1 · Diuretics and Heart Failure Drugs
Adam Wood, Pharm.D., DABAT
Instructional Objectives
- Identify diuretics and heart failure drug classes and commonly prescribed diuretics and heart failure drugs.
- Describe the molecular mechanism of action of diuretics and heart failure drugs.
- Identify indications for commonly used diuretics and heart failure drugs.
- Describe absorption, distribution, metabolism, and excretion of diuretics and heart failure drugs.
- Summarize side effects and toxic manifestations of diuretics and heart failure drugs.
- Describe adverse effects of diuretics and heart failure drugs.
- Identify contraindications for diuretics and heart failure drugs.
- Discuss potential drug-drug, drug-food, and drug-herb interactions with diuretics and heart failure drugs.
- List commonly used protocols and patient monitoring for diuretics and heart failure drugs.
- Outline appropriate patient education for diuretics and heart failure drugs.
- The standing rule for the whole lecture. “If I say something is good for mortality purposes… that means you want the patient on it no matter what. If it’s just good for symptom management, then they may not need to be on it all the time” (at 40:55). Diuretics are symptom drugs; angiotensin-converting enzyme (ACE) inhibitors, three named beta blockers and the aldosterone antagonists are survival drugs.
- Potassium, drug by drug. “You got to know what these medications are doing to your potassium… you can kill somebody very easily with potassium” (at 6:11). Every class below states whether it lowers or raises potassium.
- The digoxin target level is probably not examined. “I’m probably not going to quiz you specifically on the level on the test, but just know that this has a very tight therapeutic index” (at 48:35).
- Doses. This site leaves milligram amounts out (dosages are not tested in this course); this deck gives none.
- Where the deck is wrong, loose or out of date, the guide says so in a box headed “Deck versus truth” and follows the truth. Those points are not to be memorized as the slide words them.
1.1 · Objectives 1–3 — Diuretics: the frame and the nephron
Diuretics are drugs that increase urine flow and/or sodium and chloride excretion [slide 4]. A sustained imbalance between sodium and chloride intake and loss is fatal [slide 4]. Too much sodium and water means volume overload and pulmonary edema; too little means volume depletion and cardiovascular collapse [slide 4]. The goal is the middle zone between the two.
At 0:23 of the recording: “These are helping to block the reabsorption of sodium and chloride in the renal tubule, which will then cause water to flow with it. This is the general rule I’ll use, that wherever salt goes, water wants to follow.”
A diuretic blocks sodium and chloride reabsorption, and water follows the salt into the urine [slide 4].
The kidney fights back (“diuretic braking”). The kidneys receive about 22 percent of the cardiac output and 7 percent of the oxygen, although they are only 0.5 percent of body weight [slide 5]. Renal compensatory mechanisms prevent volume depletion and cardiovascular collapse, and this is called diuretic braking [slide 5]. It consists of activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, a fall in blood pressure (less pressure natriuresis), a fall in atrial natriuretic peptide with a rise in antidiuretic hormone, and renal cell hypertrophy [slide 5].
At 1:08 of the recording: “I always talk about the kidneys being kind of like divas… they need their blood flow… they have a lot of these compensatory mechanisms, they have this diuretic braking action, where you’ll see activation of the renin-angiotensin system, you’ll see things like increase in ADH release… The kidneys don’t like losing all that salt and all that extra volume, so they’re going to be fighting you. And again, that’s why you see synergy between things like ACE inhibitors and diuretics and calcium channel blockers, because they can all help to block some of these compensatory mechanisms.”
Diuretics set off compensation (more renin, aldosterone and antidiuretic hormone, abbreviated ADH), which limits how well they work; angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are synergistic partners because they block those compensations [slide 5].
Also tested
- Furosemide acts in the thick ascending limb. Loop diuretics work in the thick ascending limb of the loop of Henle, where about 25 percent of the sodium is reabsorbed.
Walking down the nephron [slides 6 to 11]
The nephron is the functional unit of the kidney (slide 6 pictures the kidney: cortex, medulla, nephron, renal artery, renal vein, ureter). Slide 7 pictures the nephron, from Bowman’s capsule and the glomerulus through the proximal tubule, loop of Henle, distal tubule and collecting tubule, with glucose and amino acids leaving at the proximal tubule and aldosterone and antidiuretic hormone acting at the collecting end.
| Site | What happens there | Diuretic that works there |
|---|---|---|
| Glomerulus (filtration) [slide 7] | 16 to 20 percent of the fluid and its solutes is filtered: glucose; sodium, potassium, chloride and bicarbonate; amino acids. 150 to 180 liters are filtered per day and 1 to 2 liters are excreted; the plasma is filtered about 50 to 60 times a day | None |
| Proximal tubule [slide 8] | Reabsorption of glucose, amino acids and organic solutes; weak acids and bases are excreted into the lumen; 60 to 70 percent of the filtrate is reabsorbed | Carbonic anhydrase inhibitors [slide 39] |
| Loop of Henle [slide 9] | Concentrates the urine and reabsorbs sodium. In the descending limb water leaves the lumen. In the ascending limb 25 percent of the sodium is reabsorbed and the limb is impermeable to water | Loop diuretics [slide 9] |
| Distal tubule [slide 10] | About 5 percent of the sodium is reabsorbed (the slide adds that water movement here is controlled by aldosterone; that is loose, see the box below) | Thiazide diuretics [slide 10] |
| Collecting duct [slide 11] | 2 to 3 percent of the sodium is reabsorbed. The slide says water movement is controlled by aldosterone and by antidiuretic hormone; in truth antidiuretic hormone controls the water channels and aldosterone controls sodium and potassium handling (see the box below) | Potassium-sparing diuretics [slide 11] (the aldosterone antagonists also act at this end of the nephron [slides 34 to 36]) |
Drugs are taught in descending order of potency. For the first three sites that follows how much sodium the site handles: loop (25 percent), thiazide (5 percent), potassium-sparing and aldosterone antagonist (2 to 3 percent). The carbonic anhydrase inhibitors act at the proximal tubule, where most of the filtrate is reabsorbed, but they are the weakest diuretics, because everything downstream of the proximal tubule makes up for them [slides 8 and 39].
At 4:24 of the recording: “So we’ll see that some drugs will work in the proximal tubule, some work in the loop, some in the distal tubule and some in the collecting duct… we’re going to go in descending order of potency. We’re going to start with the most potent, the most bang for our buck in terms of urine formation.”
Learn which class works at which site, and that loops are the most potent [slides 9 to 11].
- The river is the filtrate, and the glomerulus is the intake screen: it lets the small things through (water, salts, glucose, amino acids) and keeps the big things back (proteins, red blood cells), which is why protein or blood in the urine is a bad sign [the screen is slide 7; the protein and blood point is from the recording, 2:40].
- The body is a thrifty water company that wants its water back. The river has to be mostly recycled: 150 to 180 liters enter, only 1 to 2 leave [slide 7]. “Where salt goes, water follows,” so salt left in the river holds water in the river with it (the one exception is the waterproof wall of the ascending limb, below).
- The proximal tubule is the big recycling dock (60 to 70 percent back, all the glucose and amino acids) [slide 8]. A bicarbonate conveyor belt (carbonic anhydrase) runs through it. Carbonic anhydrase inhibitors jam that belt. Bicarbonate is stranded in the river and is passed in the urine, so the blood turns slightly acidic [slides 39, 41 and 43] and the urine alkaline [from the recording, 30:44]. They are the weakest diuretics because the three stations downstream (loop, distal tubule, collecting duct) simply take the extra water back [slide 39; the word “weakest” is from the recording, 31:25].
- The loop of Henle is the powerhouse station: the ascending limb has a waterproof wall and a big sodium-potassium-chloride carrier taking back 25 percent of the sodium [slides 9 and 12]. Loop diuretics jam the biggest carrier, so they give the biggest flood of urine. The same jam spills calcium and magnesium and potassium into the river [slide 13].
- The distal tubule is a small fine-tuning station (5 percent) [slide 10]. Thiazides jam its sodium-chloride gate and give a moderate flow. Unlike the loop jam, this station pulls even more calcium back, so urinary calcium falls [slide 22].
- The collecting duct is the customs office with two officers. The aldosterone officer orders more sodium doors to be installed in the wall and more sodium-potassium pumps (the sodium-potassium ATPase) to run, trading potassium out for sodium in [slide 34]. The antidiuretic hormone officer opens the water channels [slides 11, 30 and 34]. Potassium-sparing drugs board up the sodium doors [slide 30]; aldosterone antagonists jam the officer’s mailbox (they sit on the steroid receptor, so the message never reaches the nucleus) [slide 36]. Either way the sodium-for-potassium swap stops, so potassium is spared, and the flow is only modest [slides 30 and 36].
- The kidney is a diva and runs a counter-offensive. When the river is drained, it sends out the renin-angiotensin messengers, aldosterone and antidiuretic hormone to hold water back [slide 5]. ACE inhibitors and calcium channel blockers help block these compensations, which is why they pair well with diuretics (the pairing is from the recording, 1:48).
1.2 · Objectives 1–8 — Loop diuretics
Mechanism (Objective 2). Loop diuretics inhibit the sodium-2 chloride-potassium carrier on the luminal membrane of the thick ascending limb of the loop of Henle [slide 12]. The carrier takes sodium, potassium and two chlorides in together; blocked, they stay in the lumen and leave in the urine, and water goes with them. The slide 12 picture also shows potassium leaking back into the lumen to make the lumen positive, which drives magnesium and calcium reabsorption; that is why loops waste calcium and magnesium.
The four loop diuretics (Objective 1): furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex) and ethacrynic acid (Edecrin) [slide 12]. Ethacrynic acid is the one that does not follow the “-ide” naming pattern of the other three.
At 5:14 of the recording: “Most bang for your buck, loop diuretics is going to cause the biggest increases in urine outflow. We have four in this category here we have furosemide, bumetanide, torsemide, and then, just to be difficult, ethacrynic acid.”
Loops are the most potent diuretics; four agents [slide 12].
| Topic | What the slides give for loop diuretics |
|---|---|
| Major actions [slide 13] | Inhibit sodium chloride reabsorption by 20 to 25 percent; increase urine output by up to 4 liters a day; increase potassium excretion; increase calcium and magnesium excretion |
| 3 · Indications [slide 17] | Pulmonary edema (lowers pulmonary pressure); nephrotic syndrome (protein loss, so the plasma cannot hold its fluid); cirrhosis of the liver (ascites); hypercalcemia (used with saline); heart failure; renal failure or insufficiency; hypertension |
| Kidney function [slide 16] | Loops are effective in patients whose creatinine clearance is below 30 milliliters per minute |
| 5–6 · Adverse effects [slide 18] | Volume depletion (reflex mechanisms); hypokalemia (cardiac arrhythmias); hyperglycemia (diabetogenic); contraction alkalosis; hyperuricemia (gout); ototoxicity (damages hair cells in the cochlea); hyponatremia (seizures); allergic reactions (rash, photosensitivity); azotemia (raised blood urea nitrogen) |
| 8 · Interactions [slide 19] | Nonsteroidal anti-inflammatory drugs blunt the natriuretic and blood pressure response; aminoglycosides potentiate ototoxicity; warfarin competes for plasma protein binding; lithium clearance falls and toxicity rises; digitalis: the hypokalemia and hypomagnesemia of a loop diuretic bring arrhythmias |
Why the adverse effects happen (Objectives 5 and 6) [slides 14 to 16].
- Hyperglycemia has three routes: hypokalemia impairs insulin release; reflex release of catecholamines acts through alpha-2 receptors to decrease insulin release and through beta-2 receptors to increase glycogenolysis; and peripheral glucose uptake is impaired (insulin resistance) [slide 14].
- Vasodilation. Loops have systemic vasodilator actions: they stimulate prostaglandin E2, and nonsteroidal anti-inflammatory drugs block that effect; there is also a direct relaxant effect on muscle whose mechanism is not understood [slide 14].
- Reflex activity from volume depletion raises the renin-angiotensin system, aldosterone and antidiuretic hormone [slide 15].
- Uric acid: excretion falls and the plasma level rises, which can cause gout, because proximal tubule reabsorption rises, tubular excretion falls, and the shrunken plasma volume concentrates the uric acid [slide 15].
- Mild metabolic alkalosis: volume depletion raises bicarbonate reabsorption (minor) and hydrogen ion secretion is enhanced (major) [slide 16].
- Mild hyperlipidemia: increased sympathetic activity raises triglycerides [slide 16].
- Glomerular feedback: loops block the transporter in the macula densa that sends the feedback signal regulating the glomerular filtration rate and angiotensin II [slide 16].
At 8:53 of the recording: “Notably, the loop diuretics, you’re going to see these still retain efficacy even when patients have really, really poor kidney function… even though their GFR is less than 30, the loops will still work… just because the person’s making urine does not mean their kidneys are functioning all that well.”
Loops still work at a creatinine clearance below 30 [slide 16]; the thiazide contrast is in 1.3.
At 10:46 of the recording: “Note that these are going to be very similar things to what you see with other diuretics. It’s just they’re going to be less pronounced because they’re not going to be as potent at getting rid of salt and water. Loops are the biggest players here, they’re going to be the most drastic, and so they’re going to be having the most adverse effects associated with them.”
The diuretic adverse effects are shared across classes; the more potent the diuretic, the stronger the effect. The exception is potassium, where some classes lower it and some raise it [slides 18, 26 and 33].
At 5:53 of the recording: “If I’m increasing potassium excretion, well, I could see hypokalemia as a side effect… I could see hypocalcemia or hypomagnesemia as a result of this. So again, one of the big things I told you about with ACE inhibitors, you got to know what these medications are doing to your potassium… because you can kill somebody very easily with potassium. So this is a case here where these would actually lower your potassium levels.”
Loop diuretics lower potassium (hypokalemia), with hypocalcemia and hypomagnesemia, because they increase potassium, calcium and magnesium excretion [slides 13 and 18].
Contraindications (Objective 7). The slides give no separate contraindication list for the loop diuretics; the adverse-effect list is the working guide: volume depletion, gout, uncontrolled diabetes (hyperglycemia), and hypokalemia with a digitalis drug (see 1.11) are the situations to avoid or monitor.
Also tested
- Loop diuretics with saline treat hypercalcemia. Loop diuretics increase calcium excretion, so with saline they are used to treat hypercalcemia, a listed indication.
- Gentamicin and loop diuretics. Aminoglycosides such as gentamicin have their ototoxicity potentiated by loop diuretics.
- Ototoxicity from loop diuretics. Ototoxicity, damage to the cochlear hair cells, is a listed adverse effect of loop diuretics such as furosemide.
- Gout flare with loop diuretics. Loop diuretics decrease uric acid excretion and shrink plasma volume, so plasma levels rise, which concentrates uric acid and can precipitate gout.
- Calcium excretion: loops versus thiazides. Loop diuretics increase calcium (and magnesium) excretion, whereas thiazides decrease renal calcium excretion.
- Hypokalemia from loop diuretics. Loop diuretics increase potassium excretion, and the resulting hypokalemia, low serum potassium, can cause weakness and cardiac arrhythmias.
1.3 · Objectives 1–8 — Thiazide diuretics
The thiazides and thiazide-like drugs (Objective 1) [slide 20]: chlorothiazide (Diuril), hydrochlorothiazide (Aquazide), chlorthalidone (Hygroton), metolazone (Mykrox) and indapamide (Lozol). Mechanism (Objective 2): they inhibit the sodium-chloride transporter on the luminal membrane of the distal convoluted tubule (the major action); the slide adds some carbonic anhydrase activity and, at high dose, phosphodiesterase inhibition [slide 21]. Slide 21 pictures the distal convoluted tubule cell: sodium and chloride enter together on the lumen side, calcium enters through a channel, and the blood side has the sodium-potassium pump a sodium-calcium exchanger and a parathyroid hormone receptor.
At 12:31 of the recording: “So these are actually working to block sodium and chloride transport in that distal tubule. The minor action has this carbonic anhydrase activity… don’t worry so much about that.”
Thiazides act at the distal convoluted tubule; the carbonic anhydrase and phosphodiesterase side actions on slide 21 are not for the exam [slide 21].
| Topic | What the slides give for thiazides |
|---|---|
| Major actions [slides 22 and 23] | Increased sodium chloride excretion, inhibiting up to 5 percent of the filtered load; urine output up by 1 to 2 liters a day; increased potassium and magnesium excretion; decreased renal calcium excretion, because proximal tubule calcium reabsorption and distal tubule calcium reabsorption both rise; hyperglycemia (decreased glucose tolerance, decreased insulin secretion); the glomerular filtration rate falls acutely |
| 3 · Indications [slide 24] | Hypertension; renal failure; cirrhosis of the liver; congestive heart failure; renal calcium stones (calcium oxalate). The slide also lists “hypercalcemia” here, but thiazides raise serum calcium and do not treat hypercalcemia (see the box below) |
| 5–6 · Adverse effects [slides 26 to 28] | Volume depletion (reflexes); increased sympathetic activity (decreased insulin); increased renin-angiotensin, aldosterone and antidiuretic hormone activity; hypokalemia; metabolic alkalosis (contracted extracellular fluid); hyperuricemia and gout; hyperglycemia; hypercalcemia; hyperlipidemia (5 to 15 percent rise in low-density lipoprotein cholesterol); allergic skin rashes; photosensitivity; dizziness, headache, weakness, restlessness; sexual dysfunction; constipation |
| 7 · Limit of use [slide 28] | Thiazides are ineffective at low creatinine clearance, below 30 to 40 milliliters per minute; metolazone is effective at lower clearance rates |
| 8 · Interactions [slide 29] | Nonsteroidal anti-inflammatory drugs block prostaglandins and attenuate the natriuretic action; thiazides increase digitalis toxicity, so potassium should be kept above 4.0 milliequivalents (mEq) per liter |
Also tested
- Volume depletion from thiazides. Excess salt and water loss leaves the patient volume depleted, which triggers reflex responses and orthostatic symptoms such as dizziness on standing, a falling blood pressure and dry mouth.
- Hypokalemia from thiazides. Thiazides increase potassium excretion, and hypokalemia, a listed adverse effect, predisposes to cardiac arrhythmias.
- Nonsteroidal anti-inflammatory drugs weaken thiazides. Nonsteroidal anti-inflammatory drugs block prostaglandins, which aid natriuresis, so this attenuates the natriuretic action of thiazides.
Thiazides in hypertension [slide 25]
Thiazides work best in elderly patients, African American patients and sodium-retentive states (the slide also lists obese patients; see the box below). The mechanism is time-dependent. In the short term they decrease blood volume and cardiac output. Chronically there are direct vasorelaxant effects, so total peripheral resistance falls; there is less sodium in the arteriolar walls and so less “waterlogging”; the wall is thinner and the diameter larger; and the vessel is less responsive to norepinephrine and shows more vasodepressor responses. Low-dose thiazides are preferred for hypertension because they cause few adverse effects.
At 14:46 of the recording: “Who does this work well in? If you have elderly patients, obese, African American patients, who they all tend to be more sodium retentive, so if you can get rid of that extra sodium you’re going to be able to help to decrease some of this, what we call water logging… Thiazides have a more long lasting action than you would see with something like a loop diuretic, so for chronic hypertension you’re going to see far more thiazides being used than ever you would loops. Doesn’t mean they’re first line anymore, they used to be, but they can be maybe as a useful maybe second or third line add-on… they’re also well tolerated, they’re cheap.”
Thiazides suit sodium-retentive patients and are used for chronic hypertension, while loops are not, because the thiazide effect is long lasting [slide 25].
At 17:18 of the recording: “Big difference though is you can see this hypercalcemia, because you’re causing the body to hold on to more calcium. But I just said, well, it reduces calcium stones… what it’s going to do is… causing the patient to suck up more calcium out of the renal tubule, so there’s less calcium there available to crystallize out. So yes, it could cause the patient’s serum calcium levels to go up a little bit, but it’s a pretty minor bump.”
Thiazides lower urinary calcium and raise serum calcium a little, so they prevent calcium oxalate stones; loops do the opposite, wasting calcium [slides 22, 24 and 27]. The stone paradox is the one he said confuses students.
At 18:21 of the recording: “You can find the thiazides actually become ineffective when your GFR, your creatinine clearance, goes down too low. So once you get down below like 30 or 40… stop working, with the exception… metolazone… that one will still retain the efficacy even at very low creatinine clearances… I always think about that, metolazone could make a rock pee, and that’s how I know it still retains efficacy.”
Metolazone keeps working at a very low creatinine clearance (“could make a rock pee”); the other thiazides do not [slide 28]. He gave the case of a volume-overloaded heart failure patient already on a furosemide drip to whom the nephrologist added metolazone.
1.4 · Objectives 1–8 — Potassium-sparing diuretics
The drugs (Objective 1): amiloride (Midamor; the combination Moduretic) and triamterene (Dyrenium; the combinations Dyazide and Maxzide). The combinations are with hydrochlorothiazide [slide 31]. Mechanism (Objective 2): they block luminal sodium channels in the collecting duct [slide 30]. The collecting-tubule picture (slides 30 and 34) shows the principal cell: sodium enters and potassium leaves through luminal channels, the sodium-potassium pump works on the blood side, and the aldosterone and antidiuretic hormone receptors sit on the blood side.
| Topic | What the slides give for potassium-sparing diuretics |
|---|---|
| Actions [slide 30] | Inhibit 2 to 3 percent of sodium chloride reabsorption; decrease the gradient for potassium secretion (so potassium is held); modest increase in urine flow; uric acid: a modest rise in excretion acutely in the collecting duct, a modest fall chronically (volume contraction and more reabsorption in the proximal tubule) |
| 3 · Indications [slide 32] | The same as the other diuretics, but with much less natriuretic and diuretic effect; most often used in combination with other diuretics or antihypertensive drugs |
| 5–6 · Adverse effects [slide 33] | Hyperkalemia; caution with ACE inhibitors and angiotensin blockers; caution with potassium supplements; diabetes (glucose intolerance); megaloblastic anemia with triamterene; azotemia with amiloride |
At 21:55 of the recording: “I’m going to be holding on to more potassium, so I call it potassium sparing. That’s going to be handy to offset the hypokalemia that stuff like loops can cause, so it would not be uncommon to see a mixture of both, a loop plus something like a potassium sparing diuretic to offset that potassium action to a degree. This is where things get complicated, because you can have multiple meds that can cause an increase in potassium, multiples that cause a decrease, and you need to know ultimately where is the patient going to fall, because if you don’t, patient can have some major issues.”
Potassium-sparing diuretics raise potassium and are paired with potassium-wasting loops or thiazides; the hyperkalemia risk is added to by ACE inhibitors, angiotensin receptor blockers and potassium supplements [slides 32 and 33].
At 23:26 of the recording: “A little tip here, if you ever see someone on a salt substitute, so maybe they need to be on a low sodium diet, so they get a salt substitute for their food, that’s usually potassium chloride. The tongue can’t tell the difference between sodium and potassium, so it tastes salty but it cuts down the actual sodium intake they have. That can also contribute, though, to their potassium intake. They’ve got to be cautious there.”
Patient education: salt substitutes are potassium chloride, so they add to the hyperkalemia risk with a potassium-sparing diuretic, an ACE inhibitor or an angiotensin receptor blocker [slide 33; the salt-substitute point itself comes from the recording, not the slide].
Also tested
- Amiloride acts in the collecting duct. Potassium-sparing diuretics act in the collecting duct, where about 2 to 3 percent of the sodium is reabsorbed under aldosterone control.
- Triamterene and potassium supplements. Avoid a supplement unless told otherwise, because triamterene already holds on to potassium, so a supplement can push potassium dangerously high and needs caution.
- Hyperkalemia from potassium-sparing diuretics. High serum potassium is the main adverse effect of potassium-sparing diuretics such as amiloride, and it is worse with angiotensin-converting enzyme inhibitors and potassium supplements.
1.5 · Objectives 1–7 — Aldosterone and aldosterone antagonists
What aldosterone normally does (slide 34). Aldosterone binds to its receptor, which is translocated to the nucleus; in the nucleus it activates protein synthesis; this raises the number of sodium channels in the membrane and raises the activity of the sodium-potassium ATPase, and it stimulates energy production in the distal convoluted tubule. Aldosterone is the major mineralocorticoid (“mineral” means salt). More sodium channels mean sodium and water are reabsorbed while potassium is lost, which is why chronic excess aldosterone (hyperaldosteronism) produces hypokalemia. Two ways to interrupt this: block the sodium channels (1.4) or block aldosterone itself (here).
The drugs (Objective 1): spironolactone (Aldactone) and eplerenone (Inspra) [slide 35].
| Topic | What the slides give for aldosterone antagonists |
|---|---|
| 2 · Mechanism [slide 36] | Bind the steroid receptor but do not translocate to the nucleus; most effective when aldosterone is high; block 2 to 3 percent of sodium chloride reabsorption, so potassium loss falls; modest effect on lipid, glucose and uric acid levels |
| 3 · Clinical uses [slide 37] | Primary aldosteronism; hypertension; congestive heart failure (the slide says class IV, symptoms at rest); edematous conditions; cirrhosis (secondary hyperaldosteronism); nephrotic syndrome |
| 5–6 · Adverse effects [slide 38] | Hyperkalemia and mild acidosis; nausea, vomiting and gastrointestinal upset; weak androgenic effects, a “partial agonist at testosterone receptors” (the slide’s words; in truth spironolactone blocks the androgen receptor, see the box below); gynecomastia and testicular atrophy in men; menstrual irregularities and, as the slide words it, hirsutism in women (hirsutism is not a true adverse effect; spironolactone treats it); eplerenone has less effect on androgen receptors |
At 25:39 of the recording: “Spironolactone in particular has these weak androgenic effects, and it’s a partial agonist at testosterone receptors… it can both cause masculinizing effects in patients and feminizing effects in patients… with women you can see masculinizing issues, and men you could see breast development, feminizing sort of effect.” And at 29:31: “Spironolactone is an older drug, so it’s pretty cheap, so we start with that first. But if this is an issue, if the patient is complaining about breast development, or if the patient is complaining about menstrual problems, then you could… utilize eplerenone instead. That’s much less of the androgenic activity.”
His explanation (reported, not to be learned; see the box below): a partial agonist lifts the low androgen activity of a woman toward its own level and lowers the high activity of a man toward it, so he expected masculinizing effects in women and breast development in men. If a patient on spironolactone has breast development or menstrual problems, switch to eplerenone [slide 38]. He also named acne as a use of spironolactone (blocking testosterone’s effect on sebum), which is not on the slide and is itself evidence that the drug blocks androgens rather than mimicking them.
Also tested
- Aldosterone inside a collecting-duct cell. After binding its receptor and reaching the nucleus, aldosterone drives protein synthesis that adds sodium channels, increasing the number of sodium channels.
- Spironolactone with lisinopril. Lisinopril is an angiotensin-converting enzyme inhibitor; both drugs raise serum potassium, so together the risk of hyperkalemia is high and potassium must be monitored.
- Cirrhosis and aldosterone antagonists. Cirrhosis of the liver causes secondary hyperaldosteronism, which raises aldosterone, and aldosterone antagonists are used for the resulting edema.
1.6 · Objectives 1–7 — Carbonic anhydrase inhibitors
The drugs (Objective 1): acetazolamide (Diamox), dichlorphenamide (Daramide) and methazolamide (Glauctabs) [slide 40]. Mechanism (Objective 2) [slide 39]: they inhibit carbonic anhydrase, so bicarbonate absorption in the proximal tubule falls by 80 to 90 percent, hydrogen ion production falls and the sodium-hydrogen exchange falls. The short-term effect is to increase sodium and potassium excretion by about 5 percent; after 3 to 5 days the effect is reduced to 1 to 3 percent, because the rest of the nephron makes up for it. Slide 41 pictures the proximal tubule cell with the two carbonic anhydrase sites (in the lumen and in the cell) and the carbonic anhydrase inhibitors blocking both.
| Topic | What the slides give for carbonic anhydrase inhibitors |
|---|---|
| 3 · Other uses [slide 42] | Glaucoma (decreased bicarbonate in the ciliary body; the topical forms are dorzolamide, Trusopt, and brinzolamide, Azopt); epilepsy (metabolic acidosis, central nervous system effects); mountain sickness; head injury (decreased swelling) |
| 5–6 · Adverse effects [slide 43] | Metabolic acidosis; potassium depletion; drowsiness |
At 30:44 of the recording: “By blocking this enzyme, you’re gonna trap the bicarbonate in the tubule, and then you’ll just pee it out… the urine pH may go up because there’s more bicarbonate, and the actual serum pH may go down a little bit.” And at 36:15: “You could see a bit of a metabolic acidosis, that’s different than your other diuretics, which typically cause more of a contraction alkalosis.”
Carbonic anhydrase inhibitors cause metabolic acidosis with alkaline urine, unlike the other diuretics, which cause contraction alkalosis [slides 18, 26 and 43].
At 33:05 of the recording: “In the meantime we can utilize carbonic anhydrase inhibitors to cause your blood to acidify, and then how does your body respond to acidic blood? You breathe faster, you induce tachypnea to blow off more CO2 but to bring in more O2.” And at 34:35: “By acidifying a patient’s blood you actually hyperpolarize their neurons, you make it harder for those neurons to fire off and cause a seizure.”
Mountain (altitude) sickness: the acidosis drives faster breathing until the body adapts. Epilepsy: the acidosis raises the seizure threshold. Glaucoma: less aqueous humor. He also noted that they can lessen cerebrospinal fluid production, and that the drowsiness comes from the neurons firing less readily (at 36:23) [slides 42 and 43].
Also tested
- Laboratory monitoring with acetazolamide. Metabolic acidosis lowers bicarbonate, and potassium depletion lowers potassium, so watch for low bicarbonate and low potassium.
1.7 · Objectives 1–2 — Heart failure: causes, types and compensation
Causes of heart failure [slide 45]. Ischemic heart disease and myocardial infarction account for 50 to 60 percent of cases. The others are hypertension, idiopathic dilated cardiomyopathy, other cardiomyopathies (alcoholic, viral, hypertrophic) and drug-induced heart failure. Dr. Wood added that chronic high blood pressure, alcohol and heavy metals such as cobalt can all cause it (37:01).
| Type | What goes wrong | Causes | What the slides call it |
|---|---|---|---|
| Systolic dysfunction [slide 46] | Decreased contractility | Loss of myocardial muscle mass; left ventricular hypertrophy; dilated cardiomyopathies | Assessed as reduced ejection fraction |
| Diastolic dysfunction [slide 47] | Impaired relaxation: decreased ventricular filling, so decreased cardiac output | Left ventricular hypertrophy (thicker, stiffer ventricles relax less efficiently); ischemia, which impairs removal of calcium from the cytosol back into the sarcoplasmic reticulum | Heart failure symptoms with preserved ejection fraction (heart failure with preserved left ventricular function) |
Dr. Wood’s way to hold the difference: in diastolic failure the ejection fraction percentage may be fine, but because the ventricle fills less the total blood pumped, the cardiac output, is still down (at 38:13).
Compensatory response [slide 48]. The body compensates with increased preload (through sodium and water retention), vasoconstriction, tachycardia and increased contractility (through sympathetic activation) and left ventricular hypertrophy. Slide 49 pictures the cascade: heart failure lowers cardiac output; that leads to increased venous volume and pressure (congestion and edema, dyspnea and orthopnea), decreased tissue perfusion (weakness and fatigue), and neuroendocrine activation (sympathetic and renin-angiotensin-aldosterone activation) with a faster heart rate, vasoconstriction and increased afterload, and sodium and water retention. Each response worsens the failure, so it is a vicious circle. The drugs in this lecture break the circle at different points.
Common precipitants of decompensation [slide 50]: lack of compliance; uncontrolled hypertension; cardiac arrhythmias; inadequate therapy; inappropriate medications or fluid overload; and other causes: acute anginal chest pain, pulmonary infection and emotional stress. Dr. Wood’s example was the holiday season, when people travel, forget their medications and eat sodium-heavy food (at 39:21).
Nonpharmacologic therapy [slide 51]. Restrict dietary sodium and fluid (the slide gives 1 to 3 grams of sodium a day and fluids under 2 liters a day; learn the restriction, not the numbers). Physical activity may improve functional status. Exercise capacity is also how efficacy is judged: how much work the patient can do before getting winded (recording, 40:07).
Also tested
- Vasoconstriction in heart failure. Vasoconstriction is the compensatory response that increases afterload, because it raises the resistance the ventricle pumps against.
1.8 · Objectives 1–7 — Heart failure: diuretics and angiotensin-converting enzyme inhibitors
Also tested
- Serum potassium: loops versus angiotensin-converting enzyme inhibitors. Loops increase potassium excretion, so they lower serum potassium, while angiotensin-converting enzyme inhibitors elevate it.
Diuretics in heart failure [slides 52 and 53]
- Thiazide diuretics are not potent enough for most heart failure patients.
- Loop diuretics are the mainstay of heart failure therapy. They decrease sodium and water retention and so decrease preload, giving symptomatic benefit.
- Monitor the patient’s weight to detect worsening fluid overload: a gain of more than a pound a day over several days (the figure on the slide) is fluid, not tissue.
- Diuretics are for symptomatic relief only. There is no evidence that they decrease progression or mortality, and they are not mandatory therapy.
At 40:42 of the recording: “Loops are… mainstay of therapy for heart failure… it doesn’t do anything to help them live longer, it just helps with symptomatic management. This is another situation in which, if I say something is good for mortality purposes… if it’s good for mortality reasons, that means you want the patient on it no matter what. If it’s just good for symptom management, then they may not need to be on it all the time.” And at 41:46: “Diuretics are simply for symptomatic relief, they don’t do anything for disease progression or mortality, so strictly not mandatory. You may have some people who are on this more as a PRN basis, so they notice their weight’s gone up for several days in a row, they may be instructed to take the loops.”
Diuretics relieve symptoms and do not prolong survival; they are not mandatory. Daily weights guide when to take them (PRN means as needed) [slides 52 and 53]. Expect a stem that sorts heart failure drugs into “symptoms only” and “mortality benefit”.
Angiotensin-converting enzyme inhibitors in heart failure [slides 54 to 56]
ACE inhibitors decrease preload, decrease afterload, decrease sympathetic activation and decrease left ventricular hypertrophy, dilation and remodeling. They slow heart failure progression and decrease mortality [slide 54]. The benefits are hemodynamic improvements, improved exercise tolerance, decreased symptoms, fewer hospital admissions, slowed progression of disease and prolonged survival [slide 55].
ACE inhibitor problems (adverse effects) [slide 56]: impairment of renal function, hypotension, elevation of serum potassium, cough and angioedema. Dr. Wood’s advice: if the cough or angioedema is the problem, switch to an angiotensin receptor blocker (43:15).
At 42:08 of the recording: “The ACEs and/or ARBs absolutely require. These work on all aspects to decrease preload and afterload, and they decrease that sympathetic activation. Biggest thing here too, they decrease left ventricular remodeling, dilation, hypertrophy… mandatory for these patients, because we know through these big huge heart studies that we see not only hemodynamic improvements, they’re better exercise tolerance, fewer admissions, less progression of disease, and they live longer… so ACEs or ARBs have to be mandatory for these patients.” And at 42:58: “You may see some risk for hypotension depending what their other meds look like, and elevation… in potassium… potentially the decreased potassium, now we got ACEs which we’re going to increase it, so we got… monitor for this.”
An ACE inhibitor or an angiotensin receptor blocker is mandatory in heart failure because it prolongs survival [slides 54 and 55]; monitor kidney function and potassium [slide 56].
1.9 · Objectives 1–7 — Heart failure: beta blockers
Beta blockers were classically considered contraindicated in heart failure [slide 57], because they lower heart rate and contractility (the recording, 44:03). The ones with a mortality benefit are only three: carvedilol (Coreg), metoprolol succinate (the extended-release form, marked XL; Toprol XL) and bisoprolol (Zebeta) [slide 57]. Dr. Wood: carvedilol is the third-generation beta blocker, metoprolol succinate is the long-acting formulation, and the other beta blockers have not been shown to reduce mortality in heart failure (43:28).
| Topic | What the slides give for beta blockers in heart failure |
|---|---|
| 9 · Keys to successful use [slide 58] | The patient should be stable before initiation; in hospital is preferred; start with very low doses; titrate up slowly over 6 to 8 weeks in total; monitor for worsening heart failure signs and symptoms |
| Benefits [slide 59] | Improved exercise tolerance; hemodynamic improvements (increase in ejection fraction); slowed disease progression; decreased hospitalizations; decreased need for transplant; decreased mortality |
| Place in therapy [slide 60] | First-line therapy in class II to IV heart failure; patients should be on an ACE inhibitor and a beta blocker irrespective of symptoms |
At 43:28 of the recording: “The next ones we need to look at are the beta blockers. These are also going to be mandatory, but note here it’s only three specific beta blockers: carvedilol, which is that third gen type of beta blocker I talked about before, metoprolol succinate, which is the XL formulation… and then bisoprolol. These three in particular have been found to be associated with reducing mortality in these heart failure patients. All the other ones have not been found to do that.” At 44:20: “They probably need to be in the hospital when you start these, and you’re going to just gradually work them up on very low doses… low and slow, that’s the tempo, as the Beastie Boys famously said… we’re gonna start low and gradually work them up. It may take like six to eight weeks to do so, but that’s okay, this is a marathon.” At 45:04: “These should be first line therapy in class two to four heart failure. We’re just going to say anyone with heart failure needs to be on these… irrespective of symptoms, ACEs and beta blockers are go-to. Remember the three: carvedilol, metoprolol succinate, and then bisoprolol.”
The three heart failure beta blockers are carvedilol, metoprolol succinate and bisoprolol; they are mandatory because they prolong survival, and they are started low and slow because a decompensating patient can die from an abrupt fall in rate and contractility [slides 57 to 60].
Also tested
- Beta blockers in heart failure. They can worsen heart failure, because lowering heart rate and contractility can decompensate a failing heart, so they were once avoided and classically considered contraindicated.
1.10 · Objectives 1–3 — Digoxin: action, benefit and place
The drug (Objective 1). Digoxin is a cardiac glycoside: a lactone ring and a steroid nucleus are essential for activity, and the sugar molecules (three, in the picture on slide 61) influence absorption, half-life and metabolism [slides 61 and 62]. Digoxin and digitalis-type compounds come from plants (foxglove, lily of the valley and oleander), as Dr. Wood noted (45:25).
Mechanism (Objective 2) [slides 62 to 65]. There are two ways to describe it.
| View | What digoxin does |
|---|---|
| Inotropic action (the older mechanism) [slides 62 and 63] | It inhibits the sodium-potassium ATPase of the heart muscle cell, so intracellular sodium rises; the sodium-calcium exchanger then raises intracellular calcium, and fiber shortening (the force of contraction) increases |
| Neurohormonal actions (the newer mechanism) [slides 63 to 65] | Decreases sympathetic and increases parasympathetic activity; resensitizes the baroreflex (blocking the pump helps reset it, so the heart rate falls); more parasympathetic activity in the atrioventricular node and conduction system; less sympathetic activity, so lower blood pressure and heart rate; decreases renin-angiotensin-aldosterone activity, with less remodeling and structural change; better tissue perfusion; and increased cardiac output from better pumping |
Deck versus truth, a detail that is not examined: slide 62 and Dr. Wood (46:31) say the sodium-calcium exchanger “brings calcium in”. More exactly, the rise in intracellular sodium weakens the exchanger’s normal removal of calcium from the cell, so calcium builds up and more is released from the sarcoplasmic reticulum. The result, a stronger contraction, is the same.
Target level (monitoring): 0.5 to 1 nanogram per milliliter [slide 65]; higher concentrations may be associated with worse outcomes in heart failure patients. Digoxin is one of the few heart failure drugs for which a blood level is checked (Dr. Wood, 50:44). Flag: Dr. Wood said the number itself is probably not tested (48:35); know that the level is monitored and the therapeutic index is narrow.
At 48:19 of the recording: “Digoxin is what we call very narrow therapeutic index drug. It is a very narrow window in which it works… you do not need much of this drug to get very drastic effects… I’m probably not going to quiz you specifically on the level on the test, but just know that this has a very tight therapeutic index. It is very easy to get too much and end up causing major problems for the patient.”
Digoxin has a narrow therapeutic index; the number itself is not the point [slide 65].
Also tested
- Adding digoxin in heart failure. Digoxin improves symptoms, exercise tolerance and quality of life and cuts hospitalizations, but it has no survival benefit, so expect fewer symptoms but no survival gain.
Benefit and place in therapy (Objective 3) [slides 66 and 67]
- Clinical benefits: improvement in symptoms, improved exercise tolerance, improved quality of life and a decreased number of hospitalizations. No survival benefit.
- No evidence of slowed disease progression.
- Primary use: symptomatic patients who are already on optimal doses of ACE inhibitors, beta blockers and diuretics.
- It is also used for rate control in patients with atrial fibrillation and heart failure (see the box below) and is considered in patients with symptomatic heart failure and systolic dysfunction.
At 48:55 of the recording: “Clinical benefits you get with digoxin can include improvement of symptoms, better quality of life and exercise tolerance, but no survival benefits… It’s not going to be one of those mandatory ones like beta blockers or ACEs, because they don’t actually provide a survival benefit. If you’re really topped up on your ACEs and beta blockers but you’re still not really where you want to be, then maybe digoxin can be maybe a useful add-on.”
Digoxin: symptoms yes, survival no, so an add-on, not mandatory [slides 66 and 67]. He added that he prefers not to use it because it is cleared by the kidneys and accumulates in patients with kidney problems (not on the slides).
1.11 · Objectives 5–8 — Digoxin toxicity, contraindications and the antidote
| Toxicity group | What the slides list |
|---|---|
| Gastrointestinal [slide 68] | Anorexia and nausea |
| Visual disturbances [slide 68] | Blurred vision, photophobia, xanthopsia (seeing yellow), shining lights around objects and yellow-green halos |
| Central [slide 69] | Delirium, fatigue, confusion, dizziness and abnormal dreams |
| Cardiac [slide 70] | Nodal slowing with a longer PR interval (slower conduction from the atria to the ventricles), a shorter QT interval (a shorter ventricular recovery time) and a depressed ST segment; bradycardia; digoxin-induced afterdepolarization (the electrocardiogram on slide 70 shows normal sinus beats alternating with premature ventricular beats, and ST depression) |
At 50:05 of the recording: “These can be clues… you can start to see things like xanthopsia… xanth as a prefix means yellow, so they get this kind of yellow greenish sort of color discoloration, and they start to see halos around lights… that clues me in, that’s like pathognomonic for digoxin, like there’s nothing else that does that, and so that should really clue you in… we need to check a level right away.” At 51:00 of the recording: “The other big toxicity will be cardiac in nature, so bradycardia is most common, but you can see just about any arrhythmia can be caused by too much digoxin… PVCs kind of give you a clue… ventricles are a little more sensitive, and they’re more twitchy.”
Yellow-green halos and xanthopsia point to digoxin toxicity; the next step is a digoxin level [slide 68]. Bradycardia is the commonest cardiac toxicity, and any arrhythmia can occur [slide 70].
Also tested
- Digoxin contraindications: conduction and rate. Digoxin slows nodal conduction and the nodes further, so advanced atrioventricular block, severe bradycardia, sick sinus syndrome and Wolff-Parkinson-White syndrome are listed contraindications.
- Digoxin contraindications: ventricular rhythm. Premature ventricular beats and ventricular tachycardia are contraindications, because digoxin makes the ventricles more irritable.
- Digoxin immune Fab. Its affinity for digoxin exceeds that of the sodium-potassium pump, so it binds digoxin more tightly, pulls it away and reverses toxicity rapidly.
Contraindications and risk factors (Objective 7) [slide 71]
The slide lists: advanced atrioventricular block; severe bradycardia or sick sinus syndrome; premature ventricular contractions and ventricular tachycardia; hypomagnesemia; hypercalcemia; Wolff-Parkinson-White syndrome; and electrolyte problems (the slide writes hyperkalemia; see the box, which adds the hypokalemia the slide omits). Electrolyte disturbances make toxicity more likely (Dr. Wood, 51:34).
Digoxin immune Fab (the antidote) [slide 72]
Digoxin immune Fab (Fab means fragment antigen-binding, the part of an antibody that grips its target; the current brand is DigiFab, which the slide spells Digiband) is an antibody fragment that binds digoxin (the slide words this as binding the antigen-binding site of immunoglobulin, which is garbled: the fragment’s own antigen-binding site is what grips the digoxin), made by immunizing healthy sheep with digoxin coupled to human serum albumin. Its affinity for digoxin is higher than the affinity of digoxin for the sodium-potassium ATPase, so it pulls the drug off the pump and rapidly reverses toxicity.
At 52:09 of the recording: “If you had a patient who was in dire straits with digoxin and they needed to have it reversed, we do have an immune antibody… we basically hyper immunized sheep to digoxin and they produce these antibodies, and then we take that antibody and we give it to the patient, and so what this will do is bind to the digoxin and neutralize it… this will rapidly reverse the digoxin toxicity. Be careful though, because it can unmask whatever… digoxin was treating, so they may go back in afib or they may have a heart failure decompensation, but again it’s better than being dead…”
Digoxin toxicity is reversed with digoxin immune Fab, which can unmask the atrial fibrillation or heart failure the digoxin was treating [slide 72].
1.12 · Objectives 1–7 — Aldosterone antagonists in heart failure and the other inotropic agents
Also tested
- Aldosterone antagonists slow heart failure progression. Neurohormonal inhibition of aldosterone slows remodeling of the left ventricle, and so slows heart failure progression.
- Spironolactone eligibility in heart failure. Spironolactone holds on to potassium, so a potassium above 5 milliequivalents per liter excludes it, as does a high serum creatinine.
- Monitoring an aldosterone antagonist. Hyperkalemia is the main adverse effect, so serum potassium is the value to follow.
- Milrinone and inamrinone inhibit phosphodiesterase 3. They inhibit cyclic adenosine monophosphate phosphodiesterase 3, which prevents breakdown of cyclic adenosine monophosphate, so it rises in the heart, giving direct stimulation of contraction.
- Milrinone is an inotrope. Milrinone is a cyclic adenosine monophosphate phosphodiesterase (III) inhibitor, approved for short-term intravenous use in acute decompensated heart failure.
- Thrombocytopenia with phosphodiesterase III inhibitors. Thrombocytopenia is listed for these inotropes, with milrinone causing less than inamrinone, so inamrinone is more likely to cause it.
Aldosterone antagonists in heart failure [slide 73]
- Spironolactone: mortality reduction in grade III or IV heart failure (slide 37 says class IV and slide 73 says grade III or IV for the same functional scale; learn it as advanced heart failure, see the box in 1.5); patients are not eligible if the potassium is above 5 or the serum creatinine above 2.5; gynecomastia in about 10 percent of men (it may respond to a lower dose).
- Eplerenone: no gynecomastia.
- Mechanism in heart failure: neurohormonal inhibition, slowed remodeling of the left ventricle, slowed progression of heart failure.
At 53:10 of the recording: “Remember we talked about spironolactone and eplerenone. Here we do see this does provide some mortality reduction in later stage heart failure, but they will be contraindicated if the potassium is too high or the serum creatinine is too elevated… with kidney dysfunction you’re more likely to see a hyperkalemia and just more likelihood for arrhythmias… if you do see that kind of feminizing effects… switch to eplerenone, you’ll see less of that androgen sort of activity.”
Aldosterone antagonists reduce mortality in advanced heart failure but are avoided with a high potassium or a high serum creatinine; eplerenone for the breast effects [slide 73].
Milrinone and inamrinone [slides 74 to 76]
- Milrinone (Primacor) and inamrinone (Inocor, formerly amrinone) are cyclic adenosine monophosphate (cyclic AMP) phosphodiesterase (type III) inhibitors [slide 74; the structures are pictured]: by blocking the enzyme that breaks cyclic AMP down, they let it rise in the heart (the recording, 54:05).
- They are inotropic and vasodilator: direct stimulation of myocardial contraction, balanced arterial and venous dilation, decreased afterload and increased cardiac output [slide 75].
- Approved for short-term intravenous use in acute decompensated heart failure; long-term use is associated with higher mortality and morbidity than placebo [slide 76].
- Adverse effects: thrombocytopenia (less with milrinone) and ventricular arrhythmias [slide 76].
Dobutamine and dopamine [slide 77]
- Dobutamine is a selective beta-1 agonist; intravenous infusion stimulates the force of contraction more than the rate; used short term to stabilize patients.
- Dopamine: intravenous infusion; acts through dopamine and beta receptors (the slide adds that it maintains renal function; see the box).
At 55:32 of the recording: “Your main question will be, what’s the patient hypo or hypertensive? If they’re hypertensive, then milrinone works better. If they’re going to be hypotensive, then something like… dobutamine or dopamine tends to make more sense from that standpoint.” And at 54:42: “You really just want to use it for short term, because if you leave them on it for too long you can see risk for arrhythmia start to go up.”
Pick milrinone (vasodilator) for a decompensated patient with high blood pressure and dobutamine or dopamine for low blood pressure; all are short-term, started in hospital [slides 75 to 77]. Why: milrinone’s balanced vasodilation lowers blood pressure (hypotension is a known adverse effect, not on the slide), so it suits the high-pressure patient, while dobutamine and dopamine raise the force of contraction without vasodilating (the recording, 55:22).
1.13 · Objectives 1–7 — Newer agents: ivabradine, sacubitril-valsartan, sodium-glucose cotransporter 2 inhibitors
Also tested
- Ivabradine adverse effects. Ivabradine increases the risk of atrial fibrillation, causing new palpitations, and also of symptomatic bradycardia and visual phosphenes.
- Ivabradine visual phosphenes. Visual phosphenes can resolve on their own, so the patient can be reassured and told to report persistent symptoms.
- Sacubitril-valsartan adverse effects. Hypotension, hyperkalemia, cough and renal insufficiency are the most common adverse effects, so watch for low blood pressure and high potassium.
Ivabradine (Procoralan) [slides 79 and 80]
- Mechanism: a hyperpolarization-activated cyclic nucleotide-gated channel blocker that inhibits the pacemaker current in the sinoatrial node. It reduces heart rate and does not affect contractility (unlike a beta blocker).
- Use: heart failure patients who are maxed out on beta blockers, in normal sinus rhythm with a heart rate above 70 beats per minute. It has been shown to decrease hospitalization and heart-failure-related death.
- Adverse reactions: increased risk of atrial fibrillation; symptomatic bradycardia; visual impairment (phosphenes): it affects the retinal photoreceptors, with transient brightness in a limited area of the visual field, halos and multiple images (retinal persistency); it can resolve on its own.
- Contraindications: similar to beta blockers: hypotension, heart block, a pacemaker, and so on.
Sacubitril (formulated with valsartan, Entresto) [slide 81]
- Mechanism: a neprilysin inhibitor. Neprilysin normally degrades vasoactive peptides (natriuretic peptide, bradykinin and others); inhibiting it causes vasodilation, natriuresis and diuresis and inhibits growth and fibrosis of myocardial tissue. The partner valsartan is an angiotensin receptor blocker.
- Use: to reduce the risk of cardiovascular death and hospitalization in heart failure.
- Never with an ACE inhibitor: allow a 36-hour washout period to avoid adverse effects.
- Most common adverse effects: hypotension, hyperkalemia, cough and renal insufficiency.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors [slide 82]
- Dapagliflozin (Farxiga) and empagliflozin (Jardiance), used for stable, chronic heart failure with reduced ejection fraction; they reduce mortality and hospitalizations.
- Originally for diabetes: they make the kidneys not reabsorb glucose (they block the sodium-glucose transporter in the proximal tubule).
- Risks: hypotension and fungal urinary tract infections. Dr. Wood: hypotension because they cause the patient to lose fluid, and fungal infections because there is more sugar in the genitourinary tract.
At 56:22 of the recording: “This just reduces the heart rate, it doesn’t affect the contractility. So who do you use this in? This is for patients who are maxed out on beta blockers but they still have a normal sinus rhythm and heart rate above 70.” At 58:01: “Keep in mind you would not want to use this with an ACE inhibitor… to avoid having that overlap, that overlap would include things like hypotension, hyperkalemia, cough, etc.” At 59:19: “So now this is another one of those necessary add-on medications to patients… these SGLT2 inhibitors… especially reduced ejection fraction, you see reduction mortality and hospitalizations.”
Ivabradine: beta blocker maxed out, sinus rhythm, rate above 70. Sacubitril-valsartan: never with an ACE inhibitor, with a washout. SGLT2 inhibitors: a necessary add-on, with hypotension and fungal infections. [slides 79 to 82]
- Ivabradine. Slide 79 says it decreases hospitalization and heart-failure-related death. The benefit that carries its approval is fewer hospitalizations for worsening heart failure; it has not been shown to lower overall mortality, so do not sort it with the mandatory survival drugs. The “heart rate above 70” is for patients taking the maximally tolerated beta blocker dose, and it works only in sinus rhythm, which is why atrial fibrillation matters. Its halos are not digoxin’s (see 1.11).
- Sacubitril-valsartan. Slide 81 gives the washout as “to avoid adverse effects”; Dr. Wood named hypotension, hyperkalemia and cough. Not on the slides: the main reason is angioedema, because both ACE inhibitors and neprilysin inhibition let bradykinin build up, so a history of angioedema is a contraindication. Sacubitril-valsartan also carries an FDA boxed warning for fetal toxicity (stop it when pregnancy is detected).
- SGLT2 inhibitors. Slide 82 says fungal urinary tract infections; the typical infection is a genital yeast infection. Also not on the slides: they carry a risk of diabetic ketoacidosis that can occur with normal blood glucose, and they help heart failure with preserved ejection fraction too.
1.14 · Objectives 4 and 8–10 — Absorption, interactions, monitoring and patient education
Also tested
- Diuretic classes that deplete potassium. Loops, thiazides and carbonic anhydrase inhibitors; these three classes increase potassium excretion or deplete it.
Absorption, distribution, metabolism and excretion (Objective 4)
The slides give very little for this objective. Digoxin: the sugar molecules attached to the steroid nucleus influence absorption, half-life and metabolism [slide 61]. Nephron handling: the proximal tubule excretes weak acids and bases into the lumen [slide 8], and loop diuretics keep working when the creatinine clearance is below 30 milliliters per minute while the slide says thiazides lose effect (metolazone excepted; newer data show chlorthalidone still works, see 1.3) [slides 16 and 28]. Carbonic anhydrase inhibitors: their diuretic effect fades after 3 to 5 days [slide 39]. Digoxin immune Fab has a higher affinity for digoxin than digoxin has for its pump [slide 72]. Dr. Wood added in passing that digoxin is cleared by the kidneys (not on a slide).
Interactions (Objective 8)
| Combination | What happens |
|---|---|
| Loop or thiazide diuretic with a nonsteroidal anti-inflammatory drug | Prostaglandin block blunts the natriuretic and blood pressure response [slides 14, 19 and 29] |
| Loop diuretic with an aminoglycoside | Ototoxicity is potentiated [slide 19] |
| Loop diuretic with warfarin | They compete for plasma protein binding [slide 19] |
| Loop diuretic with lithium | Lithium clearance falls and toxicity rises [slide 19] |
| Loop or thiazide diuretic with digoxin (digitalis) | Hypokalemia and hypomagnesemia bring arrhythmias and increase digitalis toxicity; keep potassium above 4.0 mEq per liter [slides 19 and 29] |
| Potassium-sparing diuretic with an ACE inhibitor, an angiotensin receptor blocker or a potassium supplement | Hyperkalemia [slide 33]; the same added risk applies to aldosterone antagonists with a high potassium or creatinine [slide 73] |
| Diuretics with ACE inhibitors or calcium channel blockers | Synergy, because these block the kidney’s compensatory renin-angiotensin response (the recording, 1:48) |
| Sacubitril-valsartan with an ACE inhibitor | Do not combine; allow a 36-hour washout to avoid overlapping adverse effects, which Dr. Wood named as hypotension, hyperkalemia and cough [slide 81; the recording, 58:01]; the main reason, angioedema, is not on the slide (see 1.13) |
| Loop plus potassium-sparing diuretic | Used on purpose to offset potassium loss [recording, 21:54] |
The slides name no drug-herb interactions and no drug-food interaction, and none for digoxin. Not on the slides: amiodarone, verapamil, quinidine and macrolide antibiotics such as clarithromycin raise digoxin levels, and St. John’s wort lowers them. The recording adds the salt-substitute point: salt substitutes are potassium chloride and add to hyperkalemia risk with potassium-sparing diuretics, ACE inhibitors and angiotensin receptor blockers.
Protocols and monitoring (Objective 9)
| Topic | What the slides give |
|---|---|
| Daily weight | Worsening fluid overload shows up as weight gain over several days; heart failure patients on a loop diuretic are watched this way [slide 52] |
| Potassium and kidney function | ACE inhibitors raise potassium and can impair kidney function [slide 56]; potassium above 4.0 mEq per liter with a thiazide and digitalis [slide 29]; spironolactone is not for a potassium above 5 or a serum creatinine above 2.5 [slide 73] |
| Beta blockers in heart failure | Start low in a stable patient, titrate up slowly, monitor for worsening heart failure signs and symptoms [slide 58] |
| Digoxin level | Target 0.5 to 1 nanogram per milliliter; higher levels may do worse [slide 65]; Dr. Wood said he is probably not going to quiz the number, so know that a level is checked, especially when toxicity is suspected |
| Short-term intravenous agents | Milrinone, inamrinone, dobutamine and dopamine are started in hospital for acute decompensation and stopped as the patient stabilizes [slides 76 and 77] |
| Sodium and fluid restriction | [slide 51] |
| Washout | 36 hours between an ACE inhibitor and sacubitril-valsartan [slide 81] |
Patient education (Objective 10)
- All heart failure patients: restrict sodium and fluid; weigh yourself every day and report a gain over several days, which is fluid [slides 51 and 52].
- Loop and thiazide diuretics: expect volume depletion and dizziness; photosensitivity and rash; report hearing problems with a loop diuretic; gout and high blood sugar are possible; potassium and magnesium need monitoring [slides 18, 26 and 27].
- Potassium-sparing diuretics, aldosterone antagonists, ACE inhibitors, angiotensin receptor blockers and sacubitril-valsartan: be cautious with potassium supplements and salt substitutes (potassium chloride) [slides 33, 56 and 81; the salt-substitute point is from the recording].
- Spironolactone: breast enlargement in men and menstrual irregularity in women are the reason to ask for eplerenone [slide 38].
- Carbonic anhydrase inhibitors: drowsiness [slide 43].
- Beta blockers in heart failure: they are started low and increased slowly, and the patient should report worsening heart failure symptoms [slide 58].
- Digoxin: report nausea, loss of appetite, yellow-green halos or blurred vision, confusion and a slow pulse, which are signs of toxicity [slides 68 to 70].
- Ivabradine: a transient brightness in part of the visual field, halos or multiple images can happen and may resolve on their own [slide 80].
- SGLT2 inhibitors: dizziness from low blood pressure and fungal infections of the genitourinary tract [slide 82].
| Relieves symptoms only | Prolongs survival (mandatory or necessary add-on) |
|---|---|
| Loop diuretics (and thiazides, where strong enough) [slides 52 and 53]; digoxin [slide 66] | ACE inhibitors or angiotensin receptor blockers [slide 54]; carvedilol, metoprolol succinate and bisoprolol [slide 57]; spironolactone and eplerenone in advanced failure [slide 73]; sacubitril-valsartan [slide 81]; SGLT2 inhibitors [slide 82] |
- Milligram doses. Doses are not tested in this course. The deck gives none.
- The digoxin target level. It is stated in 1.10 because the slide gives it, but Dr. Wood said he is probably not going to quiz it.
- Percentages and numbers. The sodium percentages by nephron site, the 20 to 25 percent and 4 liters of loops, the 1 to 2 liters of thiazides, the 80 to 90 percent bicarbonate figure, 50 to 60 percent of heart failure caused by ischemia, the 45 percent ejection fraction, the sodium and fluid limits, the weight-gain figure, 6 to 8 weeks of beta blocker titration and the 36-hour washout are stated for recognition. Learn the direction and the idea, not the figure.
- Where the deck is wrong or loose, a “Deck versus truth” box says so: slides 9 and 10 (nephron), 21 and 42 (side actions), 23 (uric acid), 25 (obesity), 28 (clearance), 30 (antiporters), 36 (calcium, lag), 37 against 73 (class IV or III and IV), 38 (partial agonist), 46 (45 percent), 51, 52 and 58 (numbers), 62 (calcium exchanger), 67 (first line), 68 against 80 (the two kinds of halos), 71 (hyperkalemia), 72 (antibody wording), 77 (dopamine and the kidney), 79 (ivabradine mortality), 81 (washout reason) and 82 (fungal infection site). The boxed warnings that the slides omit (loop diuretics, amiloride, triamterene, sacubitril-valsartan, dopamine, ACE inhibitors, metoprolol) are flagged in the boxes above and are not on the slides.
- Slides not represented: 1 (title), 2 (the deck’s own objectives), 3, 44 and 78 (section dividers) and 83 (“Questions?”).