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Slow Sodium Channel and Neprilysin Inhibitors – Heart Failure and Angina Management

by Pravin Shukle, MD

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    00:01 Hi, I’m Dr. Shuckle. We're gonna add to our discussion about heart failure by talking about some of the new agents that we are using in this area.

    00:10 Now here’s the list of all of the medications that we had been talking about.

    00:13 I’m gonna focus on something called the funny channel inhibitors.

    00:17 If you’ve already watched our angina lecture you’ll have some inkling of what we are going to be talking about.

    00:23 Ivabradine is a well-known agent that has multiple names in other different countries.

    00:28 You can have a look at the list of trade names in different countries.

    00:33 Bottom line, this is a medication that allows for the treatment of heart failure by improving the dynamics of the heart.

    00:42 Adverse events of this particular agent include luminous phenomena which I’ve discussed in the angina lecture; it’s where people feel like they are walking down a bright hallway or light seems a little bit brighter with the bit of a haze to it.

    00:54 It’s a very unique kind of phenomenon and I think that this is the only drug that I can think of that has this type kind of side effect.

    01:01 So when you are looking at your exams and you see luminous phenomena, look for this drug and it may be the correct answer.

    01:09 Side effects also include bradycardia, atrioventricular block.

    01:13 You can get dizziness possibly from low blood pressure or from low heart rate and you can get blurred vision which is separate.

    01:21 We do use this medication for heart failure but be careful in using it in patients who have sick sinus syndrome.

    01:28 Be aware that this medication has interactions with the 3A4 inhibitors such as ketoconazole or some of the macrolides.

    01:36 Be aware that you may have a drug interaction with verapamil or diltiazem which are calcium blockers and be aware that this medication, when we are using it in heart failure, should have a little bit of reserved so use caution when you are using this medication in heart failure.

    01:53 The next category I wanna talk about are the neprilysin inhibitors.

    01:57 First of all, let’s define what we mean by neprilysin.

    02:01 Neprilysin has many different names because different researchers found out about this protein and called it something based on their areas specialty and now we all know it’s all the same molecule.

    02:13 The other names of this include the membrane metallic protein or MME, a neuro endopeptidase cluster of differentiation 10 or CD10 or common acute lymphoblastic leukemia antigen or CALLA, so all of these different names refer to neprilysin.

    02:36 Neprilysin is a zinc dependent metallic proteinase that you can see here in our image and it breaks down natriuretics; so if you think about that, anything that breaks down a natriuretic will enhance or make worse heart failure.

    02:55 A natriuretic is something that makes you excrete sodium and when you excrete sodium you excrete water cuz water follows sodium.

    03:03 So, some of the natriuretics that we talk about are atrial natriuretic peptide.

    03:07 ANP is released when the atria are stretched out, they’re stored in this kind of black granules inside the atria and when you have heart failure fluid overload, the stretching of the atria releases ANP so that you release sodium from the urine.

    03:27 BNP or brain natriuretic peptide is also released during heart failure and you’re familiar I’m sure with BNP because it’s one of the agents that we’re measuring to try and determine if a patient is actually suffering from acute heart failure.

    03:42 Vasodilators are also broken down by neprilysin that includes certain bradykinin vasodilators and that includes certain adrenomedullin vasodilators.

    03:55 Finally, other agents that are broken down include glucagon and these other substances that I’m not going to get into too much right now.

    04:05 Now the very first of the neprilysin inhibitors was a drug called, omapatrilat.

    04:10 Now it ended being withdrawn because of very significant angioedema and significant side effects, so we thought that this sort of category of drugs was dead when omapatrilat was taken off of the market, but along comes a drug called sacubitril where what they did was they took omapatrilat, they alter a couple of methyl groups, moved a couple of moieties around and they come out with this new sacubitril.

    04:38 Sacubitril is almost always combined with valsartan and it is being sold commercially in the United States, Canada and other areas as Entresto.

    04:49 Now Entresto is using a combination product to treat heart failure so here you see an example of a patient with an elevated jugular venous pressure.

    04:59 This patient has clear evidence of heart failure. This is actually one of my patients.

    05:05 What we do is we take the angiotensin receptor blocker and we take the neprilysin inhibitor and we put them into one and generally speaking these combination products have an acronym called ARNI.

    05:21 Currently, Entresto is licensed for use for heart failure with reduced ejection fraction or HFrEF.

    05:29 Generally speaking, we’re talking about ejection fraction that’s less than 40% however in the future we may see use of this drug with people using higher doses of these particular agents.

    05:43 Now in terms of the benefits of this agent, we know that if we take people who are currently being treated with current levels of appropriate therapy which are ACEs and ARBs and we switched them over to Entresto for two to three years, we end up preventing three deaths from heart failure, five hospitalizations for heart failure and eleven hospitalizations overall for other related illnesses, so we know that Entresto reduces significant morbidity and mortality, but I also want to point something else out from a clinical point of view as a doctor who uses this medication all the time, I am shocked at how much people feel better.

    06:27 People comeback and talk to me and they say, this is the best drug that they’ve ever been on and they are able to breathe and they are able to do more physical activities.

    06:35 So, I think that what’s going to happen probably in the next ten years is we’re going to see this medication being expanded not just to patients with heart failure with reduced ejection fraction but heart failure with preserved ejection fraction or what we call HFpEF.

    06:53 Side effects of this medication number one is, cough.

    06:55 Another potential side effect is angioedema although it tends to be relatively rare especially when you compare it to omapatrilat.

    07:03 Renal failure is a potential problem so be aware that you can't initiate this medication in patients with significant renal failure or renal impairment and be aware that you can precipitate renal failure because these are potentially renal reacting drugs.

    07:17 You can cause low blood pressure predominantly because of the valsartan side of the combination product but neprilysin inhibitors themselves can lower blood pressure so that’s a potential side effect as well.

    07:30 Finally, you can have an elevation in potassium levels.

    07:34 Remember that valsartan as in the combination product, also raises your potassium levels, it’s something to be aware of.

    07:42 We have to use this medication with caution. We have to washout patients who are on ACE inhibitors.

    07:48 If you give Entresto to a person who is on an ACE inhibitor, you can have dangerous elevations of bradykinin so be aware that we need to washout patients for at least 36 hours prior to use.

    08:02 In my clinical practice I tend to wash people out for about a week before I initiate Entresto therapy.

    08:09 The other thing I wanna mention is that the neprilysin also clears out amyloid beta protein from cerebrospinal fluid.

    08:18 This is an important consideration because we know that amyloid beta is implicated on Alzheimer’s disease so we want to make sure that anything that inhibits neprilysin doesn’t exacerbate or make worse the Alzheimer’s.

    08:32 We don’t see any signs of that at this point in time but it is an area of research that we’re keeping an eye out for so I want you to keep an eye out for that as well going forward.

    08:42 Okay, that’s it. That’s some of our noble agents used in heart failure.

    08:45 I’m sure that you’ll do really well in your exams. Go show them what you know.


    About the Lecture

    The lecture Slow Sodium Channel and Neprilysin Inhibitors – Heart Failure and Angina Management by Pravin Shukle, MD is from the course Cardiovascular Pharmacology.


    Included Quiz Questions

    1. Ketoconazole
    2. Aspirin
    3. Atorvastatin
    4. Prednisone
    1. An enzyme
    2. A hormone
    3. An antibiotic
    4. A phosphodiesterase inhibitor
    5. A gene
    1. Neprilysin inhibitors
    2. Angiotensin receptor blockers
    3. Angiotensin receptor neprilysin inhibitors
    4. Angiotensin converting enzyme inhibitors
    5. Renin inhibitors
    1. Renal failure
    2. Liver failure
    3. Heart failure
    4. Hypertension
    5. Hypokalemia
    1. 36 hours
    2. 4 hours
    3. 6 hours
    4. 8 hours
    5. 24 hours

    Author of lecture Slow Sodium Channel and Neprilysin Inhibitors – Heart Failure and Angina Management

     Pravin Shukle, MD

    Pravin Shukle, MD


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