Diabetes Medications: Quick & Dirty

I recently came across an interesting mnemonic: Ben Stiller Took Meg Griffin’s Dog Across Some Bridge. This puts in order, diabetes medication classes, from most effective, to least effective at decreasing A1c levels. The classes are as follows:

1. Biguanides

2. Sulfonylureas

3. Thiazolidinediones (TZDs)

4. Meglitinides

5. Glucagon-like peptide-1 receptor agonists (GLP1s)

6. Dipeptidyl peptidase-4 inhibitors (DPP4s)

7. Alpha Glucosidase inhibitors (AGIs)

8. Sodium/glucose cotransporter 2 inhibitors (SGLT2s)

9. Bile Acid Sequesters

First, we should define what A1c is. There are different types of hemoglobin, the protein that transports oxygen throughout our blood. The main kind in humans is called Hemoglobin A, which slowly bonds with glucose, forming hemoglobin A1c. I can’t find where the term “1c” comes from exactly. This process of adding a sugar molecule to hemoglobin happens spontaneously and slowly and creates a glycated hemoglobin. As your blood sugar increases, so does your hemoglobin A1c. The key here is that this is a process so your A1c levels are showing a weighted average over 120 days of your blood glucose levels. Neat. So managing that by decreasing that weighted average in Type 2 Diabetics in the following medication is important. Double neat. Let’s dive into the nine classes.

Biguanides are aptly first, as Metformin/Glucophage is a biguanide and is the third most prescribed medication in the US. It is available in two combination forms, with Sitagliptin: Janumet and with Empagliflozin: Synjardy. There are many benefits of biguanides. Their main MOA is the decrease of gluconeogenesis (the creation of glucose from non-glucose precursors) and the increase of peripheral utilization of glucose. It also improves your lipid profile (cholesterol) and reduces macrovascular risk. Common side effects of Metformin are GI-related, namely diarrhea. There is actually an extended-release type for this but it’s expensive.

Sulfonylureas are next. An example here is Glyburide/Glynase also known as Glibenclamide. This is the 200th most prescribed medication. Another is Glipizide/Glucotrol which is more popular (49th). Lastly we have Glimepiride/Amaryl (87th) which actually dropped 25 spots from 2019 to 2020. Sulfonylureas can cause weight gain and are metabolized in the liver and kidney. They can increase macrovascular risk yet Glipizide/Glucotrol is better for the elderly. THey work by increasing the secretion of insulin.

Next, the mouthful that are Thiazolidinediones or TZDs for short. These work by increasing the storage of fatty acids, so cells become more dependent on their oxidation of carbohydrates, specifically glucose. Examples here are the -glitazones. We have Pioglitazone/Actos (168th) as an example here. Like sulfonylureas, they can cause weight gain.

In fourth place we have the Meglitinides. There are two notable examples, Repaglinide/Prandin which you can take with renal failure and Nateglinide/Starlix which you can take with hepatic failure. Neither are on the top 300 list. Meglitinides are insulin secretagogues which means they increase insulin secretion.

In fifth place, we have the first of four of the long-named classes. Enter the glucagon-like peptide-1 receptor agonists. Whoa. We can call them GLP-1 for short. Remember that glucagon is secreted by alpha cells in the pancreas to increase blood sugar. They have a benefit over sulfonylureas and meglitinides as they have a lower risk of causing hypoglycemia. The GLP-1s all end in “-tide.” Examples are Dulaglutide/Trulicity (96), Semaglutide/Ozempic/Wegovy at 129, which should skyrocket as it has recently been used widely as a weight loss drug, and lastly Liraglutide/Victoza (146). These can cause nausea, vomiting, and diarrhea as well as gastroparesis. Wegovy is the higher-dose version of Ozempic and is marketed as an anti-obesity medication; it’s been in short supply recently in the US.

In sixth place we have the dipeptidyl peptidase-4 inhibitors or DPP-4 for short; they all end in -gliptin. Our first example here is Sitagliptin/Januvia (74). It can be combined with Metformin to create Janumet (154). The other two in the top 300 are Linagliptin/Tradjenta (293) and Alogliptin/Nesina (295). Side effects include pancreatitis, URI symptoms, and joint pain. Linagliptin/Tradjenta can be used in renal failure.

In seventh we have the Alpha-glucosidase inhibitors or AGI for short. These work by decreasing carbohydrate absorption in the GI tract. You want to avoid alcohol with these. An example here is Acarbose/Precose which is not on the top 300 list.

The penultimate eighth spot are the sodium/glucose cotransporter 2 inhibitors or SGLT2 for short. These all end in -flozin. Examples here are Empagliflozin/Jardiance (102), Dapagliflozin/Farxiga (217), and Canagliflozin/Invokana (294). You can combine Empagliflozin & Metformin to create Synjardy (238). These can cause weight loss alongside biguanides and GLP-1s. You want to avoid low carb diets and excessive alcohol here because you can go into DKA. SGLT2s along with TZDs can increase the risk of fractures. You also want strong kidney function to take these.

Our ninth and final spot are the elusive Bile Acid Sequesters. These are adjunctive only, meaning they are added onto something else. An example here is Colesevelam/Welchol. Don’t take these with gastroparesis. These can cause constipation and decreased vitamin ADEK absorption.

So there we have it! The nine classes of diabetes medications.

Glycolysis and Friends: Pyruvate, Acetyl CoA, Ethanol, and Lactic Acid

So a couple of months ago I started experimenting with a new studying style; handwriting instead of typing. I actually wrote a blog a couple of years ago about which is better, and handwriting was the winner; it was actually one of the first blogs I ever wrote and I’m as obsessed with the topic then as I am now. Yet after over two years of pre-med studies, I’ve stuck with typing. But I realized not a lot of what I’m learning is sticking and I want to fix that. So I started reading the Pearson Biochemistry book because that’s apparently what I do in my spare time, and have been handwriting notes as I go through.

I actually started with this frustration about concepts such as glycolysis; it’s a topic I’ve studied for years yet I feel I can’t truly explain it in plain language; or any language for that matter. So I went back and spent some time with glycolysis, for no other reason but my own knowledge; I actually started all the way back in my biology textbook. And I handwrote what I learned. And over the next couple of days I practiced recalling the key ideas behind glycolysis. And… I think it worked. I mean, I had to review my notes just before writing this, but most of what I recalled was there. I wanted to, for the sake of finally committing this to memory, and creating a place that I can access in case that memory lapses, talk about glycolysis.

Glyco– comes from Greek glykýs, meaning “sweet” and “lysis” means… you know, to break apart. The idea here is to break a six-carboned sugar, glucose, into two, three-carboned sugars which are called glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) but they aren’t really important here. There is, however, a 3-carbon compound that’s very important: pyruvate.

The main goal of glycolysis is to create two molecules of pyruvate. Pyruvate is a negatively charged, conjugate base of pyruvic acid. Pyruvic acid is a cool molecule, because it’s a combination of a carboxylic acid and ketone functional group. Before I talk about what happens next to pyruvate, I want to talk about oxidation. The age-old mnemonic for me is LEO / GER, where LEO stands for “lose electron oxidation.” And this is what we do to fuel, we harvest its electrons to give us energy. And a key fuel for us are carbohydrate polysaccharides like sucrose, lactose, and starch. First, however, our digestive system must hydrolyze these polysaccharides into the monosaccharide glucose before glycolysis can begin. The chemical formula for glycolysis is glucose + oxygen to create carbon dioxide, water, and “energy.” Oxygen is the oxidizer here; it plucks electrons from glucose. Unlike an acid/base reaction (glycolysis is technically a combustion reaction), however, it’s not just an electron that is being harvested, the proton goes with it or, in other words, an entire hydrogen atom; this is sort of where all of the carbon dioxide comes from. Oxygen is electronegative because it has a large number of protons in relation to its valence electrons, giving it a nice healthy positive charge that attracts electrons like crazy. Oxygen is not only the indirect oxidizer (electron harvester) of glycolysis (NAD+ is technically the oxidizing agent of glycolysis), it’s the ultimate electron receptor at the end of oxidative phosphorylation, where we get most of our ATP.

Okay, so glycolysis occurs in the cytosol. And now that we have pyruvate, which is a product of the oxidation of glycolysis (there are a bunch of steps to get there) it enters the mitochondrion (via active transport since it’s charged) and then it’s further oxidized into a high-energy compound called acetyl coenzyme-A or acetyl CoA. To become acetyl-CoA, Pyruvate is actually oxidized this time by something called NAD+, which becomes NADH because it is picking up a hydrogen. Acetyl CoA is… massive; it has 89 atoms in total! The only resemblance to pyruvate is that it’s just the lopped off ketone part, now called an acetyl group. Okay so I mean most of acetyl CoA is coenzyme A. Enzymes are proteins; they are long chains of amino acids. We’re getting serious now. It’s acetyl CoA that then enters into the citric acid cycle.

I want to talk about whether glycolysis is an aerobic or an anaerobic process. Here’s the deal. Glycolysis will oxidize pyruvate whether oxygen is present or not. If oxygen is available, then we can continue forward into the citric acid cycle; it’s about electronegative oxygen driving the cycle and the electron transport chain. If oxygen is not available then glycolysis can continue onto fermentation, an extension of glycolysis. And here’s the crazy thing, in alcohol fermentation, pyruvate is converted to ethanol.

Let’s take a step back for a second. Under aerobic conditions, NAD+ is recycled because NADH transfers its electrons into the electron transport chain. However, in the absence of oxygen, NADH can transfer its electrons directly to pyruvate. The purpose of this is to regenerate NAD+ as an oxidizer which can then further harvest electrons; that’s fermentation. There are two types: lactic acid fermentation, and alcohol fermentation.

In alcohol fermentation, pyruvate is converted to acetaldehyde which is then reduced by NADH, regenerating NAD+, the purpose of fermentation, to ethanol. Alcohol fermentation does not occur in humans, however we certainly use this process for baking and brewing.

Lactic acid fermentation, however, does occur in humans. We use this process when oxygen is scarce, like during strenuous exercise. It’s been mistakenly thought that lactic acid build up is what causes muscle soreness, but this isn’t the case (it’s likely just the stress and trauma from tearing muscle fibers). In lactic acid fermentation, pyruvate is reduced directly by NADH to form lactate, the conjugate base of lactic acid (remember the relationship between pyruvic acid and pyruvate). Lactic acid fermentation also has non-human uses and is utilized to create cheese and yogurt.

So there you have it! I found this all very interesting. Fermentation, specifically is a process I remember hearing about and “learning” about so often but I never grasped what its purpose was. Hopefully committing this all to a blog will help me remember this all!

Steroids: Quick and Dirty

Steroids. I’m taking one right now, prednisone (Deltasone / Rayos; thanks, memory palace!) because I’ve been sick for two weeks. So what are steroids, what do they do, and how does prednisone work? Let’s dive in.

What I do know is that steroids are lipid-based; they have that cyclic four-ringed structure and are related to cholesterol, which is a type of sterol, which are related to steroids. Steroids do two things: they are a part of cell membranes (I remember cholesterol also being a part of cell membranes) and act as signaling molecules, I believe as hormones. The adrenal cortex houses several lipid-based steroids, in a general class called corticosteroids: aldosterone, which is a mineralocorticoid (it increases blood pressure), and the three Cs, the glucocorticoids: cortisol (often known as the stress hormone), corticosterone, and cortisone. The glucocorticoids speed up gluconeogenesis, the creation of glucose from non-carbohydrate precursors, are anti-inflammatory in nature and suppress the immune response. So what about prednisone?

Prednisone, a glucocorticoid, was patented only in 1954 and is the 27th most commonly prescribed medication in the US. It’s mainly used to suppress the immune system and decrease inflammation. Okay, so that tracks with the three Cs. Prednisone is taken orally and is a prodrug that is converted to prednisolone by the liver before it becomes active. That’s interesting because I’ve been prescribed prednisolone (139th most prescribed) also. Prednisone is used to treat respiratory issues such as asthma and COPD. So, prednisone by itself does nothing; it’s a prodrug. It has to be converted/metabolized in the liver to prednisolone, so we need to look at the pharmacology there.

So prednisolone is lipophilic and can pass through cell membranes easily. Because steroids are lipids, they love fat, are uncharged and non-polar and mesh well with the C-H bonds of the cell membranes. They enter and bind to the glucocorticoid receptor (GCR) in the cytoplasm. I can’t find exactly where it’s located; I think it’s just sort of floating around. Once it binds, the end result is the synthesis of anti-inflammatory proteins and a block of transcription of inflammatory genes. Neat. So in terms of asthma, steroids reduce the inflammation of inflamed airways. My nose and throat are irritated and inflamed and the steroid is helping that. Double neat.

So what are other kinds of steroid medications? Well of the top 75 commonly prescribed, along with prednisone at #27, we have fluticasone (Flonase) at #18, which is a glucocorticoid and budesonide/formoterol (Symbicort) at #57, which is another glucocorticoid. And an honorable mention goes out to dexamethasone (Decadron) at #272, which is also a glucocorticoid that made me vomit when I had my wisdom teeth taken out. So there you have it. Steroids: quick and dirty.

Wait, but what about NSAIDs!? Non-steroidal anti-inflammatory drugs? That’s for another blog!

Big D-Dimer And The Kids Table

Another very common term I’ve heard in the ER is a “D-Dimer.” I mainly hear it with patients who are short of breath and are being evaluated for a pulmonary embolism. Let’s find out what exactly a D-Dimer is. 

First we need to talk about a very important duo in medicine: plasmin and fibrin and their precursor enzymes: plasminogen and fibrinogen. We’re first introduced to fibrinogen when we learn about the composition of blood. Blood contains two main components, plasma, and formed elements: 

1. Plasma (55%)

   1. Water (92%)

   2. Plasma Proteins (7%)

      1. Fibrinogen

      2. Albumin

      3. Globulins

   3. Other Solutes (1%)

2. Formed Elements (45%)

   1. Red Blood Cells (99.9%)

   2. White Blood Cells & Platelets (<.1%)

Formed elements are made up of red blood cells (99.9%) and white blood cells & platelets (<.1% each). So yes, nearly 45% of our blood is straight red blood cells. Well where does fibrinogen come in? Well the other 55% of blood composition is plasma. This is composed of 92% water, and 7% of what are called plasma proteins (the other 1% is “other solutes”). Within those plasma proteins we find fibrinogen (the others are albumin and globulins).

We can think of our bloodstream as a river, because well half of it is water. And swimming through it are a ton of salmon, like a ton of them (red blood cells). Plasma proteins are like the other animals just chilling in the river (otters, bears, beavers), far outnumbered by the salmon and let’s say one of them is a beaver. The beaver is fibrinogen and is a critical component of a blood clot (hey, let’s call that blood clot a dam in the river!). 

When our body needs to stop bleeding, it activates hemostasis (meaning a halt of blood), which includes the vascular, platelet, and coagulation phase. Fibrinogen is actually soluble so it would just wash away in the stream, but it’s activated by an enzyme called thrombin into its active, insoluble form, fibrin. 

Thrombin acts on Fibrinogen (found in blood plasma) to activate it to insoluble Fibrin

Insoluble fibrin produces blood clots, or thrombi; fibrin is like logs in a damn. So our fibrinogen beaver just needed some inspiration before doing what he does best which is why thrombin comes along and cheers him on. But here’s the thing right… blood clots can be dangerous. If this big fibrin damn were to break off and form an embolus (a traveling thrombi), it could block off a part of the river that we don’t want blocked and that could mean big trouble. 

Just for the sake of my dumb river creature metaphor, we aren’t blocking off the entire blood vessel when it’s bleeding. It’s like if the river spills over a bank into an area it’s not supposed to go, or breaks a levy, so we need to dam off that section to ensure all of the water is moving downstream where we want it.

So after the fibrin dam is built and bleeding stops, and our body recognizes that it’s all done with the fibrin dam / blood clot, it calls in the clean up crew to break it down. Enter fibrinolysis, which by its name we can see means the lysis (disintegration) of fibrin. Two enzymes come in to call the shots for the clean up crew, tissue plasminogen activator (tPA) and thrombin again (which is pretty interesting). 

Thrombin is like the superintendent of this whole project, noticed the dam is complete, and calls in the clean up crew. This clean up crew is composed of something called plasmin.

Thrombin and tPA  activate a proenzyme plasminogen to produce the enzyme plasmin, which can digest the clot and break it up. So it’s fibrin and plasmin, fibrin and plasmin. The clotter and the digester. 

And plasmin is going absolutely ham on this clot. So there’s pieces of wooden fibrin flying everywhere. A type of this shredded fibrin, or a fibrin degradation product (FDP), is called D-dimer. It’s like the splinters and parts of a shredded log. D-dimer isn’t normally present in our plasma unless some type of coagulation is happening, and thus the need for fibrinolysis has occurred. So if we notice D-dimer, a clot is being degraded, or attempting to be degraded somewhere in the body, which is an indication of a pulmonary embolism.

So here is sort of this whole process. We start with our soluble fibrinogen, which is then activated by thrombin. So then it forms this fibrin mesh, which I’m not sure is insoluble yet. It’s when Factor XIII (13) comes in (more on clotting factors later) that we form this crosslinked, insoluble fibrin mesh. Factor 13 is known as the fibrin stabilizing factor. And remember that plasmin is our clean-up crew that is deconstructing this crosslinked fibrin mesh, part of which is the D-Dimer. And we can see where the namesake comes from here. Fibrinogen has two “D” subunits, and the dimer (or two identical molecules) is two D subunits crosslinked together (both linked to an E subunit). But what does the “D” stand for!? I see there’s a D and an E domain of fibrinogen. I also see an alpha, beta, C, D, and E domain. So it’s just an alphabetical list and doesn’t stand for anything.

Pulmonary Embolisms

Okay so what exactly is a pulmonary embolism and why do we care about them? Well a thrombus is a blood clot and when it breaks off and starts to move, it’s called an embolus. See at first I thought a clot just sort of just appeared in the lungs. Or maybe it came from somewhere in the heart. So it turns out the most common source of these emboli are in the veins of our legs, known as deep vein thromboses. Blood in our legs already has a lot of work to do to fight the forces of gravity and come all the way up to reach the inferior vena cava and enter the right atrium. That’s why veins have valves in our veins to prevent backflow. Our muscles in our legs actually contract to help pump blood up through our veins. 

The vasculature of our lungs is very expansive. It’d be quite easy for an embolus to get trapped there, and cause ischemia to lung tissue and alveoli, prevent oxygen exchange, and cause us to breathe faster to compensate, and eventually be short of breath. So the embolus starts in the leg, goes into the right atrium via the inferior vena cava, and then the right ventricle, and then through the pulmonary trunk into the pulmonary arteries. So it’s deoxygenated blood that gets trapped, never getting the chance to get oxygenated. It can’t really go any further, right? It’s lodged there; the vasculature just keep getting smaller.

The interesting thing is that if you have a high risk patient, like a patient who just had surgery and is immobile for a while (there are other factors), you should just go straight to imaging (CT scan) and skip the D-Dimer as a screening test. A special type of a CT, called a CTA scan (CT angiography) with contrast to show the blood vessels in the lungs can be used.

So what’s the treatment for a PE? You can use a blood thinner to help prevent existing clots from getting bigger and from other clots forming. Some clots dissolve on their own.

Clotting Factors

In my research, I came across the mention of several clotting factors. There are 13 of them, named by roman numeral, in the order they were discovered. Our beaver fibrinogen is actually Factor I (fibrin I’ve seen is Ia) Factor II is prothrombin. Factor XIII (13) is involved in the creation of insoluble fibrin.

It’s also worth noting that there is a pretty extensive coagulation cascade with an intrinsic and extrinsic pathway featuring all of these clotting factors, but I think that’s outside the scope of this post.

Sources

Martini F, Nath J, Bartholomew E. Fundamentals of Anatomy & Physiology. 2018. Eleventh Edition. Pearson Education. 

Bounds EJ, Kok SJ. D Dimer. [Updated 2021 Jul 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431064/

National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 439199, Fibrin. Retrieved March 3, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Fibrin.

Mpt-matthew, CC BY-SA 3.0 https://creativecommons.org/licenses/by-sa/3.0, via Wikimedia Commons. https://commons.wikimedia.org/wiki/File:D-dimer_production.pdf

https://www.mayoclinic.org/diseases-conditions/pulmonary-embolism/diagnosis-treatment/drc-20354653

How Big is Your Brain (Natriuretic Peptide)?

While shadowing some all-star PAs in the ER, I’ve heard the term/lab value BNP mentioned often in relation to heart failure patients. Let’s see what BNP is all about.

BNP stands for “Brain Natriuretic Peptide” or B-type natriuretic peptide and is also called ventricular natriuretic peptide. What a mouthful. It’s a biochemical marker that can help diagnose heart failure and is measured via the serum or plasma of our blood.

In terms of anatomy and physiology which I’m currently studying, BNP is first mentioned in the endocrine chapter as one of two hormones secreted by cardiac cells (the other is ANP, which stands for atrial natriuretic peptide). Now I know what you’re thinking, if these are both secreted by cardiac cells, why on earth is BNP called “brain natriuretic peptide.” Because… reasons: it was initially found in brain tissue of pigs and the name stuck. 

ANP is secreted by cells in the wall of the right atrium, and BNP the ventricles (mainly the left). ANP responds to blood volume and pressure and BNP responds to stretching/tension.

The word natrium (Latin) refers to sodium, -ouresis means urination, and peptide is a protein. This hints that BNP probably increases the expelling of salt in our urine, meaning a fluid loss, meaning an eventual blood volume loss and loss in blood pressure. Natriuresis literally means the excretion of salt in the urine. What triggers the release of BNP is the abnormal stretching of the heart walls. So if our heart is being stretched abnormally, something is wrong, right? Either there is too much pressure or blood, or the heart is weakened and not pumping blood effectively, which is where heart failure comes in. And if the heart is weakened, then pressure and volume will increase as it struggles to keep up. Makes sense.

Remember that heart failure can cause respiratory symptoms, distress even. If there is a problem with the heart, then either too much or not enough blood is going to enter the lungs. If there’s not enough, then proper gas exchange isn’t going to occur and our body will be starved of oxygen, causing us to breathe faster. Fluid build up can also enter the alveoli causing respiratory problems.

Effects

We learn more about ANP and BNP in the blood vessels and circulation chapter of A&P where we learn their effects:

1. Increase sodium ion excretion by the kidneys. 

2. Promote water loss by increasing urine volume.

3. Reduce thirst.

4. Block the release of ADH, aldosterone, epinephrine, and norepinephrine.

5. Stimulate peripheral vasodilation.

Yea, so they don’t mess around. Once these five things reduce blood volume and pressure (therefore restoring homeostasis), the natriuretic peptides stop being excreted by our cardiac cells because they’ve done their job. That’s a negative feedback loop.

Let’s talk a little bit about #4 because we just mentioned four other hormones. 

• ADH, the antidiuretic hormone, is secreted by the posterior pituitary (which also secretes oxytocin). Its function is in its name; it prevents uresis, or urination. In other words, it retains fluids. This is the hormone inhibited by alcohol, which is why we urinate when we imbibe. BNP does the same thing (except for making us drunk); it makes us urinate. BNP is blocking the release of ADH.

• Aldosterone is secreted by the adrenal cortex of the adrenal gland. I like to think that it keeps “al dos” salts. And salt retention = fluid retention. Aldosterone is involved in the renin-angiotensin-aldosterone system (RAAS). BNP is blocking the release of aldosterone.

• So what about epinephrine and norepinephrine? Well norepinephrine and epinephrine are vasopressors, which raise blood pressure. BNP is blocking those too.

Heart Failure & Shortness of Breath

When I was studying for the NREMT, I made the following note about heart failure:

LEFT-SIDED HEART FAILURE is associated with pulmonary edema and leads to shortness of breath because as blood is returning via the pulmonary veins to the left atrium and then left ventricle, the ventricle can’t pump out as much and there is fluid build-up in the lungs. Pink and frothy sputum found here. THINK L AND LEFT FOR LUNGS AND LYING DOWN! You will see respiratory issues like shortness of breath. The patient worsens when they lie down and worsens when they exert themselves because they can’t breathe adequately.

“An accurate and rapid diagnosis is crucial for the diagnosis of patients who present to the emergency room or outpatient examination room with acute respiratory distress.” (Yoo, 2014). So respiratory distress is a major symptom of heart failure. There we go.

Questions

1. What about other sources of high blood pressure? Wouldn’t that trigger BNP? Can’t you have HBP but not heart failure?

2. Aren’t BNPs block of epinephrine and norepinephrine counterproductive towards making the heart stronger? Don’t these make the heart, that is already struggling, weaker?

3. If BNP is a protein and water-soluble, can it be detected in the urine?

   The data suggest that urine BNP is a new candidate marker for diagnosis and prognosis of HF mortality and cardiac events. This raises the possibility of using this relatively simple noninvasive test in primary care settings or in specific conditions where the collection of blood samples could be difficult. Source.

4. Could high salt levels in the urine also point to heart failure?

Sources

Cortés R, Rivera M, Salvador A, García de Burgos F, Bertomeu V, Roselló-Lletí E, Martínez-Dolz L, Payá R, Almenar L, Portolés M. Urinary B-type natriuretic peptide levels in the diagnosis and prognosis of heart failure. J Card Fail. 2007 Sep;13(7):549-55. doi: 10.1016/j.cardfail.2007.04.007. PMID: 17826645. https://pubmed.ncbi.nlm.nih.gov/17826645/

Martini F, Nath J, Bartholomew E. Fundamentals of Anatomy & Physiology. 2018. Eleventh Edition. Pearson Education. 

Yoo BS. Clinical Significance of B-type Natriuretic Peptide in Heart Failure. J Lifestyle Med. 2014;4(1):34-38. doi:10.15280/jlm.2014.4.1.34 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390764/