Hypertension and Antihypertensives

In this Blog i will be discussing about Hypertension and pharmacology of Antihypertensive drugs 

Overview:

So let's get right into it hypertension or high blood pressure is a quite common disorder affecting many people who typically don't even notice any symptoms now in order to gain a better understanding of pharmacology of antihypertensive agents first we need to review a basic physiology of blood pressure regulation. 

Blood Pressure and Its Mechanism:

Blood pressure we are generally referring to the force or tension of blood pressing against the artery walls now this pressure in the arteries is maintained by among other things contraction of the left ventricle systemic vascular resistance elasticity of the arterial walls as well blood volume in other words blood pressure is simply a product of cardiac output and systemic vascular resistance there are a couple of major systems involved in blood pressure regulation first arterial blood pressure is regulated by pressure sensitive neurons called baroreceptors located in the aortic arch and carotid sinuses so 

for example if blood pressure falls too low those baroreceptors can send signals to the adrenal medulla causing release of catecholamines and thus increase in sympathetic activity through activation of alpha and beta receptors so activation of beta-1 receptors causes increase in heart rate and stroke volume and thus increased cardiac output which leads to increase in blood pressure on the other hand activation of alpha-1 receptors on smooth muscle causes vasoconstriction and thus increase in vascular resistance which again leads to increase in blood pressure now another major system involved in blood pressure regulation is the renin-angiotensin-aldosterone system so we also have baroreceptors in the kidneys that respond to fall in blood pressure or reduction of blood flow by releasing enzyme called renin additionally renin secretion is also stimulated by sympathetic activation of beta-1 receptors in the kidneys now renin is necessary for the production of angiotensin II  is a very potent vasoconstrictor which constricts systemic blood vessels thus increasing peripheral resistance angiotensin II also constricts renal blood vessels and stimulates aldosterone secretion which leads to sodium and water retention thereby increased blood volume cardiac output and ultimately increased blood pressure.  

Antihypertensive Agents:

Antihypertensive agents so there are several major classes of antihypertensive drugs which work by interrupting different parts of this blood pressure regulating system first we have, 

• Aliskiren, ACE Inhibitors and ARBs:

A group of antihypertensive agents that is agents that work on the renin-angiotensin-aldosterone system so here we have three pharmacological targets that can be used to reduce the activity of angiotensin II which is ultimately responsible for causing blood pressure to increase first we have renin the enzyme responsible for conversion of angiotensinogen to precursor of angiotensin II that is angiotensin I so renin is the target of renin inhibitors which selectively inhibit this enzyme thus decreasing production of angiotensin II the example of drug that belongs to this class is Aliskiren. 

 

Secondly we have angiotensin-converting enzyme that is responsible for conversion of angiotensin I to angiotensin II this enzyme is the target of ACE inhibitors so just like inhibition of renin inhibition of angiotensin-converting enzyme also leads to decreased production of angiotensin II however what makes ACE inhibitors different is that in addition to lowering angiotensin II levels they can also elevate bradykinin levels bradykinin is a peptide that causes blood vessels to dilate by stimulating the release of nitric oxide and prostacyclin however normally angiotensin-converting enzyme inactive bradykinin so it's inhibition leads to bradykinin induced vasodilation the example of drugs that belong to this class are Benazepril Captopril Enalapril Lisinopril Quinapril and Ramipril. 

Finally we have angiotensin II receptors type 1 or AT1 receptors for short so binding of angiotensin II to these receptors is actually responsible for most of the effects of angiotensin II including vasoconstriction and stimulation of aldosterone release these receptors are the target of angiotensin II receptor blockers or ARBs for short the example of drugs that belong to this class are Candesartan Irbesartan, Losartan, Olmesartan and Valsartan so in summary the agents that work on this renin-angiotensin-aldosterone system either block the production of angiotensin II or block its actions on the AT1 receptors this in turn leads to decreased systemic vascular resistance but without significant changes in cardiac output additionally these agents reduce the effects of angiotensin II on  renal hemodynamics specifically angiotensin II constricts the efferent arteriole thereby generating back pressure in the glomerulus which can lead to injury so by reducing activity of angiotensin II these agents also improve renal blood flow and thereby reduce the risk of renal injury now when it comes to side effects because these agents suppress aldosterone release their use can contribute to development of hyperkalemia furthermore ACE inhibitors in particular may cause dry cough or in rare cases angioedema  which can be life-threatening this is thought to be due to increased levels of bradykinin and substance P.

•  Alpha-1 Blockers:

Alpha-1 blockers such as Doxazosin and Prazosin which block alpha-1 receptors on the smooth muscle thus causing decrease in systemic vascular resistance and ultimately decrease in blood pressure.

• Beta Blockers:

Selective beta blockers such as Atenolol and Metoprolol which selectively block beta-1 receptors on the heart thus causing decrease in cardiac output and thereby decrease in blood pressure as you may remember we also have non-selective beta blockers such as Labetalol and Carvedilol that can additionally block alpha-1 receptors and thus simultaneously decrease vascular resistance furthermore beta blockers can inhibit beta-1 receptors present on the kidneys and thus suppress release of renin formation of angiotensin II and secretion of aldosterone so these effects result in decrease in systemic vascular resistance and again fall in blood pressure.

 

• Clonidine and Methyldopa: 

Now the next major class of antihypertensive agents are centrally acting adrenergic drugs which work by blocking sympathetic activity within the brain example of drugs that belong to this class are Clonidine and Methyldopa now Clonidine selectively stimulates presynaptic alpha-2 receptors thus providing negative feedback to reduce catecholamine production and release this leads to decrease in systemic vascular resistance and cardiac output and ultimately decreased blood pressure Methyldopa on the other hand also lowers blood pressure through the same mechanism however unlike Clonidine it is not an agonist itself so first it must be converted to its active metabolite called methyl norepinephrine.

•  Calcium Channel Blockers:

Another major class of antihypertensive agents that is calcium channel blockers so calcium channel blockers are divided into two main subclasses dihydropyridines and non-dihydropyridines now dihydropyridines selectively inhibit L-type calcium channels in the vascular smooth muscle under normal conditions when calcium enters the smooth muscle cell it causes it to contract which leads to increased vascular resistance and thus increase in blood pressure so when dihydropyridine drug blocks the entry of calcium into the vascular smooth muscle cell the contraction is inhibited which leads to decreased resistance to blood flow and thus lowering of blood pressure example of drugs that belong to this group are Amlodipine Felodipine Nicardipine and Nifedipine when it comes to side effects of dihydropyridines they're related to systemic vasodilation so you can expect dizziness headache flushing and peripheral edema another side effect that may occur with this class is swelling of gums also known as gingival hyperplasia now let's move on to non-dihydropyridines which are non selective inhibitors of L-type calcium channels in other words they are not only capable of blocking calcium channels on vascular smooth muscle but also calcium channels on cardiac cells such as those of SA node and AV node which leads to reduced myocardial contractility slower heart rate and slower conduction that's why these agents exhibit significant antiarrhythmic properties f now it's important to remember that even though decreased heart contractions typically result in decreased cardiac output non-dihydropyridines do not significantly decrease cardiac output most likely because of the reflex tachycardia that occurs as a result of vasodilation currently there are only two drugs that belong to this group namely Diltiazem and Verapamil now when it comes to side-effects non-dihydropyridines can cause excessive bradycardia and cardiac conduction abnormalities additionally Verapamil which happens to be the least selective calcium channel blocker can exert significant inhibition of calcium channels in the smooth muscle that lines the GI tract which can lead to constipation.

• Diuretics:

The next major class of antihypertensive agents are diuretics there are three major classes of diuretics that are used in the treatment of hypertension first we have Loop Diuretics such as Furosemide which work by reducing reabsorption of sodium chloride in the kidneys leading to significant diuresis with less volume in the vascular space less blood returns to the heart so cardiac output decreases this in turn leads to decrease in blood pressure particularly in patients with volume-based hypertension and chronic kidney disease. 

 

Secondly we have Thiazide Diuretics such as Hydrochlorothiazide which also reduce reabsorption of sodium chloride in the kidneys but to a much smaller degree than loop diuretics this leads to initial decrease in intravascular volume decrease in cardiac output and ultimately lower blood pressure however the long term effects on blood volume are minimal and sustained antihypertensive effects are thought to be produced by thiazide induced vasodilation. 

Lastly we have Potassium-Sparing Diuretics such as Triamterene and Spironolactone which increase diuresis by either interfering with the sodium potassium exchange in the kidneys or by blocking the actions of aldosterone potassium-sparing diuretics are often used in combination with loop and thiazide diuretics to reduce loss of potassium that can occur with the use of these drugs. 

• Nitrates:

Another fast-acting agents that are also used for hypertensive emergency are Sodium Nitroprusside and Nitroglycerin which simply serve as a source of nitric oxide a potent peripheral vasodilator. 

• Hydrazine and Minoxidil:

Direct acting smooth muscle relaxants namely Hydralazine with mechanism of action that has not been entirely determined yet and Minoxidil which works by stimulating opening of ATP-activated potassium channels in the smooth muscle which leads to membrane stabilization making vasoconstriction less likely while these agents significantly decrease peripheral resistance they also produce significant compensatory reflex tachycardia and renin release for that reason these drugs are typically administered in combination with a diuretic and a beta  blocker on the flip side topical application of Minoxidil promotes hair growth which is why this drug is used more often for treatment of baldness rather than hypertension.

 

• Other Antihypertensives:

Other antihypertensive agents that do not fall into any of the classes that we covered thus far so first we have Bosentan which is a competitive antagonist of a potent vasoconstrictor called endothelin-1 which acts on the endothelin-A and endothelin-B receptors located on pulmonary vascular cells by blocking the action of endothelin-1 on these receptors Bosentan leads to vasodilation which decreases pulmonary  vascular resistance for that reason Bosentan is often a drug of choice for treatment of pulmonary hypertension. 

Next we have Fenoldopam which is a selective dopamine-1 receptor agonist the dopamine-1 receptors are located on the smooth muscle cells in the peripheral vasculature as well as the renal coronary cerebral and mesenteric arteries by stimulating dopamine-1 receptors Fenoldopam produces generalized arterial vasodilation which leads to decreased peripheral resistance and thus lower blood pressure additionally Fenoldopam inhibits tubular sodium reabsorption which results in natriuresis and diuresis due to its rapid onset of action and short duration of action Fenoldopam is often used in the hospitals for short-term management of severe hypertension and with that I wanted to thank you for reading this blog.

Thanks

Regards: Asad Ullah

Remdesivir Mechanism of Action Against Coronavirus

Are you looking for Remdesivir mechanism of action against coronavirus?. I will explain you about the mechanism of Remdesivir.  

I am going  to do is about the remdesivir mechanism of action against coronavirus and we are going to see that if we are going to explore what it has been used for and if there is a place for this for covid19 treatment or can it work against our scope too.

 REMDESIVIR Dosage Form

 so let's start that discussion so we are talking about the Remdesvir and its antiviral effects and can it be used for covid19 so let's start our discussion first of all I'm going to show you so let me tell you the basic outcome there have it is not an FDA-approved drug but it is not an approved drug anywhere in the world yet however it has been shown that it is promising against Covid19 for reducing the viral load so the it interferes with the viral replication so when the weather application is lowered or reduced the attack of the virus on our body systems becomes less which allows time for our body for our immune system to ramp up and take care of the virus so that is the basic idea what is not really clearly known is that what are the side effects and secondly how well it can actually handle the Covid19 there have been some studies that have shown very promising results for example in one of the studies I will  show you is there is 68 percent of the patients benefited from this and then there are some studies that showed that it did not do very well so I think that this is this is true for all medicines that some studies show it is working and some show that it does not work and probably the reason for that is the patient's profile the patient's age distribution the patient state of the disease itself I feel that all those drugs that are going to prevent the virus replication this should be administered early on and then continued later on the problem with the later stages of the disease is that we are now in let's say acute respiratory distress syndrome or we are in septic shock and at that time the type of medication may be different and maybe it is not interesting at that time to try to reduce the viral viral load because our own immune system has kicked in as well and that can actually do a better job than the drugs so it may be useful at that time to kind of help the immune system but early on when given it can reduce the burden of the virus so much that it prepares the immune system to help with that so that is the basic outcome and now let's see what we are going to talk about is how the corona virus replicate in our body in ourselves what are the necessary things for is for it to replicate what are the mechanisms and where does the ramp des if we had come in and interfere with the mechanism of the virus replication so let's start so I'm going to share my screen and we will start so the Remdesivir does agree against our scope to it is as I said it is not yet approved although FDA has cleared it for emergency use and emergency use in trials so there are many clinical trials that are continuing I would quickly show you this is the Gilead that is the Gilead Sciences is the company that has made it and if you go to this site I will put the link in the description after this talk if you go to their site they mention a few studies that are going on right now both in the US and in the rest of the world so that is what is the status at this time it is a broad-spectrum antibiotic so I should put an L over here so it is a broad-spectrum antiviral it was originally made to help combat Ebola although with Ebola what we have seen is that it is not very encouraging because the virus develops resistance very quickly they say that it is possible that the that the drug itself may not have resistance in those areas where the drug is not used yet so that is what we have for Ebola then I talked about it that this is Gilead Sciences and us are so United States Army's Medical Research Institute against infectious diseases they had worked together with julia to to build this drug encouraging results so far against our scope - so that is a good news active form so this is a pro drug so that means when it is introduced in our body so let's say this is the drug when it is introduced in our body it is metabolized to an active form and that active form is called GS 44 one five to four that is the active form of the drug so it needs to be metabolized in our body to convert into an active form which it does so now let's look at it how does it work hey guys thank you very much for all joining I am seeing people from joining all over the world so thank you very much hopefully we will continue our discussions and keep becoming smarter about the about various topics for task of true and covert nineteen so here is a quick discussion of how this virus enters our body and what are the steps in the virus replication and I would elaborate those steps afterwards but let's look at the summary of the steps so here is the corona virus this is corona virus it binds to ace to receptors we all I think know that by heart now so these five protein or s protein on this virus connects with the ACE 2 receptor which then causes the virus to start fusing with our cell membrane and the genome genome of the virus or the RNA of the virus enters into our cells so this is the RNA here once it is inside the cell I am just going to put the steps here and then will the first step is that it goes through a translation to produce some proteins and we will discuss that in detail that how does that happen so there are some viral proteins that are created then there is a step of proteolysis where those proteins are broken down into functional smaller proteins one of the important protein in there is the RNA dependent RNA polymerase enzyme and that enzymes function is to start transcripting more genome of the virus that is the enzyme that helps the virus take over the cell so remdevir disappear interacts at this stage and interferes with the RNA dependent RNA polymerase and makes it less efficient actually I will explain what it does is that the result of the binding with that enzyme is that the new a messenger RNAs that are formed are incorrect and so there is an early termination of the transcription but imagine if the ramp disappear was not there after the transcription many messenger RNAs are formed which are then translated into many many proteins that are viral protein so that is the hijacking of a cell and now the virus is making their own proteins then the viruses are assembled and then they are exited from the cell and that is how a new very on is made so we are going to look at that mechanism so before we go through the detail of the mechanism one more thing that is important is to notice that when we build genome that means DNA or RNA there are nucleotides that are the building blocks of the DNA or RNA these nuclear nuclear tides are of two types we call them purines and pyrimidines purines can be remembered as pure as gold mnemonic and these are adenine and guanine and pyrimidines can be remembered as cut the pie and the pie standing for prima Dean's cut is C for cytosine you for uracil and T for thymine the RNA manufacturing does not use thiamine and it uses uracil DNA manufacturing on the other hand uses thymine instead of the uracil so that is the basic difference now what happens is remdesvir disappear is a uracil analog so it kind of mimics the shape of uracil which allows the viral machinery to accidentally incorrectly pick this drug up as a building block and then try to make genetic material with it and this would then cause the enzyme that is making the genetic material disabled so that's a clever technique for the antiviral activity and there are many other drugs that do this as well so this is one of the one those for drugs so keep this in mind that we need the uracil to build the RNA and this drug when available will get stuck in place of uracil and terminate or interfere with the production of the messenger RNA or viral RNA so let's now see how this happens ready so this is a very very interesting topic the first thing that we'll do is how does the virus replicate so let's look at that virus once more over here this is the corona virus attaches to the is to receptors on our cells so that allows the virus to then I'll make the second step over here that allows the virus to start fusing with our cell membranes and then in the third step the virus stays the virus itself membrane becomes fused with our host membrane but the genome the RNA from the virus enters into our cells so viral genome enters into the cell the viral genome for the corona virus we call it a positive-sense messenger RNA or positive sense RNA what that means is that this genome so if this is the RNA from the virus it has a 5 end and 3 end for the medicals here and what happens is in this genome so pay attention here there is a open reading frame 1a and then open reading frame 1b and then there is s protein gene many other genes than a protein gene then M protein gene then n protein genes so there are genes to make other proteins we are more interested in the open reading frame 1b over here in the early part of this part of the genome is a special protein instruction this protein when is made from this gene that protein makes an enzyme called RNA dependent RNA polymerase so pay attention to this mechanism because this is the enzyme that Remdesivir where would inactivate or interfere with interferes here Remdesvir appear with this guy so let's see what this guy actually does so once the genome comes this is the viral genome once it arrives into our cell the very first thing that happens is our cells ribosomes these are the machines in ourselves that take an RNA ribosomes and they translate it we use the term translate they take this RNA for example and they translate that into proteins so they take that genetic code and make proteins according to that  code so now for the corona virus starts off to when this genetic material is picked up by our ribosome the very first protein that is made is a big blob it's a big structure a big structured blob which has tiny proteins embedded in it or part of it imagine this at when you buy the children's toys sometimes you buy a plastic sheet which has cutouts of various animals and soldiers and those things and you have to then remove those cutouts and that is the actual toy in there so same way this is a big protein that is formed in the first translation step and in that protein are smaller  proteins we are interested in this protein here let's say this is the RNA dependent RNA polymerase enzyme so what happens is there is a step that is called proteolysis proteolysis which causes the breakdown of this bigger protein and those smaller protein becomes free so let's say this RNA dependent RNA polymerase becomes free once this becomes free what it does is it picks up the original genome it picks up this guy this guy the viral genome that had come in and what it does is so let's make the viral genome here it picks up this genome attaches to this so let's say this is the attachment of RNA dependent RNA polymerase and it starts building negative sense RNA from it so let's say this is the  process of transcription in this process what happens is that this positive sense messenger RNA is converted into a negative sense messenger RNA sorry not messenger RNA just negative sense RNA this process would need this enzyme here to go through the whole line of genes and then convert them into complements and for that as I mentioned for this enzyme we'll need the building blocks and remember the building blocks for RNA are the adenine guanine cytosine and uracil now this drug if Remdesvir is present in the system so let's say this is the uracil looking drug but this is actually rammed as a beer let's make it a happy drunk instead of a sad drug so this is the ram desi where it looks like the uracil so when the RNA dependent RNA polymerase when this enzyme picks up accidentally incorrectly the rammed a severe thinking that it is uracil building block it's a wrong brick this is just like when you are eating let's say nuts and you have a bad nut in there and you accidentally chew it and it is hard and it is sour and it is bad and you say what the heck same way when the uracil is picked up by this enzyme and enzyme tries to work with it instead of that working the enzyme the uracil binds to this protein and does not let go it attaches to the protein the result  of that is that as soon as the first uracil building block is needed and REM disappear comes and attaches to the enzyme enzyme cannot function anymore  and it tries to move further down the line to make the continue to make the complementary strand instead of that it actually becomes disabled or you can say that we throw a wrench in this gear in  the machinery of the enzyme and the poor enzyme then which is good for us it  separates from the function it was doing so now it is separated and it cannot  continue down the line so the result is that the resultant - RNA for negative  sense RNA that was to be made which would then help make the viral proteins and genome  that mess - RNA is not completely formed why because the enzyme that was making a complement of it that enzyme got interfered with interfered by lambda severe so the result is what do we get we get partial genomic genomic material so this is partial it's not complete the remaining piece here I'll make that in dotted line the remaining piece is not going to appear now why because Remdesvir has interfered acting as the nucleotide uracil and it made the enzyme go away so the result is there are no more viral proteins that will be formed viral proteins will not be formed because the genome has become damaged and there is no virus that is the basic idea if there was no drug then what would happen is if we bring this picture over here then what would happen is that here is the viral genome here is the Rd RP it will convert that into a negative sense negative sense messenger RNA or negative sense RNA negative sense RNA from this again the same enzyme would then work on this piece that it just made and convert that into many small messenger RNA's so these are small messenger RNA's for the viral proteins and viral genome and from here viral genome will be produced that is the original viral RNA and many proteins will be produced that make the virus for example s proteins will be made and proteins will be made what is that the M proteins will be made and so on so the result and then we'll take those proteins will give them into the the endoplasmic reticulum of our cells so let's say this is the nucleus around  we have endoplasmic reticulum and the plasma make and Lance make reticulum these things are happening here and when from there the viral proteins are produced these proteins will then go into the Golgi apparatus in the Golgi apparatus these will be put together in the form of a very on and then also let's say this is the very on here being built and then Golgi operators will put a membrane around this for the for the exiting from the cell so this is a video on with the  membrane and that would go to our cell membrane and from there it will exit out and we will have a a virus very on out in the tissue so what happens is if we allow this process to continue from here we will have a virus but rammed a severe comes into the play and it kind of stops this enzyme from doing is its function so that is how this drug causes the function it does now. 

For detailed explanation visit; (Covid 19 insights: Remdesivir mechanism of action)