due to loss of beta2 mediators vasodilation in the skeletal muscles another thing could you understand it or not you could not understand okay let's start with the basic uh normally we have epinephrine circulating normally that act on The beta2 receptors and skeletal muscles blood vessels normally epinephrine endogenous epinephrine keep the skeletal muscles vessels slightly dilated due to Beta 2 mediate reduction is that right so we say that in a normal person there is some degree of beta-2 mediators vasodilation to skeletal muscle is that right and when you do exercise you know you get inhibited or stimulated yes empathetic nervous system gets stimulated during exercise you are excited usually right when you do exercise the level of epinephrine and norepinephrine is more in the blood especially epinephrine which is released by adrenal medalla this circulating epinephrine during exercise right act on the beta2 hydrologic receptors on skeletal muscles blood vessel and produce beta2 mediated dilation so that increases blood flow to the skeletal muscle so during exercise skeletal muscles blood flow increase number one due to which are two mediated vasodilation plus during exercise cultural muscle produce local factor which dilate the skeletal muscles the blood vessel right now you imagine you have taken propranolol beta2 receptors is that right because when you have taken propranol beta2 receptors are blocked on this skeletal muscles blood vessels then yes beta2 you have loss of beta 2 mediated what vasodilation to skeletal muscles so when you will do exercise while you're on propranol do you think these blood vessels will dilate significantly no you will get tired easily the multiple reasons when patients on Propranolol they feel very fatigued with little assertion there are some Central action I will discuss later plus this is one action another point which is clinically relevant that our skeletal our you know these blood vessels which are going to the skin and going to the distal part of the limbs these blood vessels have more Alpha One receptors than less which are two receptor now listen have you heard of a disease called Raynaud disease or raynard's phenomenon Raynaud r a y Reynolds disease actually in you have never heard of things like this okay you will hear right now I'll tell you something in Reynolds disease there is increased tendency of vasospasticity of distal blood vessels our distal blood vessels are having increased transition to undergo vasoconstriction whenever skin is exposed to the cold you know normally when you are exposed to the cold cold temperature when you expose to the cold normally your blood vessels construct but in some people who are suffering with Reynolds problem when they are exposed to the cold skin distal blood vessels in the limbs construct so severely that they develop severe cyanosis and even sometimes necrosses of fingers and severe Reynolds disease is that right in these patients who have a high tendency of vasoconstriction in the limp blood vessels if you give them propranolol a little bit or too mediated a little bit are too mediated whether dilation is also lost your understanding will be contraindicated in the patients with peripheral peripheral blood vessel disease like Raynaud's disease because they are already having a tendency of vasoconstriction at the top you give the Propranolol and then there is loss of beta2 mediated vasov dilation and more sphere construction is that right and so how how many points about beta2 receptors I was talking Propranolol should not be given in a patient with asthma because beta 2 mediated Vaso oh beta2 mediated bronchodilation will be lost Propranolol should not be given to the patients uh with Reynolds disease peripheral vascular disease because beta2 mediated whether dilation will be last am I clear then so you know beta 2 actions and the beta2 actions which we have learned up to now yeah there is another smooth muscle which is also having beta2 receptors up to now we have said beta2 receptors are present abundantly on bronchial smooth muscle which are two receptors are present abundantly on the vascular smooth muscle and beta2 receptor the present also on the myometrium of pregnant uterus we mentioned previously that in the uterus right in the myognition of the uterus there are beta2 receptors also and beta2 stimulation lead to yes if you give a drug which is better to stimulant what it will do it will produce dilation of what uterus dilidation drug is not a Hagar's dilator we don't use the term uterus dilation that is what I'm going to say right if even theoretically or practical even you are right that when you give us beta2 stimulant as bronchioles will dilate uterus will also relax as a better term right we don't say uterus is constructing and uterus is dilating I don't know why but this is what they say right so beta 2 mediated myomaterial relaxation is achieved when you give beta to stimulant and I told you previously this has clinical importance that when uh uterus start Contracting a pregnant uterus start Contracting before a time there's premature labor pains and labor contractions right premature and it threatens to produce premature birth of the baby you can give beta to stimulant drug which will produce relaxation of the myometrium so that uterus should not threat to push the baby out before time am I right what is the section called if a drug produces relaxation of the uterus this section of the drug has given a very specific name in medical literature someone who has done gyneob yes yeah detergent I'm saying if I give a drug to a female and that Drug Act on the myomaterial smooth muscle and relaxes them right so drug action is called tocolysis the section is called in medical literature Toco lysis or chocolate drug doctors have a special related drug ritodrine albuterol Albuterol are butaline or rightodrine these are all beta2 stimulant specially stimulate the beta2 receptors on on uterus right so what are the typical beta2 action bronchodilation vasodilation especially to the skeletal muscles which are two action there is relaxation of myometrium of course only in the females right then no I should tell you the basic information right so then any other beta2 actions any other beta2 action beta2 receptors are present on the liver metabolic action oh my God there is something called liver which has hepatocyte there are also beta2 receptors adrenergic receptors of course on the hepatocide you must be knowing that when when you are under stress epinephrine is released in the blood from Adrenal medulla epinephrine will bind with the beta2 receptors on the what hepatocide and that will give signal for breakdown of glycogen glycogen will break down into glucose and glucose will come out into blood am I clear glyco glycogenolysis so there is beta2 mediated glycogenolysis on the hepatocytes is that right release of glucose do you think this thing has any importance this information yes this physiological importance as well as pharmacological importance physiological importance is that that when you are under stress as I told you there was a big black dog after Mr Gavin that will remove a lot of epinephrine come into blood epinephrine act on the hepatocytes through beta2 receptors and do glycogeno lyses and release lot of glucose into his blood so that glucose which can be used by muscles and by the brain so to fly away appropriately from the threat right it is pharmacological importance that you must know there are beta2 receptors on the liver cells you know very commonly used drug is propranolol and Propranolol blocks what is this funny thing beta2 receptors what will happen the gluc liver loses the capacity liver loses the capacity to release glucose by glycogenolysis when you have hypoglycemia now let me tell you another thing whenever you have hypoglycemia listen carefully let's suppose due to any reason I get severe hypoglycemia hypoglycemia stimulate sympathetic nervous system strongly so we are hypoglycemia and sympathetic nervous system number one produces the signs of warning signs of hypoglycemia what are the warning signs of hyperglycemia sympathetic overflow sympathetic overflow produces sweating anxious look like you become irritable and anxious and in hypoglycemia when this oversympathetic flow you develop tachycardia palpitations and when sympathetic overflow tremors is that right these are the warning signs especially the patients who are diabetic patients especially those diabetic patients who are insulin dependent listen carefully with both ears the patients who are insulin dependent diabetic patients they have a high risk to undergo hypoglycemic attack because if I'm a patient who is insulin dependent sometimes I may not take food and take insulin and I dwellers we are hypoglycemia or sometimes I take insulin and food in normal amount or do some lot of physical exercise I will develop hypoglycemia so the patient who are insulin dependent diabetics they have higher risk of developing episodes of hypoglycemia when they develop severe hypoglycemia because they are taking insulin injections and if insulin is more and glucose in the blood is less by mistake hypoglycemia is precipitated what happens to this patients when brain has less glucose sympathetic overflow these patients develop sweating a strange look which their relatives become very familiar they develop some anxious and some strange type of looks Tremors and palpitations is that right these are the warning signs of diabetic patient on insulin dependence and what should we do we should give them a lump of sugar to abort hypoglycemia but liver also help a lot because once due to hypoglycemia the severe sympathetic overflow epinephrine goes to liver stimulate the pita2 receptors and beta2 mediated yes glycogenol lysis occur and glucose come into blood so that hypoglycemia does not become more worse immaculate you are not clear about it you are clear yes you are clear about it that patients who are insulin dependent diabetics they have higher risk of hypoglycemic attack during the hypoglycemic attack they develop anxious look palpitations Tremors and sweating right all these sympathetic overflow feature with that epinephrine acts on the liver and releases glucose from there so that hypoglycemia does not get worse am I clear now you imagine patient who is diabetic insulin dependent at the top here some ischemic heart disease or some problem which is very common in diabetic patient and you are the wise doctor to put him on propanolol you have to be very careful you know why if insulin dependent diabetic patient is on the beta blocker specially propranolol whenever he will develop hypoglycemia he will not develop warning sign because he will not develop anxiety because beta1 receptors are blocked you will not develop palpitation because beta 1 receptors are blocked you will not develop Tremors because beta 2 receptors are block so such patient who is insulin dependent diabetic patient and you are keeping him also on the Propranolol whenever they undergo hypoglycemic episodes they don't develop warning sign they don't know they are having hyperglycemia at the top you fail the internal glucose provision mechanism propranol also block this receptor so endogenous release of glucose from liver is also blocked so they have a risk of undergoing life-threatening hypoglycemic episode so what did I say that patient or diabetic and insulin independent diabetic if you give them drugs like propranolol they will lose the they will not develop the warning signs of hypoglycemia so they will not take sugar from outside and unfortunately these drugs will also block the hepatocyte activity to release the glucose and endogenous release of glucose from the liver is also not there and they have a heightened density to undergo life-threatening hypoglycemia what is the message here that Propranolol drug should be contraindicated in patients on insulin dependent diabetes because these are very very important things if you do these mistake you give properly to a person with asthma or with a Raynaud's disease or a patient with insulin dependent diabetes I tell you surely you will have lot of patients swing you they will get one systematic attack they will get it managed but you will not be able to manage those millions of dollars for them right and next time you know insurance company will be very much wary of you right so this is all clinically relevant that beta to mediated drugs are good and bad Peter too stimulant again are used as bronchodilator beta2 stimulant are used as tocolytic drugs is that right but at the same time you must know that yes beta 2 blocker can precipitate asthma beta 2 blockers can worsen the Reynolds disease beta2 blocker can uh hypoglycemia in patient with diabetes mellitus which is insulin dependent right then one more thing about this about the beta2 there is something about we should talk about primers I told you in last video lectures that you know there are introfusal muscle fibers which are having beta2 receptors and beta2 receptor right when they are functioning well on the muscles which are two receptors when they work in functioning well right they help the muscles to keep their tone properly for example if I'm keeping my hand outstretched without Tremors the main one of the reason is that my intrafusal muscle fibers are working well but whenever I get anxious I will develop primers because during anxiety epinephrine will come and over stimulate the beta2 receptors on skeletal muscle introfusal fiber so whenever beta2 receptors on skeletal muscle fibers are over stimulated you will develop tremors what is the importance of this yes there is you give bitter to stimulant for bronchodilation one of the side effect is tremor is that right one of the side effect is primer now come on another thing if someone has undue Tremors there are people who have essential tremor essential tremors mean they have Tremors essentially all the time there may not be any clear-cut reason why they have Tremors but they do have tremors so what we will do they can be treated by propranalol you can block the beta to receptors and Tremors will be subsided Emma clear so when you will be you will become doctor soon and you will be playing with these drugs what is the difference in every doctor and a great doctor the difference is how you use your tools how wisely or clumsil you use your tools your tools are drugs not illicit drugs right so let's have a break here today we are going to talk about that when adrenergic receptors are stimulated how they induce intracellular signals right what are the molecular basis of adrenergic receptors function right so let's take different tissues let's suppose here is your central nervous system neuron and then post-ganglionic neuron releasing norepinephrine here and here here and here let's suppose these are the nerve endings and from here it is releasing nor epinephrine now we have to see that how norepinephrine work on the adrenergic receptors I will put one model here I will explain in this diagram first how the Alpha One adrenergic receptors work right alpha 1 adrenergic receptors work so this is a nerve ending which is going to release yes nor epinephrine right now once norepinephrine is released it will bind with the adrenergic receptors all the adrenergic receptors are belonging to the family of seven path receptors right why we call them seven pass receptors because these receptors are peptide chain and this peptide chain passes through the cell membrane seventh time one two three four five six and seven now this pocket where norepinephrine binds right this pocket of the peptide chain this pep red peptide chain is the adrenergic receptor let's suppose that this is Alpha One adrenergic receptor right now Alpha One hydrologic receptor like other adrenergy receptors it is a seven pass receptor we also call it Serpentine receptor Serpentine mean snake snake-like receptor right and intracellularly these receptors coupled with G proteins so third name for such receptor is G protein coupled receptor so what we have to remember that all adrenergic all adrenergic receptors are yes there are three names they can be called seven pass receptors because this receptor pass through the membrane seven times seven pass receptors they can also be called yes Serpentine receptors right because they are like snake and then there can also be called G proteins yes coupled receptors even receptors are sexy you know G protein coupled receptors right now Alpha One hydrologic receptor like other receptors they must have one extracellular domain where norepinephrine binds so norepinephrine binds over here right and this point where norepinephrine bind this is called ligand binding domain and this intracellular part of the receptor this is called effector domain this is called effector domain now this effective domain in case of Alpha One adrenergic receptor when right effective domain become activated and norepinephrine bind with the receptor and this activated effector domain will stimulate G protein right now which G protein stimulates it yeah which G protein it stimulates G G Q it stimulates the G Q G proteins are primarily yes G proteins are primarily primeric proteins they have Alpha component they are having beta component and they are having gamma component right what really happens when this receptor is stimulated by epinephrine now or norepinephrine it will stimulate the alpha component of the G protein and this G protein is called yes this is called G q and this Alpha is called Alpha Q now as soon as receptor activate the alpha component of the G protein Alpha component which was previously binding G DP it loses the GDP and binds GTP GTP is high energy molecule where it bind with the GQ Alpha component then Alpha component dissociate with beta and gamma right Alpha component dissociate from beta and gamma this dissociated Alpha component this is now Alpha q and it is loaded with g t p and now it is fully active and this activated Alpha component and of course your friends beta and gamma have been dissociated beta gamma dissociated from this primeric complex now Alpha component will bind with yes there is an enzyme here what is the name of this enzyme adenylial cyclase and this enzyme is very happy because you remember its name very good right so everyone is happy when you remember their name including the enzyme so is the effector molecule on which oh you know we are wrong we are dead wrong because it is Alpha stimulatory which bind with adrenaline cyclists enzyme is happy because you are fooled yeah GQ does not bind with adenylial cyclase rather G2 bind with a different enzyme and that enzyme is called yes who will tell me the name of that enzyme yeah this is the name of that enzyme let me tell you yeah this enzyme can attack the cell membrane this enzyme can attack the cell membrane when this enzyme is activated what is the name of this enzyme phospho lipase C so actually when GQ is stimulated the alpha component of GQ stimulates a phospholipase C and when phospholip C is activated this enzyme attacked the lipids in the cell membrane right this will attack the lipids in the cell membrane a very special lipid which is in the cell membrane uh this is called Jess this lipid is called phosphatidyl inocytol diphosphate what is the lipid phosphatidyl inocytol diphosphate and this lipid will be attacked by the phospholip C when phospholipids C you will attack the phosphatidial inocitorial diphosphate this will break down into two components right it will break down into two component one is inocitol yes triphosphate ip3 other is dye acyl glycerol then you must be knowing that inocytol triphosphate actually act on intracellular stores of calcium within the cell calcium is stored in endoplasmic reticulum right so calcium is stored well in endoplasmic reticulum and here is a calcium transporters right and calcium is well stored what is this endoplasmic reticulum which is very rich in calcium and what really happens that ip3 will stimulate this pump ip3 will stimulate this pump when this pump is stimulated by ip3 or exchanger stimulated calcium will come out and intracytosolic calcium levels will go up and this calcium will bind with special type of kinases right calcium will bind with curl Model N right and this protein to which calcium is binding that is called call Model N pioneers this protein is called palmodolin kinase right calcium will bind with coal model in kinase protein right now if you really want to the to know the steps calcium will bind with cold modeling and calcium carb model in complex will activate certain kinases which are called cam kinases now once calcium carb model and kinases or Cam kinases are activated this group of enzymes will phosphorylate Target protein for example one example of Target protein in smooth muscle is yes you know Alpha One adrenergic receptor produce smooth muscle contraction remember that very good so how it will do calcium will phosphorylate light chain kinesis there is an enzyme called yes light chain kinases right and when this light chain Kinesis are acted upon acted upon by calcium uh cam kinases then light chain light chain kinases are phosphorylated they become active they become phospho violated because kinase enzyme at phosphate to light chain kinases how they take the ATP and break the ATP into ADP and phosphate is added to this when light chain kinases are phosphorylated who will tell me the next step they will phosphorylate they will phosphorylate myosin light chains they will lead to phosphorylation of myosin myosin light change phosphorylated when they become phosphorylated right the phosphorylated myosin light chains can participate in actin myosin interaction what will happen myosin light chains which are phosphorylated they can participate in actin myosin F10 myosin interaction and this active myosin interaction will lead to yes smooth muscle contraction so this is one example how alpha one adrenergic receptors work that Alpha One adrenergic receptors once they are binding with the ligand they stimulate the GQ protein the alpha component of GQ stimulate phospholipase C enzymes which break down the intramembranous phosphatidyl inocetyl diphosphate into ip3 and diethyl glycerol what ip3 is doing ip3 can act on certain calcium exchangers on the endoplasmic reticulum and release the sequestered and calcium right from the endoplasmic reticulum into cytosol calcium will bind with the coal modeling and calcium carb model and kinases will be activated which will phosphorylate Target protein in smooth muscle Target protein is chain kinases when light chain kinases become phosphorylated their phosphoryl phosphorylate myosin light chains and myosin light chains are phosphorylated yes now they are very happily interacting with the actin so actin myosin interaction start a smooth muscle will contract am I clear secondly don't forget this dog not dog tag diazyl glycerol diesel glycerol is another second mediator produced by phosphatidyl anocytal diphosphate and diacyl glycerol can yes can activate who will tell me the iso glycerol can activate yes please another kinase what is that protein gas protein kinase C right so protein kinase C protein kinase c will be phosphorylated and when protein kinase C is phosphorylated right or activated dioxide glycerol activate listen again diazyl glycerol actually let me repeat it again disalglycerol will act on protein kinase C and protein kinase c will become yes she will become activated no I please correct it is not phosphorylated it becomes simply activated when protein kinase is activated in the presence of disalglycerol then protein kinase C can phosphorylate certain Target proteins right target proteins Target proteins phosphorylated phosphorylated so what did we really learn we learned that when whenever norepinephrine or epinephrine or any other compound which is having Agonist action on Alpha One adrenergic receptor right that will lead to activation of interstellar GQ protein activation of phospholipes C increase intracellular level of ip3 and disalglycerol and ip3 will increase interest cytosolic calcium levels calcium will bind with calcium carb model and kinases and and disalglycerol will bind with protein kinase C when both of these kinases are activated they will phosphorylate their target proteins and phosphorylated Target proteins will alter the function of the cell am I clear any problem here so this was how alpha one adrenergic receptors work if someone asks a very simple question that when alpha 1 adrenergic receptors are stimulated which intracellular second messengers concentration is increased then Dr Nikita will answer you know only she will answer which intracellular second messenger level will increase what is the second messenger here yes okay ip3 and disul cholesterol but more importantly calcium the right intracellular calcium will increase right now we come to action of we have studied the action of Alpha One adrenergic receptor now we'll study the action of alpha yes two adrenergic receptor how alpha two hydrologic receptors work right let's suppose this is Alpha 2 and logic receptor again you can find Alpha two hydrologic receptor as also 7 path receptor or other name is Serpentine receptor or it is G protein coupled receptor and whenever norepinephrine or epinephrine binds here and Alpha 2 adrenergic receptor is stimulated intracellularly it will stimulate not GQ you know Alpha One was coupled with GQ Alpha two receptor is not coupled with GQ it is coupled with yes please G inhibitory this is coupled with G inhibitory protein and G inhibitory protein is Alpha inhibitory and with that it has beta n I think I should change the color so that you you don't get confused right so G inhibitory has Alpha inhibitory with that it is having yes beta inhibitory and Gamma inhibitory so whenever Alpha two receptors stimulated Alpha Alpha inhibitory component of the G protein will lose the s g DP and acquire the GTP and now it will become energized and it will dissociate from its friends right Alpha inhibitory which is energized now it is activated right because it is loaded with yes g t p and of course when Alpha inhibitory will dissociate from beta and gamma as Alpha inhibitory has separated in the same way beta gamma units will be also separated beta gamma inhibitory units then what will happen that Alpha inhibitory will interact with your friend yes you remember now adenylial cyclase and now yeah what will happen to other null cyclist it will bind to this component of the adrenaline cyclist and whenever adrenaline cyclist has two domain at one domain Alpha inhibitory bind it has one another domain and with this domain this is a different domain with this domain Alpha stimulatory bind so Alpha inhibitory binds to this domain and whenever Alpha inhibitory bind it will lead to inhibition of action of Aden allyl cyclase and when adrenaline cyclase is inhibited then ATP cannot be converted into cyclic amp so Gene inhibitory or Alpha enability component of G inhibitory inhibit adenal cyclase so conversion of ATP into cyclic amp is reduced when there is reduced cyclic amp so of course then there is reduced cyclic MP activate yes protein kinase a so there is reduced activation of protein kinase a then protein kinase normally phosphorylate Target protein but now because protein kinase is not stimulated because cyclic MP levels are less intracellularly so protein kinase a dependent intracellular activities are reduced so what should I write when protein sign is a is not activated then phosphorylation of protein can is a proteins don't occur and we say that there is reduced activity of protein kinase a dependent yes intracellular cellular functions for example if in this cell there was an enzyme which was acted upon by protein kinase a and when that when that enzyme was getting phosphorylated a metabolic pathway was run but when Alpha 2 receptor is stimulated G inhibitory is activated an activated G inhibitor inhibited an allyl cyclist cyclic MP level become less protein can is a activity become less then that enzyme will not be phosphorylated and that enzyme-dependent metabolic pathway will be inhabited Amic layer secondly a very important factor which you must know is beta and hibitory in gamma inhibitory component once they're dissociated from alpha inhibitory they can bind with the potassium channels their special potassium channels and these potassium channels have intracellular component where beta inhibitory and Gamma inhibitory can bind so this beta and gamma inhibitory bind with the what is this potassium Channel and as you know the potassium is more potassium concentration intracellularly is high so naturally potassium will start moving from intracellular compartment to extracellular compartment so what really happened beta gamma unit of Gene inhibitory increase potassium e flux so when the cell is losing the potassium naturally what will happen to this situation yes cell will become electrically more negative because cell is losing positive charges so we can say if this cell was having restroom membrane potential of resting membrane potential of suppose minus 70. minus 70 millivolt but once potassium is lost then resting membrane potential will become more negative because positive charges are lost so it will become minus suppose 90 millivolt so what really happens the stimulation of receptor right which when it activates the G inhibitory activated beta and gamma units of Gene inhibitory activate the potassium channels and let the potassium be lost from the cells and when intracellular potassium is lost outside so restroom membrane potential become more electronegative it means cell become more polarized towards the negative side or we simply say cells become hyperpolarized and they become electrically inhibited am I clear to everyone another point uh this is what very few very good students know only that Alpha hydrologic receptors have one more function this is Alpha 2 adrenergic receptor when ligand binds with that when ligand bind with it not only these receptor activate G inhibitory they also activate a very special type of G which is called G naught Alpha naught and beta gamma units this is a different this is type of G protein this is called G not you must be knowing GQ you must be knowing G inhibitory you'll study about G stimulatory and this is a different which is called G naught actually Alpha two and Magic receptors can stimulate the G naught also and when G naught is stimulated of course Alpha component will lose the Alpha component to lose the GDP and acquire the GTP and Alpha component become activated and when Alpha component becomes activated then Alpha not loaded with yes GTP write this binds with the calcium channel That Binds with the yes with channels calcium channels and when this will alpha naught will bind with the calcium channel it will inhibit the calcium channel so calcium and flux will stop calcium influx will stop this is what happens in the presynaptic nerve endings if you remember that in the very early lectures of heterogic system if this is one neuron and this neuron is releasing not epinephrine here right and this is your target tissue I told you norepinephrine work on presynaptic membrane right through which receptors through yes Alpha Alpha two hydrologic receptor and I mentioned that when norepinephrine act on presynaptic membrane in inhibit the nerve ending functions how it inhibit number one it will when G inhibitor is stimulated activated it activates the potassium channels and when this nerve ending will lose the potassium it will become hyper polarized it becomes very negative so this will be difficult to stimulate this now ending this is one change secondly G naught will block the calcium and flux and when calcium influx is blocked to this nerve ending the exocytosis of the neurotransmitter release will be less thirdly Gene inhibitory right will inhibit at an allyl cyclase and intracellular protein kinases and at this point will be inhibited and they will inhibit the enzymes and Transporters which are concerned with synthesis and storage of norepinephrine so these are multiple mechanisms how uh pre-synaptic Alpha two hydrologic receptors inhibit the presynaptic membrane is that right no problem after this now we come to the we have learned what are the interests what are the signaling mechanism of Alpha One hydrometric receptor we have learned what are the signaling mechanisms in alpha or molecular mechanism in Alpha two hydrologic receptors and now we'll talk about what are the molecular basis of signaling mechanism of beta1 adrenergic receptors and beta2 adrenergic receptors and beta three adrenergic receptors again there is a question if let's have a break now we will talk about the intracellular signaling mechanism for beta receptors right beta 1 beta 2 and beta 3. the good news is that the intracellular intracellular signaling mechanism for beta 1 beta2 and beta 3 are same right so let's study the beta1 intracellular mechanism and beta1 adrenergic receptor is stimulated let's suppose this is beta 1 adrenergic receptor right and if epinephrine or not right with beta 1 Let's suppose epinephrine binds here right epinephrine this is the beta1 adrenergic receptor you remember Alpha One adrenergic receptor was coupled with GQ Alpha two adrenergic receptor was coupled with G inhibitory where beta1 adrenergic receptor is coupled with G stimulatory right it is coupled with G tribulatory protein so let's suppose this is Alpha component of alpha stimulatory this is beta and gamma stimulatory right when epinephrine bind with or with beta 1 hydrologic receptor it intracellularly stimulate the G stimulatory which component of the G stimulatory Alpha component of the G stimulatory and then of course Alpha component and stimulation loses GDP and acquires GTP right and this Alpha component also dissociate from beta and gamma this Alpha stimulatory component which is loaded with GTP right it loses it dissociates from beta and gamma component right and it interact with yes please has two points because one point where G inhibitory could bind other point where Alpha component of G stimulatory could bind and when right this adenaline cycle is is stimulated by Alpha stimulatory right then what really happens that this will stimulate the activity of Aden allyl cyclists an adrenaline cyclist will start converting ATP into cyclic amp so there is raised intracellular cyclic amp level again when beta 1 and logic receptors are stimulated they are coupled with intracellular G stimulatory protein and G stimulatory protein Alpha component stimulate Aden allyl cyclists which convert more ATP into more cyclic amp and this cyclic amp is the second messenger of this system the second messenger molecule will stimulate yes molecule will stimulate yeah what is this protein kinase a right and this protein kinase a will start phosphorylating the target protein it will start phosphorylating Target proteins right whatever Target protein is there right that protein will be phosphorylated now when proteins get phosphorylated their functions are altered in this way a target cells functions will be altered as you know now let me give you few examples beta 1 receptors when they are stimulated there is cardiac stimulation right there is cardiac stimulation there is increased heart rate there is increased contractility now how it really happens it happens by two ways the one of the target protein may be calcium channel here is the calcium Channel and if protein kinase a phosphorylate the calcium channel and when calcium channel get phosphorylated it work more efficiently and there will be more calcium and flux there will be more calcium in flux and calcium dependent intracellular mechanisms will be accelerated for example when calcium will again protein can is a when it is stimulated it can phosphorylate calcium channels suppose this calcium channels are present in SA node then there will be more calcium influxin as a node and you know that in essay node and AV node action potential is dependent on calcium right in the same way calcium and flux will occur in atrial and myocardial and myocardial cells from ductility is also dependent on calcium so there will be positive ionotropic action right so but one thing which many students don't know that Alpha stimulatory can directly now this is a very important Point Alpha stimulatory can directly stimulate Alpha stimulatory and directly bind with the calcium channels and stimulate it directly also right so in in this way we can say that when G stimulatory proteins are stimulated right by the stimulation of beta1 receptors right intracellular cyclic MP level increase protein kinase a activity increase and proteins and is able phosphorylate Target proteins and bring changes in intracellular function Plus what we have to talk about that Alpha stimulatory can directly bind with the calcium channels and increase the activity of calcium channels so calcium and flux influx becomes more and calcium dependent electrical activity in The myocardium and calcium dependent contractile activity of the contractile activity of The myocardium will be Amplified am I clear as I told you the good news is that that beta 1 receptors which are two adrenergic receptors and beta-3 adrenergic receptors all of them are coupled with intracellular G proteins and in all of them there is increased intracellular cyclic amp level right so the intracellular signaling mechanism for beta 1 and beta 2 and beta 3 is the same right now let's do a little review and then we'll continue further let's let me put here adrenergic receptors right already you know adrenergic receptors are divided into Alpha and yes beta Alpha are divided into alpha 1 adrenergic receptors Alpha 2 adrenergic receptors beta are divided into beta 1 adrenergic receptors beta2 adrenergic receptors and beta 3 adrenergic receptors now these are Technologic receptor which is Alpha 1 adrenergic receptors they are coupled intracellularly with which type of G protein just Place G q and what is the second messenger system yes please IP 3 diazyl English roll lead into and eventually leading to increased intracellular calcium level excellent now we'll talk about Alpha 2 adrenergic receptors receptors they are intracellularly coupled with which G protein G inhibitory and that will lead to yes please decreased that will lead to actually two types of rather three types of activity G inhibitory when it is stimulated number one yes decreased intracellular cyclic a m p number two there is increased potassium e flux and number three there is decreased yes yes decrease calcium decreased calcium in flux am I clear no problem now we come to beta1 adrenergic receptors beta 1 adrenal energy receptors are intracellularly coupled with yes please G stimulatory and what will be the result in the cell there is yes increased intracellular yes cyclic amp level plus it has one more thing G stimulatory has two activities one is this and other is yes increase calcium and flux increased calcium influx and then there is a good news that beta2 receptor mechanism and beta3 receptor mechanism is the same as beta 1. a new question after this there's no question that's it yes [Music] which components stimulate the potassium Channel potassium channels are stimulated by Beta gamma unit of the G inhibitory right okay and calcium channels are blocked by the G not right and here calcium channels are opened by the G stimulatory directly Alpha stimulatory and also by the phosphorylation of the calcium channels any more question no okay so now we go to the next area next area is really really very important and applies to lot of areas in Pharmacology and endocrinology and neurotransmissions central nervous system and peripheral nervous system right now we will talk about the concepts of desensitization how The receptors and signaling mechanisms can be desensitized first we talk about what is the concept of desensitization actually when a specific Agonist specific agonisters continuously stimulating a receptor and signaling mechanism then with the time receptor and signaling mechanism become less efficient it becomes less efficient and responds to the same concentration of The Agonist progressively decreases right let me give you first example of desensitization from the Practical life romantic life from marital life it's very common that uh before the marriage has men are very very super sensitive to the would-be wife but after the marriage Men start getting these sensitized to their wife for example if wife is very demanding right she is too much demanding and too much interaction you know whenever this excessive interaction of anything it's just biological system May undergo desensitization right now if wife is too much stimulatory or you can say demanding on the husband or interacting too much after some time to prevent the over stimulation Maybe the person put cotton in his years so that it doesn't listen much right this is early stage of desensitization that she is talking but he doesn't listen he's still in the home but doesn't listen but if she still keep on having Agonist action then what he will do he will run out of the home he will spend more time out of the home he will spend time where his wife cannot approach and do some Agonist activity is that right but if still whenever he comes back sometimes she's too much Agonist activity what he will do most probably will commit suicide this is what exactly happens with receptor and molecular system that when receptors are too much stimulated first they put the cotton plugs what are cotton plugs there are no cotton in the cell the cotton plug for the receptor is phosphorylation phosphates The receptors are over stimulated they get phosphorylated and they become less sensitive to agonists if still stimulation is too much the phosphorylated receptor go intracellular we call it sequestration the run away from the cell surface to avoid The Agonist activity right and if the turn back to the membrane and again there's too much stimulation then they go inside the cell and get catabolized committing suicide let me explain step by step let's suppose that here is a cell and here this cell has adrenergic receptor let's suppose this is beta 1 adrenergic receptor in the same cell let's suppose has one more receptor which is called Alpha II adrenergic receptor all of you know that beta1 adrenergic receptor stimulate G stimulatory Alpha component of G stimulatory and Alpha two hydrologic receptor stimulate intracellularly yes Alpha component of G inhibitory and then as you happen to be very intelligent so you must be knowing that if here is your friend adrenalyl cyclase right here G inhibitory can interact and here G stimulatory can interact right so when G stimulatory or Alpha stimulatory interact here this stimulate adrenaline cyclist right that will lead to stimulation of Aden allyl cyclized activity but if G inhibitory is activated through Alpha two hydrologic receptors then what will happen that Gene inhibitory will gauge here and G inhibitory will lead to inhibition of adenaline cyclase activity and what is the activity of adenylial cyclist is responsible to convert yes ATP into cyclic amp and cyclic amp yes stimulates protein kinase a it stimulates protein kinase a is that right now let's suppose that if we are stimulating beta 1 hydrologic receptor strongly there are lot of epinephrine molecules and there is strong stimulation of beta 1 adrenergic receptors now even these receptors are stimulated right their intracellular component undergo a change and this alteration in intracellular component of the receptor has two Effect one effect is it will stimulate G stimulatory other effect is that it will open a very special area and with this area there is an enzyme inside it will activate here the enzyme is like I don't know how to make a dog do you know how to make a dog okay let's suppose this is some dog I don't know it's unusual dog I think right this is barking B a r k this is an enzyme present within the cell all the time all those cells which are beta one hydrologic receptors right this enzyme is barking why because its name is beta adrenergic receptor kinase what is the name of this enzyme yes beta adrenergic yes receptor kinase it means that it can do kinase activity with beta adrenergic receptor right this enzyme can do kinase activity on beta adrenergic receptor but when it will do kinase activity it will do kinase activity to beta adrenergic receptor only when beta adrenergic receptor is loaded with The Agonist right so whenever beta adrenergic receptor are loaded with The Agonist they are bound with The Agonist they are bind with suppose epinephrine right this this Alters an intracellular domain and this intracellular part of the molecule becomes available to this doggy enzyme and this doggy enzyme which is called beta adrenergic receptor kinase will act on that point and what it will do it will phosphorylate it will phosphorylate some part of the receptor and when this part of the receptor is phosphorylated when this part of the receptor is yes what is happening to this part of the receptor it is getting phosphorylated then receptor become resistant to the action of The Agonist so what what has happened we can say that receptor has what has happened here the receptor has been phosphorylated and this phosphorylated receptor will undergo further change when this receptor becomes phosphorylated then there is an other another protein present in this protein will go and bind with the phosphorylated okay I'll make this protein like that right this protein will go and bind with phosphorylated receptor right and when this protein will bind with phosphorylated receptor when this protein has bound the phosphorylated receptor do you think now G stimulatory can bind here attention please lets me review what happened epinephrine came stimulated the receptor receptor stimulated the G protein and of course Alpha component of G protein went to stimulate the adrenaline cyclase is that clear meanwhile receptor got phosphorylated by the beta adrenergic receptor kinase when receptor got phosphorylated then another protein went and bind with the phosphorylated receptor and when this protein bind with the phosphorylated receptor can Alpha component again bind with this no it means presence of this protein will arrest the signaling mechanism are you understanding presence of this protein will arrest the signaling mechanism so this protein is very appropriately called beta Restin rest in what is the name of this protein this is called beta arrest in right and once receptor get phosphorylated by beta adrenergic receptor kinase and then receptor get loaded with beta Reston do you think then Agonist may be still binding here but can signals go forward no so it means receptor system is getting desensitized to the presence of Agonist that receptor is having The Agonist but not passing the signals forward so what will happen to the same those and same concentration of the Agonist the response of the cell and tissue will be less so we'll say receptors is desensitized or we can say cell the decent price or we can say tissue is desensitized or even we can say patient is decent styles to this particular drug am I right this type of receptor phosphorylation and binding of the arresting with the receptor produces desensitization within few seconds is that right so we call it rapid desensitization this mechanism is rapid yes please rapid d sensitization is that right if walking again go back to that example when wife is talking too much to the husband he is worried about his office matter but she is more worried about our shopping and she is talking and talking and talking what will happen first husband will get phosphorylated and maybe some other women come and bind there and even resting activity may occur so be aware both parties right it's dangerous for both am I right and this type of desensitization can occur rapidly is that right now but remember if we remove the agonists for short time wife become less demanding and less about the shopping right he will turn back most probably if she in time she withdraws same is true that if this again is you know for a short time is kept away right they arresting will go away the phosphorylation will occur and receptor will become what again sensitive am I right this is one example then there is another type of then there is an other type of desensitization let me show you here this is this type of desensitization is called yes homologous this is an example of homo logus desensitization d sensitization what is meant by the homologous desensitization homologous desensitization means that agonists bind with one receptor and the same receptor becomes desensitized is that right now you imagine another thing listen carefully first to the example there are few couples living together in an apartment building and one wife is very hard on her husband right always demanding for shopping I want this I want this and shouting and everyone is listening so not only husband of that wife will become desensitized the risk is that other husbands in the building may also get desensitized the advisor like that and they may not listen to their why other husbands may not listen to their genuine parts of their wife that is called heterologous desensitization are you understanding me really right so again if my wife is shouting to me a lot and if I get desensitized by phosphorylation and arrest in what is this homologous desensitization but if other husbands see what's happening with me and they learn something and they also become decent strives to their wife it means too much you know Agonist activity on me lead to my homologous desensitization and other receptors other husbands heterologous decentralization let me tell you the exact molecular mechanism of heterologous desensitization let's suppose you know this receptor system is giving signal then what will happen at another cyclist will be activated right and then protein kinase a will be stimulated protein kinase a does many function you remember it does phosphorylation of Target proteins and Target proteins will undergo phosphorylation phosphorylation of Target proteins but you will be surprised to know that protein kinase a may also do phosphorylation may do the phosphorylation of receptor which stimulated as well as it may do phosphorylation of some other receptors which are working through the same signaling mechanism you are getting it and I told you when receptors are getting phosphorylated they are becoming less efficient so what was happening that this receptor was having too much Agonist activity stimulating its G stimulatory stimulating adrenaline cyclists getting more cyclic amp increased activity of protein kinase a and this protein kinase a will phosphorylate many proteins including some receptors which are acting through the same molecular mechanisms is that right so if this receptor which is Alpha two hydrologic receptor that is phosphorylated it means that sensitivity of this receptor and response of this receptor mechanism to The Agonist will be also reduced this type of receptor desensitization is called heterologous the sensitization what is this called hetero logus the sensitization of receptors is that right remember in homologous desensitization phosphorylation is followed by attachment of restain but in heterologous desensitization there is simple phosphorylation but that is also enough to bring bring some decreased response of the receptor mechanism am I right any question after this so this is a rapid type of desensitization then there can be relatively slow mechanisms of desensitization as I told you don't forget let's go to our basic examples of decentralization wife demanding husband too much what will happen that husband does not listen and even he gets some rest in some beautiful other lady right what is that rapid homologous desensitization but if that husband is suffering listening to wife doing lot of shopping and suffering financially write too much Agonist activity then other husband take a lesson from him and they don't listen to their wives unfortunately what is that heterologous desensitization but if that wife is really very persistent you know she believes in perseverance so then whatever happened she disturbed him too much too much Agonist activity what will happen he will run away from home he will run away from home and he would like to stay away from his wife he will write like to stay at places where his wife cannot come with the demands and Agonist activity same thing happened with The receptors also is there really too much stimulated they decide to run away from the cell membrane to inside and hide into cell like the poor husband right so what really happens that let me put simple diagrams of these receptors what are these receptors suppose adrenergic receptors all these receptors are strongly stimulated when these are strongly stimulated I told you they will get phosphor ylated if receptors remain phosphorylated repeatedly then receptors bind with some special intracellular proteins these intracellular proteins are called collect frames what are the name of this protein these proteins are called latharines this phosphorylated receptor specially with rusten they bind with the clathrines and clathrines are special proteins Which pull the membrane inside they pull the membrane inside so this piece of the cell membrane loaded with the receptor will go in right and receptors are still present over there you are understanding and they are still having what phosphorylation you remember and they are also having their okay I'll change the color what was this calathrine so clathrin we call it this collection coated part of the membrane pulls in so this is a vesicle is being formed after a little time this will go inside the cell now inside the cell this was caletrin coated pit now it has become intracellular vesicle receptors have escaped from the cell membrane or cell surface to the intracellular area is that right and they are still phosphorylated what are they phosphorylated and collectorin coated then what happened when receptors have gone in can epinephrine stimulate these receptors which have gone intracellular no because epinephrine cannot go into cell because epinephrine molecule is highly polar molecule it is highly charged molecule so it cannot go in so in a way when receptors have gone in the intracellular vesicle inside the cytoplasm they are not available to The Agonist so tissue responds to that Agonist will reduce right this this receptor remain in for short time right as husband ran away from House and when he will go away after for example for two three days and then he will remember he will forget his anger and he'll remember no my wife is good there was a time I used to laugh still I can try something and maybe as it happened he will come back same happens with these receptors what happened that they remain inside sequestered which here receptors have been sequestered this process is called sequestration what is this mechanism called sequence operation so we say that not over second over minutes many receptors are internalized by the cell and they are sequestered by the cell and number of receptors transiently available on the membrane are less but when receptor go in like that poor husband right they again become activated how that there are enzymes here which are called phosphatases they will dephosphorylate it and they are now again ready to undergo action right and after that when they become dephosphorylated and they become again fully sensitized what will happen you know what will happen what happened to that husband he came back right so this vesicle will come to the surface right and receptors are again available on the surface so this was a transient what was this a transient desensitization so listen again previously we talked about that receptor was phosphorylated it was available on the surface but not responding well that is called rapid desensitization by phosphorylation and second example we took that when receptors are really stimulated too much eventually they undergo process of sequestration right they go inside the cell and they hide it from the stimulating agent there get default phosphorylated and again develop their full sensitivity to the membrane and again recycle on the surface is that right so that you know they have come back to the home and again you know that wife is there but unfortunately she has not learned much she come back with all her demands look at her she's very happy that stupid man is back right and now again too much stimulation it will it means this group of receptor will again again and again cycle n look it will get phosphorylated cycle in sequester D phosphorylated and then again re-express but every time when it is treated with too much stimulation over a long time over hours oh my God you know what will happen to that man repeatedly come back suffer too much again goes get emotional energy come back again suffer eventually he will decide to commit suicide so same will happen to this receptor business that eventually with repeated sequestration Cycles they become so heavily phosphorylated they cannot be dephosphorylated and then these vesicle take a different pathway they don't express on the surface again man does not come back home what happened to this man now not man I think we were talking about receptors these receptors which were initially transiently over stimulated and they was phosphorylated and sequestered now they will fuse with what is this this is endosomes you know lysosomes every cell has lysosome with dangerous enzymes these are lysosome with dangerous enzymes eventually these endocytic vesicles loaded with the receptors will fuse with the fuse with the lysosomes and very dangerous lysosomal enzymes will attack the receptors and then receptors will be yes receptors will be catabolized and these receptors which are catabolized of course they will not cycle back and what will happen the receptor concentration or receptor density on the cell membrane will be reduced for long time is that right this is called down regulation of receptor this is called down regulation of receptor this is that right now down regulation of receptor occurs in many ways one way is The receptors which are already over stimulated they are internalized and eventually they bind with the lysosomal their endosome bind with the lysosomes and then receptors are destroyed so we can say there is increased catabolism of receptor what is there there is increased bullism of receptors disruptors have committed suicide and listen if many receptors are committed suicidal care lesson in your town if many husbands are committing suicides do you think young boys will love to marry it's a good example or a bad example marriage rate will go down this is exactly what happened in the cell also that when many many receptors are committing suicide they are internalizing and they are undergoing catabolism the signals go to the nucleus and in the nucleus if this is the nucleus this is the DNA you know how receptors are made from the DNA we make yes from the DNA will transcribe RNA and then RNA come out bind with the ribosomes and then peptide chain is made and this peptide chain convert into receptor is that right this is the normal mechanism DNA to rna2 DNA transcribed into RNA and RN is translated into peptide and this peptide will appear on the surface as receptor normally normally small percentage receptors are going under catabolism and small percentage of new receptors are continuously being made this is normal physiological receptor turnover mechanism but when receptors are too much stimulated the rate of catabolism becomes fast at the same time signals go to this all synthetic process and the synthetic process also get inhibited those cells those cells which are over stimulated by agonists then messenger RNA for the formation of those receptors which are over stimulated that messenger RNA undergoes less concentration so it means synthetic processes are also down regulated is that right Amma clear so what really happens that eventually synthesis of receptors become less catabolism of receptor becomes more and number of receptor on the cell membrane become permanently low is that right all this process is called yes please what is this called down regulation of receptors down regulation of receptor as means there is permanent permanent yes decrease in receptor number by two mechanism increased catabolism of receptor catabolism of receptor plus there is decreased synthesis of receptor am I really clear to you is that right so all this is called receptor signaling mechanisms desensitization is that right again I will just make it briefly that when agonists come an over stimulate a receptor first of all receptor will undergo phosphorylation and undergo rapid desensitization receptor stays there but does not lessen right this is the mechanism phosphorylation is two type there is homologous desensitization and there is heterologous desensitization in homologous desensitization the receptor which is loaded with The Agonist this receptor exposes the domain intracellular domain to be acted upon by the is a whole family of enzymes Kinesis which are called Jeep G protein coupled receptor kinesis the dog belonged to a big family of dogs all those dogs actually phosphorylate the G protein coupled receptor so beta adrenergic receptor kinase is the one member of G protein coupled receptors Kinesis right when receptor is loaded this will phosphorylate that and then with the phosphorylated receptor a restine will bind after that when receptor has phosphorylated and bound with the erection intracellularly then G proteins cannot bind with this and receptor cannot give signal right this is homologous desensitization another example is of decentralization when the separate is given signal and activated an adrenal cyclase cyclic amp has gone up protein kinase is stimulated stimulated protein can is able to do many Target function but it may also phosphorylate the same receptor which is which produce the whole activity plus it may phosphorylate some other receptors which are also acting through the common what is this effector system and when other receptors are phosphorylated and they become desensitized to their Agonist we say there is heterologous desensitization then I told you if there's too much stimulation now Etc I have to run away at at least transiently that is an example where phosphorylated receptors especially with the restroom bind the clathrens and they make what is this endocytic vesicle and transiently receptor disappear from the membrane to the internal environment and become unavailable to The Agonist but initially when the vesicles are formed they are internalized there is sequestration of The receptors phosphatases will dephosphorylate the receptor and like a stupid husband they will come back to the membrane when they will come back to the membrane if wife is not intelligent you will again push more and more Agonist activity if repeatedly see questions sequestration internalization and reex recycling these Cycles go many time eventually a change come and this endocytic vesicle with receptor start fusing with the lysosomal granuled and lysosomal enzyme destroy the receptors and then receptors numbers become permanently less meanwhile signals go to the nucleus The receptors are too much stimulated we don't need so much receptors there and what really happens that messenger RNA which is involved in the synthesis of this receptor that is also reduced so the net result is over prolonged stimulation that increased catabolism of receptors and decrease synthesis of receptor and receptor number on the cell membrane become permanently low and we say that there is down regulation of receptor so there are three types of desensitization right rapid desensitization by phosphorylation right then there is transient disappearance of receptors sequence depression and permanently receptors are reduced yes down regulation am I clear for sure now let me tell you another thing have you heard of upregulation of receptors have you heard of it you know the concept I should explain that when a group of receptors are not stimulated on the membrane they become more sensitive to The Agonist let me tell you the Practical example for example a person's wife is very good but she goes to her parents for two three months and he miss her too much then what will happen he will become less sensitive to her or more sensitive to her you'll become so sensitive even again he will talk on the telephone value romantic things so she should stay for enough time there your understanding that is up regulation of husbands emotions right but remember a little distance increases love or too much distance decreases it someone else may come right now let's come back I don't know you laugh at that this is a very important thing more important than Medical Science anyway let's come back so what I'm talking about receptors can be upreculated also let me give you an example here let's suppose this is beta-1 receptors right okay I will okay I'll give the example here let's suppose this is a cell from the heart and these are beta1 adrenergic receptor we are you are giving the person Propranolol for many many months and years for example I'm a person with hypertension and you give me Propranolol beta blocker and there's a very good response and my blood pressure is controlled so you keep me on Propranolol for a long time meanwhile if I get some what is that well controlled if here is propranolol and Propranolol is blocking the receptors if these receptors are blocked do you think epinephrine can stimulate these receptors no epinephrine cannot stimulate these receptors so this under stimulation of receptor when receptors are under stimulated none of them will be phosphorylated none of them will be sequestered all of them will be on the surface and nucleus will be getting message you know whenever receptors are activated a message goes up to the nucleus that receptor and signaling mechanism is working but when receptors are blocked by Agonist nucleus loses those signals so nucleus assumes the genetic Machinery assume that if there is no signal coming probably receptors are not there so they will start expressing receptor Associated Gene more and the separate synthesis will increase remember if you over stimulate the receptor G receptor G is under expressed if you do not stimulate the receptors hmm genetic operators think probably there is why there is no signal coming probably they are less receptor so genetic operator starts synthesizing more receptors so what will happen what will happen synthesis of receptor will be more and receptor become more and more and more and more and more membrane become overloaded with the receptors and you keep on giving Propranolol and keep on them blocking them is that right now receptors are upregulated but you are keeping them blocked with problem it is a very big clinical significance if I'm hypertensive patient you are giving Propranolol for long time and on my heart beta1 receptors have been blocked for a long time then receptors are upregulated their concentration on the SA node AV node and other myocardial tissue become very high and if due to some some doctor who doesn't know these sense one day I go to doctor and I say my hypertension is not being controlled by bittercept he checked my hypertension and with the time over five years my hypertension is no more controlled by Propranolol and that doctor decide to change my drug and he abruptly stopped my beta blocker and all receptor become available for endogenous epinephrine heart is super driven by the endogenous epinephrine heart rate goes up contractility goes up palpitations are there and if I have some coronary artery disease due to hypertension myocardial infarction May precipitate only because doctor did not know that if someone has taken beta blocker for a long time and his receptors will be upregulated in such cases Propranolol should not be stopped abruptly it should be gradually tapered off this is that right it says doctors even though it was I was just talking about adrenergic receptor but in whole pharmacology you must be clear about the concept of receptors decentralization sequestration and down regulation as well as you must be very clear about concepts of receptor upper regulation today we are going to discuss the structure activity relationship of sympathomimetic amines you already know what is sympathomemetic amines in pathometic amines are those endogenous compounds or drugs which produce activities in the body which may make the stimulation of sympathetic nervous system again what are sympathomimetic drugs sympathomimetic drugs are the group of drugs and the compounds right which produce such actions in the body which are normally produced by stimulation of sympathetic nervous system so these compounds have their actions mimicking the actions of sympathetic stimulation now normally usually you are not supposed to learn structure and function relationship between most of the drugs but as far as sympathome and metal drugs are concerned it's very important for you to understand the relationship between the structure and function of the drug because if you alter the structure of the drug the function of the drug on the receptor is altered even duration of action of the drug is altered right even the drug absorption and distribution in the body is altered so let's concentrate on the structure of the drugs so mathematic group and their different altered compound the primary structure is the parent compound is having a Benzene ring or phenyl ring this is a Benzene ring with this Benzene ring it is having ethyl chain it is having ethyl chain and with this ethyl chain it is having Amino and so this structure is called this is Benzene ring this is also called phenyl ring right and I must tell this carbon is called Alpha carbon and this carbon is called beta carbon so in this is the parent compound from with the sympathomimetic drugs are derived this is the parent compound now in this parent compound we can see that to the beta carbon of ethyl chain there is attachment of phenyl ring this is phenyl ring as well as Benzene ring so this compound is called beta because to the beta carbon beta phenyl phenyl is the ring phenyl ethyl a mine compound so this compound or the parent compound is phenyl ethyl Amine right compound and this is its phenyl ring [Music] this is its ethyl component of the chain and here it is amino side chain right now this is the primary structure of all sympathomimetic drugs how this structure fit into adrenergic receptor to produce its action let me draw a cell on which there are many adrenergic receptors now suppose this is a cell and here I put one adrenergic receptor now let's suppose this is the hypothetical structure which of the adrenergic receptor and of course all of you know adrenergic receptor is seven pass receptor so actually from here now this is the point where the drug is binding right now because drug is binding here how this drug fits into the structure right basically this component of the drug this Benzene ring that is fitting over here Benzene drain and this component of the drug which is ethyl group that has to fit into this area and in the end you are having here yes Amino and which will fit here now listen carefully this is how this drug is primary compound is binding with the receptor is that right now listen if this primary structure the Benzene ring has some side components then it will fit strongly into the receptor can it Escape now but if let's suppose these two compounds are not added on the side of the Benzene ring then struggle bind and bounce back so it will not bind here strongly so for a strong binding of the drug on the receptor we need that there should be some special groups on the sides of this Benzene ramp now what are these two special groups because if these two special groups are present on the side of the Benzene ring right then this will bind here for it will bind here strongly and for longer duration and will produce stronger stimulation to the receptor now let's see what are these two side special groups as you know this is our benzene ring orphanyl rain right here it has carbon number one carbon number two three four five and six right now actually if we add here hydroxyl group hydroxyl groups right then this compound is called now this compound is called die yes die hydroxy Benzene ring the other name for dihydroxy dihydroxy Benzene ran the other name for dihydroxy Benzene ring is yes catecholine catechol yes catechol rank so it means that if you take this primary compound and you add hydroxyl at Carbon number three and carbon number four of the Benzene ring then you have converted Benzene ring into catacol ring and then this compound will be called catacol ethyl amine or simply we call it catacola means so all those in pathometric graphs which are having hydroxylation and carbon number three and four on the Benzene ring with Ethyl group and amino and those are called catekola means now listen carefully look at the activity of these two hydroxyls when these two hydroxyls are present of course the catecholamine drug will bind more strongly with the receptor so action of the drug on the receptor will be increasing and such sympathomimetric drugs which bind directly with the receptors adrenergic receptors and stimulate the adrenergic receptors such as in pathometric drugs are called direct acting sympathomimetic drugs those sympathomimetic drugs which directly stimulate the synthesis adrenergic receptors they are called directly acting direct acting sympathome memetic drugs now you can understand because all catecholar means all catacola means are having these two hydroxyls so all of them strongly bind with the adrenergic receptors so all of them are directly acting sympathomemetic drugs so these hydroxylation will determine determine that catecholamines are directly acting as sympatho memetic drugs now let me tell you for example here is your heart I don't want your heart to be black but anyway it's there there is your heart and this is sympathetic nerve ending right you know that norepinephrine is stored in the vesicles and from the vesicles when sympathetic stimulation come norepinephrine is released and then norepinephrine work on it s receptor is that right now lesson those drugs those drugs which directly stimulate the receptors those drugs which are strongly bind with the adrenergic receptors and directly stimulate the receptors those drugs are called yes directly direct actin sympatho magnetic agents or compounds or drugs opposite to that there is another group of drugs which do not bind with the receptors properly but these drugs are taken up by the sympathetic nerve and ends this is the second group of drugs which do not bind with the receptors valve they don't bind with the receptor valve but they enter into sympathetic nerve endings and go into neurotransmitter vesicles and increase the release of increase the release of norepinephrine of course such drugs group number two which are going to sympathetic nerve endings and increasing the release of norepinephrine of course this increasingly increasingly releasing norepinephrine will also act on the receptor and produce in pathomagnetic action but such drugs are said to be indirectly acting sympathomimetic drugs what are in indirectly acting sympathomagnetic drugs indirectly acting some pathometric drugs are those drugs pathometric drugs which enter into sympathetic nerve endings and increase the release of endogenous catecholamines increase the release of endogenous catechola means right now and of course there is another group the group number three right and this group number three has some activity to bind with the receptor and they are also taken up into nerve ending so this the drugs which belong to the third group they slide they to some extent slightly they stimulate the adrenergic receptors directly secondly some of the this drug enters into nerve ending and increases the endogenous release of norepinephrine so this drug is working directly acting as well as indirectly acting sympathomemetic drugs this is also called mixed action sympathomagnetic drugs we'll go into detail later so you understand when we say when I when I say to you there's a directly acting simple metric drugs it means this is a drug which is strongly bind with the adrenergic receptors and stimulate them and when I say there is indirectly acting sympathomimetic drugs I'm telling you that this drug is going to sympathetic nerve endings or into Adrenal medulla and releasing the endogenous stores of norepinephrine and producing sympathomimetic activity indirectly and there are some drugs which can bind receptors as well as they can be taken up by the nerve ending so this produce direct sympathomagnetic activity as well as by increasing the release of endogenous sympathomimetic drug they produce and endogenous endogenous release of catecholamine they act as indirectly acting sympathomagnetics as well side drugs are called mixed acting sympathomimetic drugs so these are mixed actins sympatho magnetic drugs and here you have mainly working here and not working on the receptor this is called yes indirect acting sympathomimetic drugs Immaculate now come back to this structure if these two hydroxyls are present the compound will be catecholamine is the right any sympathomemetic drug which is having hydroxylation at three and four carbon of the third and fourth carbon of the Benzene ring such drugs as a group are called catecholamines right and of course which are the members of catecholamines category means they have yes who will tell me the members of catecholamine norepinephrine epinephrine yes epinephrine yes please dopamine dopamine and isoproterinol ISO protarenol now look these four are catacola means three of them norepinephrine epinephrine and dopamine are endogenous catecholamine right they are produced within our body and and also they are available as drugs and isoproterinol is a drug it is not endogenously produced in our body but these four compounds norepinephrine epinephrine dopamine isoproterinol these are having catechol ring in their structure so they are called catecholamines and of course now you know catecholamines are directly acting sympathometric drugs because catecholamine has third and fourth hydroxylation and Benzene ring so they bind with the receptor strongly and they produce their action valve we also use another word when drugs strongly bind with the receptor and strongly stimulate the receptor what is the world used there we say drug has high potency look when drug binds strongly with the receptor which has a strong Affinity but when drug bind the receptor as well as stimulates the receptor we say drugs is a strong Agonist it means if drug is strongly binding with the receptor that even in low doses it can produce High action even in low doses it can produce High action because even small amount will bind strongly so we'll say drug has high potency so what does it mean all the catacolumines are high highly potent drugs potent mean as far as binding with the receptor right high they have high potency now look from all this discussion you can infer it look here if you remove these hydroxylations there is catacol let us pose from here we remove these hydroxylations this hydroxylation is removed and this hydroxylation is removed do you think now this compound will bind strongly to the receptor of weekly so when it will lose its direct so what will happen when it will bind with the receptor weekly then it will become High potency drug or low potency drug right it's affinity for the receptor will decrease its activity on the receptor will decrease and it will become low potency sympathometric drug and it will be it as a direct acting sympathometric drug it will fail but there is something very good when you knock off these two hydroxyl drugs become more lipid soluble when you knock off you know knock off these two hydroxyls you remove them drugs become more lipid soluble am I right or wrong because hydroxyl there are the negative charges and by reducing the removing these hydroxyles actually what you are doing you are making the drug less polar and more lipid soluble so such drug which has Law which is not having third and fourth hydroxylations that can easily enter into nerve ending look here you need to enter into nerve ending it should be more lipid soluble so such drugs which don't have third and fourth height oscillation they can enter into nerve ending and they can stimulate the release of norepinephrine from the nerve ending they convert into indirectly attention drugs so again compare this compound this structure right and that structure the primary difference is here third and fourth hydroxyls are present in this structure in this compound third and fourth hydroxylations are absent this structure is called yes Kate Cola mean and this structure is called just please non-catecholamine non Cate mean now if someone asks you the difference in catecholamine and non-catecholamine of course first difference is the catecholamines are third fourth dihydroxy Benzene ring they are having non-catecholamine do not have catecholine they do not have third fourth hydroxylation or Benzene so they are strongly binding with the receptors so these are directly acting sympathomimetric drugs so catecholamines are yes please you need to tell me that directly acting sympatho magnetic drugs I will write here these are direct ly acting sympathome metal drugs and non-creator column in the mainly yes they are indirectly acting very good indirectly acting sympathomimetic drugs is that right no problem into this then another thing you see catacolumines have one more important thing because they are having hydroxyl group catacolumines are highly polar compound means are highly polar compound now let's make a small this is suppose your gastrointestinal system right here is your liver here is your general circulation and here is your central nervous system let's talk some very fundamental things listen if you if catecholamines are taken orally actually catacolumines are never taken orally why let me tell you when catecholar means that taken orally from here they are highly polar compound can they absorbed well no and whatever little amount is absorbed that will be destroyed by comt and monoamine oxidase in the git mucosa and also they will be destroyed by yes destructive enzions in liver monoamine oxidase which is present in liver and liver has some small amount of catechol O methyl transferase as well now listen if you take catecholamines right if you take catacola means orally number one they are highly polar compound they will not be absorbed number two whatever is absorbed will be destroyed by destroyed by monoamine oxidases and catechol O methyl transferages especially catacol o methyl transferase enzyme you know where it attacks this enzyme CMT enzyme this enzyme will attack this hydroxyl remove a hydroxyl and add their methyl group so that is why it is this enzyme is called catacol o methyl transferase an enzyme which attacks the catechol ring remove the hydroxyl and add methyl group now because this enzyme is abundantly present in our body especially in git and liver so what happens when catecholamines are taken orally number one they are because they're highly polar they are not absorbed well and whatever is absorbed will be destroyed by these enzymes so do you think significant significant amount of catecholamine will be reaching to the systemic circulation through oral root no so we say for catecholamine oral bioavailability is very less oral if you take the drug orally catacola means bioavailability is very less that is why catecholamines are given power entry that is why that when you need to use catacola means in a systemic fashion you need to give a injection am I clear is that right so catacolumines are given is the right and they are not absorbed orally well and they their bioavailability is very less am I clear now imagine compare it with non-cater columns non-catecholamine right because they do not have these hydroxyls so they are more polar or less polar they are less charged or more child they're less charged because non-cata column means let me tell you examples of non-cater column means examples of non-catecholamines are classically like ephedrine ephedrine and amphetamines the other is also amphi that means now ephedrine and amphetamines they do not have three four hydrophilations it means they are more polar or less polar they are less polar so they are more lipid soluble so they can be taken orally this is first thing so write it here that these are given catecholam in the given parental par entely and these are preferably given orally because when non-catecholamines are taken orally as they do not have these two hydroxyls they will absorb better and not only they will absorb better there is one more thing what is that that do you think this enzyme can attack no because non-catecholamine do not have hydroxyl here non-getacolamine does not have catechol ring and if non-catecholamine does not have catechol ring how means cannot be attacked by catacol o methyl transferase or non-catecholamines cannot be attacked by c o m t so duration of action of non-catecholamines will be for a long duration of action of non-catecholamine is prolonged so there is increased Half-Life orders increase duration of has short duration of action short duration of action right category means Ecto for me in minutes you know catecholamine duration is counted in minutes but non-cate is acting over hours is that right now you understand not no up three things we have learned you remove these two hydroxyls number one you convert the direct acting drug into indirect rectang first when you remove these two hydroxyl you convert catecholamine into non-catecholamine and of course when catecholamine is converted into non-catecholamine then non-critical amine are less polar right they bind with the receptor less but they have taken a more nerve ending and help in release of endogenous noropina frame so non-cater column means are indirectly acting sympathomemetic drugs number two they are less polar they are better absorbed from git secondly because they don't have catechol ring so they are not acted upon by co-mt so they have longer duration of action and better bioavailability so they can be used orally is that right then another thing they here is blood brain barrier there is blood brain barrier this is also a biological barrier made of leopards catecholamines are highly polar compound right even though they are given parent relay but can they go to central nervous system no when you give epinephrine or norepinephrine intravenously they cannot cross the blood brain barrier efficiently because catecholamines are highly polar compounds due to the horizon catacola means once they're administered parentally they do not have any direct action on sympathetic they do not have any direct action in the central nervous system but look at non-catecholamines non-creative column means are not having hydroxide they are less polar they can be absorbed from git they can fool the comt and go in higher concentration there but they have a problem they cannot bind with the receptors strongly but they can concentrate in nerve endings and release nor epinephrine from they are indirectly acting plus as Norm catecholamines are more lipid soluble and less polar they can Cross Blood wind barrier so they can go to central nervous system and they can produce yes effects and side effects in the central nervous system that is why when we talk about amphetamines or acid rains which are non-cater columnines they have very important actions and side effects in central nervous system is there clear let's have a break so we were studying about structure and function relationship of the sympathomemetic drugs and as we discussed that basics in pathometric parent Compounders phenyl ring with ethyl and Amine addition right so this is beta phenyl ethylamine and previously we have discussed that if there are two hydroxylations at third and fourth it's catechol compound catecholamine if these are not there then they are considered non-catecholamines and when we were applying this structure to the receptor then what we were talking about that catecholamines due to the presence of these hydroxyls bind strongly to the receptors but non-cater column means because they do not have hydroxylation and third and the fourth carbon of the Benzene ring so they do not bind strongly with the receptors they have low affinity for the receptor and they bind and bounce back due to that reason they are not direct practice in pathometric drugs they are indirectly reactants in pathometric drug now we will come to another thing another characteristic of this molecule is that for a maximum activity the amino group and the Benzene ring amino group and the Benzene ring they should be separated by two carbons why because this area determines the primary binding of the drug and this binding in this area determines the potency of the drug and Affinity of binding right but this area this part of the receptor right this determines intrinsic activity this part determines intrinsic activity to have a good intrinsic activity it's very important that sympathomimetic drug should have its Benzene ring bending ring and amino group separated by how many carbon atoms two carbon atoms so this is another important feature of structure and function relationship of sympathomimetric drugs now we come to very very interesting phenomenon what is that you know some of the sympathometric drugs bind with alpha 1 receptors some of them bind more with beta1 some of them bind with Alpha One beta 1 and beta 2 receptors how this happen why difference in pathometric drugs stimulate different adrenergic receptor in a different fashion let's try to answer it let me draw difference in pathomimetic receptor actually this model receptor which I've made here this is Alpha One adrenergic receptor what is this alpha 1 adrenergic receptor now I will draw the beta one hydrologic receptor and beta two hydrologic receptor and you have to tell me where is the difference you know as kids find the difference in between the drawings so I am going to draw beta 1 receptor here and beta 2 receptor there and you are going to tell me what where is the difference it is beta 1 receptor this is beta 1 adrenergic receptor and now I'm going to draw beta 2 adrenergic receptor foreign this is beta true adrenergic receptor Alpha One hydrologic receptor of beta one hydrological receptors beta two hydrologic receptor yes where is the difference in that the difference in is in that points of the receptor where a minor end binds Alpha receptor has a small area where Amino ends bind beta 1 receptor has larger area where yes a minor end of the drug bind and beta2 receptor has very large area where what will bind a minor end of the compound will bind now I will make once you have appreciated this difference in the receptor structure we will make a compound here look at this compound hydroxyl so it is going to be catecholamine or non-catecholamine it's going to be category means okay I'll make it by okay what is this compound will tell me the name of this compound yes what is this compound okay this is one compound I will make another compound here you compare the structure Benzene rank look double hydroxylation so it is also going to be at a column means choh ch2 and only nh2 the difference in compound a this is compound a and this is compound B the difference in compound a and compound B is that it is having methylation on a minor end it does not have methylation right okay this compound is produced by converting this into categoromy hydroxylation here and adding methyl group here is that right every one of you knows the name of this compound and every one of you know the name of this compound I'm not 99 sure I'm 100 sure very good the second one is this B compound is epinephrine have you heard of it and this is norepinephrine the difference in epinephrine and nor epinephrine is epinephrine is methylated you remember in previous lectures when we discussed that when norepinephrine is produced in the vesicle the norepinephrine go to the cytoplasm there is a enzyme called methyl transferase which transfer a methyl group to norepinephrine a minor end and compound convert from norepinephrine to epinephrine you know what what is the easiest way to remember epinephrine epinephrine is methylated epinephrine is methylated norepinephrine that's so simple is that right now listen carefully this is our balanced compound right epinephrine look here attention please this is it minor end epinephrine look here attention this point this end of the epinephrine can fit here it can also fit here it can also fit there your understanding because epinephrine Amino and is methylated amino and right and it can fit into alpha 1 receptor it can yes fit into Alpha One adrenergic receptor and this Amino end can fit into yes beta 1 adrenergic receptor as well as this end can fit into yes beta 2 adrenergic receptor even though it fit into this part and remaining is empty receptor as well as epinephrine can bind with the beta 2 adrenergic receptor is that right due to this reason epinephrine has which actions epinephrine has alpha 1 actions and also beta 1 action and also beta2 action we can say epinephrine is a balanced sympathomimetic drug this term I'm telling you made myself that's a balanced drug balanced in a way it worked on all etymological receptor with this almost same Affinity am I clear there's no problem right now you imagine look attention please from this epinephrine you remove methyl group you remove methyl group what is the result now norepinephrine can fit with alpha 1 receptor you know this point can fit into Alpha One receptor can also fit and stimulate beta 1 receptor but to have stimulation on the beta2 receptor you need relatively heavy so you have knocked out this when you remove this methyl right actually this drug loses its action on the beta2 receptor listen the principle is this attention please look at these points Amino end more heavy Amino and more it become heavier beta1 and beta 2 action become increased and amino and you make it lighter it will have more Alpha One action we can make it like this this is the balanced epinephrine is that right if you are making a minor end of the drug lighter action will move to the side and if you are making a minor and heavier actions will move in that direction it's so simple so norepinephrine has ability to stimulate alpha alpha 100 magic receptor has ability to stimulate beta 100 magic receptor but does not significantly stimulate beta2 receptors so what are the actions of norepinephrine Alpha One actions beta one actions and very little beta2 it's so simple if next time someone asks tell the physiological and pharmacological actions and the difference of these actions between epinephrine and not epinephrine is so simple when you tell about the pharmacological actions of epinephrine tell all the alpha 1 neurologic actions in the body all the beta 1 hydrologic action the body for example for one action like vasoconstriction all beta one action for example one of them is cardio stimulation which are two action like bronchodilation but when you go to norepinephrine it has Alpha One action like most of the vasoconstriction it has beta one action it is cardio stimulation but it is not bronchodilator is that right it is not relaxing the uterus which is beta 2 action it is not releasing glucose from the liver glycogenolysis which is beta 2 action now it's so simple now let's produce another compound in which we make Amino and heavier right hydroxyl hydroxyl and choh CH and here report now NH ch2 NH ch okay ch3 and ch 3 now what we have done here now we have changed the mono and minor and has what are these has become heavier because it has become heavier it is so heavy it cannot fit into Alpha One well but it will fit very well into beta 1 and beta 2 receptors so naturally intuitively you can tell me that this drug will have very little Alpha One action but heavy beta 1 action and heavy beta 2 action is that right and can you tell me the name of this track isoproterinol what is the name of this drug ISO protar a null am I clear no problem so what happens in isoprotearinol that at the amino end there is substitution with heavy heavy alkyl group and due to this reason uh because minority is very heavy so it loses Alpha One action but it keeps the beta 1 and beta 2 action am I clear no problem now I will make one more right this is of course catecholam in c h o h c h two and now we'll put a minor group here and at C H three ch3 ch3 so it become even more heavier a minor end has become really very heavy it is so heavy that it will bind with beta1 weekly because beta1 cannot accommodate Alpha One cannot accommodate such a heavy a minor substitution at all beta1 bind it very little and beta2 action remain very strong so now this drag with very heavy a minor substitution it has very little beta 1 action but real action is beta 2 is that right what is the name of the drug you know it turbital in very good solvitama all these turbitaline solvitamol albuterol all those drugs which are strong beta2 stimulant have very heavy Amino groups is that right so I should write the drug name here buta terbitaline you know it is having a strong beta2 actions and because it has strong beta2 stimulatory action of course it is very commonly used as bronchodilator in patients with asthma what is the advantage you play with the molecules and you get advantages or disadvantages what we have played look here this primary structure was come here you have not epinephrine is the right or you have epinephrine what did you do there you made this end very very heavy so it lost Alpha One action when you want a patient would you have a patient with bronchospasticity or patient with uh asthma you want to do bronchodilation but you don't want Alpha One action you don't want beta one action so to remove the Alpha One action and beta 1 action you simply make this end very very heavy so alpha one side effects are lost even beta 1 unwanted actions are less but when you give this drug in very high concentration then it's also start binding significantly to beta 1 and beta 1 side effects will start appearing that is why these solventum all orbital in Albuterol these drugs in higher concentration start cardio stimulation otherwise in low concentration the good bronchodilator with some other beta2 action like primers orbital two action on the lever and producing ah high glucose release from the liver by glycogenolysis is that right no problem into this so this is how you understand now that differences between norepinephrine epinephrine isoprotorinol and terbutaline what we have learned up to now is what we have learned up to now is that as you are making a minus end heavier you're losing the Alpha One action and getting more beta actions and if you make it very heavy even beta1 action is last and strong action is on beta2 but as you keep on making a minor and lighter beta actions are reducing and Alpha One actions are more right let's have a break now let's play some tricks and you know these are norepinephrine epinephrine isoproterinol and terbutylene all of them are catecholamine let's alter their structure and get some non-catecholamines for example first first we alter the structure of epinephrine right and how we alter the structure of epinephrine first I draw the epinephrine and then we produce some alteration in epinephrine structure to get some non-catecholamine now this is of course your what is this what is this compound this is epidinephrine and now what we do with epinephrine that just knock off these two hydroxyls remove these two hydroxyls is that right from not epinephrine you remove these two hydroxyls and plus you add a methyl group here foreign group here now we see this is a different compound and it will have different pharmacodynamics and different pharmacokinetic property right number one step by step will move when we remove remove these two hydroxyls the drug become less polar and more lipid soluble so it means this drug can cross git barrier it can be absorbed from the Git it can also Cross Blood band barrier right this is one thing secondly first of all what is the name of this compound this compound is a field drain this compound is acid rain right now when you remove these two hydroxyl it becomes more lipid soluble it can absorb from Git it can Cross Blood print barrier it can act in central nervous system secondly when you are removing these hydroxyls it is no more catechol rain because it is no more catecholine then this enzyme you know what is this enzyme catecholomethyl transferase this attack this component of the catechol ring but because we have removed the hydroxyl and it is not catecholamine it does not have catechol range so catecholo methyl transfers cannot attack this compound so this combined compound will not be destroyed in Gat or in the liver so duration of action of the drug will become more and oral bioavailability of the drug will also become more so it can be better absorbed orally because it is not destroyed by Co c o m t in the git or liver so oral bioavailability is more secondly because these two hydroxyls are not there so drug does not bind properly with adrenergic receptors so it does not have direct sympathomagnetic action it has very little direction pathometric action but it has because it is non-cater columnine it can have more in direction pathometric action so we can say aphidrine is non-catecholamine which can absorb well orally right which can cross the blood beam barrier and act in central nervous system right and it is indirectly acting sympathomagnetic drug another thing because we added a methyl group here by addition of methyl group we make this compound more we make this compound more lipid soluble and when we make this compound more lipid soluble again that help an absorption from jit and help in crossing the blood wind barrier and having more action in the central nervous system is that right another thing as you know this is the enzyme mono amine oxidase monoamine of it is enzyme is sitting on the alpha carbon and then what it is doing it is oxidizing the beta carbon hydroxide now what we do when we put methylation here this enzyme cannot bind with the compound because this enzyme monomide oxidase binds here because monomial oxidase cannot bind there you know its mouth is closed this is monomite oxidase weeping why because it cannot bind here well and cannot attack here so mono minus oxidase fail to destroy ephedrine so it means that when ephedrine is taken up into adrenergic nerve endings then within the adrenergic nerve endings monomine oxidase cannot destroy this drug efficiently so it will stay in the nerve ending for longer duration and it will produce indirect sympathomimetic action for longer duration is that right any question after this there's no question now we play another trick let's modify norepinephrine and convert into another non-catecholamine now this was your amphetamine now we are going to make another compound this is also non-catecholamine this compound is also non catecholamine what we do this is its Benzene ring we have removed these two hydroxyls these two hydroxyls here we have removed so it means we convert the catechol compound into compound please correct in ephedrine we have removed this hydroxyl and F will drain no it is there it is okay now we have to come to the new compound what we have done that we have taken the norepinephrine remove third and fourth height oscillation Plus we have also removed yes and other hydroxylation from this point so there are three hydroxyls has have been removed again you took the norepinephrine you move the third and fourth hydroxyls and also remove the hydrophil from beta carbon is that right when so many hydroxyls are removed it become highly lipid soluble this is the right very good oral absorption and very good Crossing from from blood vein barrier is that right and of course it is not directly acting sympathomimetic drug it is indirectly acting sympathomagnetic drug and because this hydroxyl is not there this hydroxyl is not there can monomial oxidase attack here it is just like this someone does not have ear can you remove his ear no so monoamine oxidase cannot attack here co-mt cannot attack here so drug absorption from git and bioavailability from git become very good and destruction of the drug where compt and monomino series is far less due to that reason these drugs this drug has a long duration of action and remaining thing is the same that CH as we added methyl here we will also add methyl there is that right we have also added the methyl there and what is the last thing there yes and H2 and what is the name of this drug now yes who will tell me the name of this drug this non-cater column this is m feta mean so this was one two examples in which I have shown you the structural and functional difference between catecholamines and non catecholamine now do you have any question do you have any question no questions now I will rapidly review something right you will tell me if these two hydroxyls are present in the structure with the Benzene ring it is strong direct acting action or non-cato Colombian of strong direct acting action means because these hydroxyls are not there there will be more liquid soluble or less lipid soluble okay now I will ask in another way right you have to tell me drug is catecholamine or non-cata Colombian there is sympathomimetric drug which is well absorbed from the git and going to Central of a system foreign duration of action catecholamine there is sympathomimetic drug uh which can absorb orally and long duration of action and go to the central nervous system yes okay there's a drug which is catecholamine I'm telling you which is catecholamine it has very very heavy a minor substitution it is strongly Alpha One action or strong beta2 action beta to action there is another drug and amino end is very light it has strong Alpha One stimulation or its strong beta tool stimulation strong Alpha One stimulation now I will tell the drug and you will tell me the name okay I will tell the action and you will tell me the name of the drug the profile of the drug is there is a sympathometric catecholamine which has equal Alpha One action beta 1 action and beta 2 action what is the drug epinephrine very good it is another drug it has a strong Alpha One and beta 1 action where beta2 is very less this is not epinephrine very good there's another drug in which beta 1 and beta2 actions are very well but there's very little Alpha One action isoproterinol very good and if I say there's a drug which has very little bit of one action but strong which are two action what is that turbital lane that's great class dismiss thank you

Channel: Dr. Najeeb Lectures

Views: 140,665

Keywords: medical lecture, dr najeeb, dr najeeb lectures, usmle step 1, medical video, kaplan, neet pg, adrenergic receptors, adrenergic system, sympathomimetic drugs, adrenergic drugs nursing, adrenergic pharmacology, agonists, receptors, adrenergic agonists, autonomic, autonomic pharmacology, adrenergic agonist, pharmacology, epinephrine, autonomic nervous system, medicine, alpha adrenergic receptors, g protein coupled receptors, beta adrenergic receptors, adrenergic receptors pharmacology

Id: hg-zaWU6Ql8

Length: 236min 9sec (14169 seconds)

Published: Sun Apr 02 2023