this is Dr busty and we're going to do a drug class review with the focus being on calcium channel blockers um calcium channel blockers are broken up into those that are considered non dihydropyrene which includes dilm and Verapamil and then those that are um di hydrop purines and there's a long list of those um amlodipine clapene fotene nicardipine motene um those are some of the more common ones that are used in practice and we're going to go through them you'll see this list again in a minute when I do a cross comparison in a table format to help you to kind of see what makes them similar what makes them a little bit different for the most part they're similar um with the exception of a few that I'll point out okay um they are uh specifically the non dihydropyran calcium channel blockers are considered anti-arrhythmic medications and they're classified as class 4 Von Williams um anti-ar rythmic drugs and that's specifically DM and Verapamil only not the other um calcium channel blockers or the dihydro pering type um but dtis them and Verapamil specifically and I'm going to spend a moment explaining why it is that they're considered anti rythmics it has to do with what they do to noal cells in the heart and what I mean by nodal cells I'm talking about SA node and um AV node those are pacemaker cells and they have different Action potentials that are different from the ventricular myosite of The myocardium um and so so when you're thinking about anti rythmics they do different things and they focus on different areas within the heart um cardiac conduction as it relates to the class 4 activity this has to do with their in um their impact on phase zero of the uh action potential and and one of the things that I would like to do is just go ahead and jump to that um diagram here you can see that the inside of the cell um has a resting um uh charge of that's net negative right um and then as uh during phase 4 um as sodium comes in which is a Caton that becomes more and more positive and less negative and the the rate of that slope or the rate of the slope the the degree of the decline of the incline influences how fast or slow the pulse is going to um go but once it achieves a certain threshold then this is where phase zero um occurs and there's a rapid influx of a dive veent Caton um cat calcium which is a two charge and so the inside of the cell becomes less and less negative right and eventually then becomes positive um and then obviously being pacemaker cells they have to get themselves back to the square one so they can start the cycle all over with again and so during phase three uh there's a movement of Cal potassium out so we're taking positives outside of from inside to move it it outside and that makes makes the inside of the cell more negative now you may be saying well where's one and two um in the fa phase one and phase two well I don't know I didn't make this thing up um but in part uh it it's lost or buried in this um whereas in the ventricular M site we do have a phase one and phase two and that what what creates part of the confusion about anti rhythmics if you're not oriented to the right action potential but when we look at drugs that Target this um certainly our class 2 anti-arrhythmic medications those are beta blockers are primarily going to work on phase 4 and a little bit of phase zero um and then when you look at our class four agents dilm and Verapamil they're predominantly working on the calcium inward current and that sort of makes sense they're calcium channel blockers so they're going to be affecting the channels that influence calcium movement in uh predominantly and so they work on this phase causing a negative chronotropic as well as dromotropic this is the uh speed at which that connection moves through the node is the dromotropic activity whereas the rate um basically that achieves this how fast it achieves the threshold is the chronotropic effect um associated with that particular medication now what's important to recognize with these drugs is that while they have negative chronotropic and negative um uh negative dromotropic effects they also have negative inotropic effects and the negative inotropy comes from the fact that they reduce the movement of cytool calcium moving inside of cytool for actin and me and to be able to contract and so you get a reduction in the force of contraction now the thing that looks very similar to beta blockers okay Class 2 agents but what's important to differentiate and was noted on the previous slide is that there is no benefit of remodeling especially in the context of patients with heart failure and that's unfortunate um but they have very similar mechanisms hemodynamics on the as it relates to cardiac conduction and on the on the hemodynamics of the vascular system but they lack the ability to have uh remodeling effects DM of romil being the case now when you administer these medications you're going to see that slope change um and so when you look at it um we have the normal conduction here okay uh on this gray the the dotted line and then after the administration of a deltis and Verapamil we can see that the slope has changed and it's slower it takes longer for that calcium to move in so the the the degree of being positive not only takes longer but doesn't reach the same potential but then it begins to space out longer than this interval right here and so that starts to slow the pulse okay because we're slowing conduction through those nodal cells and that's the negative chronotropic and negative inotrope um negative dromotropic and chronotropic effects and so we have a a reduction in the heart rate now how does that impact mean arterial pressure so mean arterial pressure is generally what we see is contributing to the blood pressure of the system and that is known by cardiac output times systemic vascular resistance well cardiac output is influenced by the the heart rate and the stroke volume now with any equation this is just simple math if you change one of the variables like make one go up the other one must go down in order for there to be no change in the mean arterial pressure if one of these variables exceeds the influence of the other then there's going to be some net movement up or down in the blood pressure and so in this case we're reducing the heart rate okay um and that is going to reduce our cardiac output but at the same time um the calcium channel blockers are known to reduce uh the inotropy and even reduced afterload so you get a little bit of both and so they they can work pretty decently on lowering the blood pressure this table over here is looking at the medications that impact dromotropy okay again that's the speed or the velocity of which the action potential carries through the tissue and you can see that we have our non- di hydrop perian calcium channel blockers listed here we also have beta blockers up here listed and then class one antiarrhythmic uh medications can have a little bit of that effect as well okay uh when we talk about the negative inotropic effects okay so impact on on inotropy the force of contraction if you look up here we have calcium channel blockers and we have all these calcium um catons sitting out here in the extracellular environment okay outside the cell and they move through these voltage gated calcium channels to get inside of the cell and that becomes important because the concentration of calcium inside the cell like I was just mentioning is what is necessary for actin and myosin monofilaments to interact so if they're not calcium isn't present there's not going to be any amiin interaction there's going to be relaxation of that muscle and it won't the force to contraction w't be less and so when we block that we reduce that sosolid calcium we cause negative less actin amise interaction that then in turn causes a negative inotropic effect okay and so again looking at the equation we reduce inotropy that reduces the stroke volume we just saw in the previous slide that we're already reducing the heart rate so there's a net overall negative or reduction in cardiac output now calcium channel blockers even NM and Verapamil also lower the systemic vascular resistance so when you have two parts of the equation the net effect is a reduction in mean arterial pressure but at the same time we're getting a reduction in pulse and reduction in inotropy with dilt and Verapamil and again listed here drugs that impact inotropy uh drugs that would decrease that and I put the other drugs listed in here as well because I think it's important to recognize and integrate other drug classes and other information into your knowledge base so that when you have medications uh that are being used simultaneously in a patient sometimes you can see additive or synergistic effects and that's important as it manifest not only the the hemodynamic effect that you're seeing but also the side effect profile that patient may be having to um experience okay all right so uh the mechanisms um that uh continue on with the mechanisms of heart they do not as I mentioned appear to reduce Remodeling and that like we see with uh bet beta blockers so Dil and Verapamil okay that's what we're still mainly talking about they influence the heart just like beta blockers do they reduce chronotropy reduce dromotropy they have a negative inotropic effect so they both share that okay but where they differ is in their Remodeling and this is one of the primary reasons that they don't have a mortality benefit in heart failure now we're talking about hypertension but we also talk about heart failure these drugs are used in more than one condition including even angena okay so they do not protect against sudden cardiac death in patients with heart failure like beta blockers do all right now when we look at their effects on the blood vessels this is uh blood vessel diameter and degree of contraction or Vaso dilation this is influenced uh this is talking about both dtis and vomel plus all of the dihydro perine calcium CH blockers amlodipine nikar opine fotene nimodipine all of those drugs will also influence the blood the blood vessels okay and this is where we again inhibit calcium entry inside of the smooth muscles cells that line those blood vessels and when there's less calcium inside of the cell therefore actin and mein cannot okay interact now this is showing you this diagram here this is the you know outside of the cell this is the inside of the cell okay in the cell membrane we have again um calcium Channels with all the calcium coming in again to increase the presence of calcium inside the cell now the other contributing um factor of calcium inside the cell is the sarcoplasmic reticulum that is sometimes also influenced by the alpha receptors and that's where alpha 1 blockers work um but if we reduce cytosolic calcium then actin and mein here will not interact they will relax that will cause a vasod dil now in causing a vasod dilation okay if that was the Drug's main mechanism and it did not affect chronotropy or dromotropy um then you might see a reflex tacac cardia that that could occur and that was described on this previous slide here reflex tacac cardia is possible when you use di hydrop perian calcium channel blockers especially like immediate release products because you vasodilate and as a compensatory mechanism the pulse will try to increase to comp compensate for that reduction in cardiac output and so um so the I'm sorry so the reduction in blood pressure so it doesn't tries to maintain it to make it equal um and sometimes that process won't happen if you're on a drug that does influence the rate so delm and vpam not only dilate the periphery but they prevent The Reflex tacac cardia if you're on a beta blocker and use a drug like amlodipine or nicardipine or something like that well then you could offset that reflex tacac cardia the patients can sometimes experience a little bit of orthostasis or dizziness depending on the timing and the degree of reduction in the blood pressure so it's just something to consider when you cause vasod dilation so these drugs are reducing afterload which will reduce stroke volume and in reducing stroke volume you will reduce um cardiac output but we also learned that with dtis and Verapamil okay specifically we will reduce the pulse so you can see where that deltis and romile do both impacts on cardiac output now afterload is also very similar to systemic vascular resistance and so you tend to see a reduction in that and so that's why we these are good anti-hypertensive medications typically useful in a lot of different patient populations including blacks or African-Americans uh that may not be as responsive to initial monotherapy with ACE inhibitors or arbs because of the reductions in physiologic amounts of renin that is produced now unfortunately all smooth muscle is going to be impacted all smooth muscle requires calcium for acting and and interact and one of the other organ systems that's affected is the GI tract and remember the GI system intestines are constantly Contracting that's called peristaltic movement to keep things that you've uh you've ingested and is being being digested and formed into stool so that you can um um eliminate that and if you inhibit calcium movement even inside the smooth muscle cells surrounding the intestines then the transit or the perosis is going to start to be affected and you slow down that contraction and that's what contributes mainly to the constipation that many patients can't experience and unfortunately I've even seen especially in some older patients um paralytic ilas or impactions because they get so so many much reduced of that peristalsis that they they they obstruct basically and they get they when you start getting obstruction or you start getting severe constipation then the patient starts to experience nausea and they can go on to develop vomiting and then that obviously causes a lot of issues with some of their you know puts them at risk for a lot of uh interventions that are unfortunate but it also increases uh the chance they may not be very compliant now there is also an impact on the coagulation Cascade uh when you look at platelets uh when they're activated and degranulate one of the things that they release is calcium and calcium is necessary for the coagulation Cascade to propagate to form the fiin monomers that help to form a clot and so calcium channel blockers theoretically do increase the chance that you might have a greater risk of bleeding because if you block the calcium release by the platelet then the coagulation Cascade um may not propagate itself as efficiently as it would to form the clot in the midst of bleeding and so there have been case reports and sort of evaluations looking at patients to take um calcium Chanel blockers and that they seem to have maybe a subtle increased risk of developing GI bleeds on occasions okay um and so it's important now this does not affect skeletal muscle um we're talking about smooth muscle cardiac muscle but not skeletal muscle because these are mediated by the uh neurotransmitter acetycholine on nicotinic receptors and that has nothing to do with uh the uh calcium channel ums in particular in that situation what tells the calcium to move in to the cell so let's look at our let's do our drug class review this is our again non di hydropod calcium channel blockers we have DM and Verapamil so these are our class four antiarrhythmic drugs when you look at their indications you see hypertension is obviously one of them but you also see chronic stable angena and and that's because when these drugs reduce the rate right we decrease the workload and the oxygen um demands that are necessary and so patients with underlying angena they can see improvements in their chest pains um especially when it's chronic and stable because we're we're not stimulating the heart and we're not increasing that workload it also works for vasospastic angena this is called Prince mle angena and patients many times can't differentiate is it a heart attack or is it their vasospasms or you know what um but it can block them in addition to it we also use it for rate control in patients with apib with rvr we can use deltis or Verapamil in that scenario they're very effective at slowing down the pulse when somebody has rapid ventricular response in the context of atop fibrillation the one exception to that uh little comment there is in patients with wpw that is Wolf Parkinson's white syndrome and in those patients they have a uh a unique pathway where electrical impulses can go down an accessory pathway around the AV node where these drugs are working to suppress the pulse and if they work if you and and you have somebody with atrial fibrillation with rvr the atrium can be beating you know up to 300 times a minute and so all those impulses are coming down to the AV node but the AV node normally kind of regulates how many Action potentials move through the AV node down in the ventricular myocardium but if you've got this accessory pathway like in wpw and you block the AV node well you might shunt all of those electrical impulses from the atrial fibrillation down that accessory pathway and you may actually increase the pulse okay so I know it sounds a little confusing but wpw has an accessory pathway that can bypass where the calcium channel blockers work and if you blunt that protective mechanism that is regulating some of the flow of those Action potentials through uh the AV node then all of them will get shunted towards the um accessory pathway and that will increase the pulse and that's why we generally avoid the use of not di hydrop paradine calcium CH blockers in wpw not the dihydropterin not drugs like amlodipine and nicardipine and those medicines I'm talking about non dihydro calcium channel blockers um you can see that many of these are available as long acting agents okay and so we can give them once a day if you're not using the long acting agents unfortunately you may have to repeat the doses for to maintain the adequate 24-hour lowering and control of the blood pressure you will also see that they are substrates and Inhibitors of the cytochrome p450 system specifically 3a4 therefore not only are they subject to drug interactions but they themselves can be precipitants of causing clinically relevant drug drug interactions and there are recommendations in some medications that have a dose limitation when you're using it concominant with a DM or Verapamil medication for example zore has a dose limitation of around 20 mg if you use it with ver romile because of that inhibition of its metabolism and elimination the other thing that you see here is in the e-lux cell membrane transporter pglycoprotein which is also prone to causing a lot of drug interactions because a lot of medications are a substrate of plyo protein and so it's important to recognize that if I block these two um you might be treating one thing but you need to factor in the fact that the patient's on other medications and you could cause a clinically relevant drug drug interaction in that patient population okay relatively if you used it in pregnancy it would probably be okay it's not an absolute contraindication now let's look at our dihydro Pine calcium channel blockers all right so we have amlodipine here in clopine listed here the next couple slides list them as well you see that obviously we have the brand uh the generic and then the Branded product you'll see that some of these Brands um have also combination with other medications where I give you the uh the other branded name so you can see that for example amlodipine is combined with a wide range of other drugs to facilitate improved compliance in those things that you're trying to treat so for example catet is combined with a tvasta in here you know for the purpose of you know treating blood pressure and the lipids okay but you could separate them out it doesn't matter um you could see again these are used for hypertension Anga and then in patients uh certain you'll see some variations in the indications like coronary disease in patients with uh improved EFS um the nice thing about amlodipine is it's once a day and has a very long halflife without being an extended release product or A Time release product it is just a chemical that has a long halflife so if you actually crushed this tablet it would maintain the same duration or halflife and that would still allow you to administer once a day and so you can put it down a tube and that's very helpful so it's a very good drug provided once a day Administration that provides 24-hour um control of blood pressure uh only having to be administered once a day and is combined with a lot of other medications now clevidipine is unique um CLX is mainly an IV formulation and the reason it has to be given IV via infusion and Via a pump is because it has a very short halflife of 1 minute so this is one of those drugs that we use in acute hypertensive mergency or emergency which is old terms we use or hypertensive crisis um because it has a quick on quick off and you titrate to the response that you're looking for um and so we only use it like in the emergency department environment or in the ICU where you need precise fluctu titration of the blood pressure to uh have it be controlled the the one thing that's important to recognize about clevidipine is it's a lipid Emulsion so it's formulation is white and milky looking and so when you infusing people on this medication you have to be careful that you can increase their triglycerides and they can get high enough to where you could even potentially put someone at risk for pancreatitis especially if their triglyceride levels are already elevated so it is something just to keep in mind we see the same sort of issues with um propofol or Diovan uh when you're using it in in sedation if you're having them on um long infusions you have to kind of check other labs uh for that reason all right moving on to some of the other agents we have phoa which is plendil there rapine Nik carpene and Nik carpene is available orally as well as an IV formulation and then we have netop which is predominantly only now available in Long acting formulations because the short acting caused that reflex tacac cardia that I was mentioning um you can see that they're all pretty much used for hypertension occasionally you see some of these others vasospastic Anga you can also see calcium channel blockers um used in patients with cocaine reduced Mi where they're having spasms and again it's to relieve those muscle contractions in the smooth muscle of the coronary artery um the most of these can be given uh once a day there are a few that have to be given twice a day and that obviously would influence or impact the compliance um as I mentioned nicardipine also comes as a premixed solution can be used as an IV infusion for uh controlling blood pressure and an acute emergency uh hypertensive crisis kind of situation many of them are substrates of 3a4 and may also inhibit some of those enzymes and you have to watch out there are small risk for drug drug interactions uh with them now I do want to spend a moment talking about ppine it is important to recognize that neopine is not used okay it's not used for hypertension it's only used for improving neurologic outcomes in patients who have had ruptured aneurysms in the brain that cause subarachnoid hemorrhage yeah you have to start it within 96 hours of the bleed and you continue it for 21 days and that has been shown to reduce some of the negative neurologic complications associated with subid Hemorrhage where does the subid Hemorrhage cause problems well when blood leaks outside of the blood vessels it unfortunately causes the blood vessels to spasm and so when you spasm blood vessels and you constrict them when that spasm occurs then you're going to reduce blood flow to vital parts of the uh brain and obviously that brain is going to suffer and reap the consequences of having lack of blood flow and so once you've sort of damaged or you have a noxic brain injury from lack of profusion to an area that isn't good the other thing that happens in sub rag noid Hemorrhage is that the increase there's an increase in interial pressure and so the blood vessels get constricted and so if you further cause more constriction you're only de further decreasing the profusion to the tissues distal to that spasm and so it's it's very important that you start this early on in therapy and you continue it for 21 days nline or suar is the last agent not really commonly used but to be complete is listed here um and so what I try to do with this summary table uh if you like these kind of things if you don't you can obviously ignore it but I tried to kind of summarize the main effects on the uh heart as well as the vascular system from a bird's eye perspective right so we have Dil and ramile so you can kind of see which ones can decrease heart rate some of these shorter acting if you have them can cause some slight increase in the pulse right those that do rate control okay those that can uh cause a negative inotropic effect and then they all will work on the peripheral vasculature and which is why they're pretty decent um anti-hypertensive medications please please do not ignore or forget that deltis and vpam do have clinically relevant drug interactions I dedicated a whole slide to it to try to drive this point home okay so substrates of both P glycoprotein which is an eflux cell membrane transporter and then then our phase one um met enzyme called cyto 45034 um these are are clinically relevant um in many patients can also sometimes be on dexin and dexin is a known substrate of plyo protein so if you inhibit plyo protein you're going to elevate the concentrations of DED doxin that's not good because um DED doxin has a neurotherapeutic index and so it doesn't take much to elevate the levels um and as I mentioned some of the Statin also are dependent on 384 for their metabolism and have dose limitations in the FDA approved product package insert if you co-administer things like Verapamil with simvastatin for that reason so please recognize DTI and Verapamil mainly some of the other D other droping calcium channel blockers may also influence that but those for sure you don't want to mess with the or miss those now let go through some of the side effects I broken up the side effects by the class or type of calcium channel blockers so first we're going to talk about the non-d hydrop pering calcium channel blockers dilet and Verapamil so we've already mentioned the negative chronotropic negative dromotropic effects that can lead to braic cardia um the other thing is Av heart block all right so if you have patients with type a second degree or third degree uh heart block you probably want to avoid these um drugs in that patient population I mentioned this earlier but using caution in patients with wpw that's with Parkinson's white again because in especially in aib r with rvr and they have underlying wpw as I mentioned it can worsen the condition and increase the pulse because the all those atrial contractions will then go through that accessory pathway and it will just accelerate the activation of the ventricular myocardium and increase the pulse I also mentioned that they lack remodeling benefits that would be beneficial in heart failure and so this is one of the primary reasons we do not use these drugs in heart failure whereas we would push and advocate for beta blocker use because beta blockers have that remodeling benefit and reduce sudden cardiac death now calcium CH blockers all of them okay so now we're talking about all side effects some of them can have reflex tacac cardia especially our dihy perine obviously dilm and Verapamil will not do that because they have negative chronotropic effects uh we talked about the constipation because of the reduced peristalsis gingival hyperplasia okay there's a lot of case reports about this in the literature um another drug that does that is phenin or Dilantin and then also cyclosporin so those are good little pearls to know um because the the gums can actually get pretty enlarged and obviously cause self-esteem issues cuz people can see it is very noticeable uh lower extremity edema okay this is the ankles the feet um sometimes the lower extremities of the calves can sometimes um swell up and they they get pitting edema and that has to do with the vasal dilation and the increased permeability that pushes the fluid from inside the vasculature outside the vasculature is a little bit more problematic with these drugs um GI bleeds because of the inhibition of the calcium mediated release from platelets uh that can then um not allow that coagulation Cascade to occur and then drug interaction potential we talked specifically about delm and Verapamil so our Core Concepts to summarize for the non-op Pines they're class four agents so they have anti- rythmic remember negative chronotropic negative dromotropic but they also have negative inotropic effects without any benefits of remodeling so they work for good for rate control especially in apid with rvr except do not give to uh wolf Parkinson's white patients drug interactions 3a4 p glycoprotein and then don't forget the the side effects you can cause heart block as well as um braic cardia with the Diop Pines they are not anti- rythmics okay not um and nimodipine is specifically used for subarachnoid hemorrhage within the first 96 hours and then you administer it for 21 days clevidipine is a lipid-based um IV infusion with a rapid onset of action and elimination halflife of approximately 1 minute and then all of these drugs can cause constipation low extremity edema gingival hyperplasia uh is a risk that has been um published in the literature