Lecture 9 (diuretics and heart failure drugs), Adam Wood Pharm.D. DABAT. Lectures 10 to 13 are added as delivered. ★ = professor emphasized (from the recording); a star only sets weight and adds no fact the slides lack. Rows marked FLAG say where a slide and the pharmacology disagree.
| Term | What you need to know |
|---|---|
| ★★ Mortality or symptoms? | His standing rule for this whole lecture: good for MORTALITY → the patient should be on it no matter what; good only for SYMPTOMS → may not be needed all the time. Symptoms only: diuretics and digoxin. Survival: angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), the three beta blockers, aldosterone antagonists in advanced failure, sacubitril-valsartan, sodium-glucose cotransporter 2 inhibitors. |
| ★★ Know every drug's effect on potassium | “You can kill somebody very easily with potassium.” LOWER it: loop diuretics, thiazides, carbonic anhydrase inhibitors. RAISE it: potassium-sparing diuretics, aldosterone antagonists, angiotensin-converting enzyme inhibitors, sacubitril-valsartan. Several drugs on one patient: work out which way the total falls. |
| ★ Where salt goes, water follows | Diuretics work by blocking sodium (and usually chloride) reabsorption somewhere along the nephron, and water leaves with it. Too much fluid: volume overload and pulmonary edema. Too little: volume depletion and cardiovascular collapse. |
| ★ Digoxin level | Digoxin has a very narrow therapeutic index and its level is checked. The slide gives a target range; he said he is probably not going to quiz the specific level. Know the narrow index, not the number. |
| ★ Xanthopsia is the digoxin clue | Yellow-green vision with halos around lights is the classic clue to digoxin toxicity; in his words it is “pathognomonic,” nothing else does that. (Ivabradine also causes halos and brightness, but without the yellow-green tint.) It means check a level right away. |
| ★ Heart failure decision shape | His rule of thumb: hypertensive patient in decompensated failure → milrinone (it dilates vessels). Hypotensive patient → dobutamine or dopamine. Ask what the blood pressure is. |
| Doses | This site leaves milligram amounts out; doses are not tested in this course, per the earlier lectures. Timings, routes and clinical thresholds are kept. |
| Term | What you need to know |
|---|---|
| Why diuretics are dangerous | Diuretic = a drug that increases urine flow and/or sodium chloride excretion. A sustained imbalance of sodium chloride intake against loss is fatal: too much gives volume overload and pulmonary edema; too little gives volume depletion and cardiovascular collapse. |
| ★ Diuretic braking | The kidneys receive about 22% of the cardiac output and fight back against volume loss: sympathetic nervous system and renin-angiotensin-aldosterone system activation, lower blood pressure (less pressure natriuresis), antidiuretic hormone up, renal cell hypertrophy. He called the kidneys “divas.” This is why diuretics show synergy with angiotensin-converting enzyme inhibitors and calcium channel blockers, which blunt those compensations. |
| Proximal tubule | 60 to 70% of the filtrate is reabsorbed here (glucose, amino acids, organic solutes; weak acids and bases are secreted into the lumen). Carbonic anhydrase inhibitors work here. |
| Loop of Henle | Concentrates the urine. Descending limb: water leaves the lumen. Ascending limb: 25% of sodium reabsorbed, impermeable to water. Loop diuretics work here. |
| Distal tubule | About 5% of sodium reabsorbed. Thiazide diuretics work here. |
| Collecting duct | 2 to 3% of sodium reabsorbed; aldosterone and antidiuretic hormone act here (antidiuretic hormone opens the water channels). Potassium-sparing diuretics work here. Aldosterone adds sodium channels and pump activity, so sodium is reabsorbed and potassium lost. |
| ★ Order of potency | Loops (inhibit 20 to 25% of sodium chloride reabsorption) > thiazides (up to 5%) > potassium-sparing diuretics and aldosterone antagonists (2 to 3%) > carbonic anhydrase inhibitors (the “wimpiest”; the early 5% fades to 1 to 3% after 3 to 5 days). He presented the classes in descending order of potency. |
| Term | What you need to know |
|---|---|
| ★ Agents and mechanism | Furosemide, bumetanide, torsemide, ethacrynic acid (the one that breaks the naming pattern). They inhibit the sodium-potassium-2 chloride carrier on the luminal membrane of the thick ascending limb. |
| Major actions | Inhibit sodium chloride reabsorption by 20 to 25%; urine output up to 4 liters a day; more potassium, calcium and magnesium excreted → hypokalemia, hypocalcemia, hypomagnesemia. |
| ★ Works when the kidneys do not | Loops remain effective when creatinine clearance is below 30 milliliters a minute. Urine flow does not mean the kidneys are working well. |
| ★ Indications | Pulmonary edema, nephrotic syndrome, cirrhosis of the liver (ascites), hypercalcemia (with saline), heart failure, renal failure or insufficiency, hypertension (volume-driven; not good for chronic hypertension). |
| ★ Adverse effects | Volume depletion; hypokalemia (arrhythmias); hyperglycemia; contraction alkalosis; hyperuricemia (gout); ototoxicity (hair cells in the cochlea); hyponatremia (seizures); allergic reactions (rash, photosensitivity); azotemia (blood urea nitrogen rises). Loops are the most potent, so they carry the most of these. |
| Why the side effects happen | Hyperglycemia: low potassium impairs insulin release; catecholamine release; insulin resistance. Gout: volume contraction concentrates uric acid and less is excreted. Metabolic alkalosis: volume depletion plus enhanced hydrogen ion secretion (the major factor). Mild hyperlipidemia from sympathetic activity. Reflex renin, aldosterone and antidiuretic hormone rise. |
| Vasodilation | Loops also dilate vessels: they stimulate prostaglandin E2 (blocked by non-steroidal anti-inflammatory drugs), plus a direct muscle-relaxing effect of unknown mechanism. |
| ★ Interactions | Non-steroidal 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: hypokalemia plus hypomagnesemia gives arrhythmias. |
| FLAG: boxed warning | FDA boxed warning, not on the slide: furosemide, bumetanide and ethacrynic acid carry a boxed warning for profound diuresis with water and electrolyte depletion when given in excess. Torsemide does not. |
| Term | What you need to know |
|---|---|
| ★ Agents and mechanism | Chlorothiazide, hydrochlorothiazide, chlorthalidone, metolazone, indapamide. They inhibit the sodium/chloride transporter in the distal convoluted tubule (major action). |
| Major actions | Inhibit up to 5% of filtered sodium chloride; urine output 1 to 2 liters a day; more potassium and magnesium excreted; LESS calcium excreted (more calcium reabsorbed in the proximal and distal tubules). Acutely lower the glomerular filtration rate. |
| ★ The calcium paradox | Thiazides keep calcium from being excreted, so they help patients with calcium oxalate kidney stones yet can cause a small rise in serum calcium. Less calcium in the urine means less to crystallize. Loops do the opposite. |
| ★ Hypertension | Cheap, old and well tolerated. He described them as a useful second- or third-line add-on (current hypertension guidelines still list thiazides among first-line choices). Works best in elderly patients, African American patients and sodium-retentive states. Short term: lower blood volume and cardiac output; chronic: vessel relaxation, less sodium “waterlogging” of vessel walls, lower total peripheral resistance. Low-dose thiazides are preferred, with few adverse effects. |
| Other indications | Hypertension, renal failure, cirrhosis of the liver, congestive heart failure, renal calcium stones. |
| ★ Adverse effects | Volume depletion with reflex sympathetic and renin-angiotensin-aldosterone activation; hypokalemia; metabolic alkalosis; hyperuricemia (gout); hyperglycemia (less insulin); hypercalcemia; hyperlipidemia (a modest rise in low-density lipoprotein); rash, photosensitivity; dizziness, headache, weakness, restlessness; sexual dysfunction; constipation. Much of the loop list, only milder; the differences are that thiazides RAISE calcium and are not ototoxic. |
| ★★ Metolazone | Thiazides lose effect at low creatinine clearance, but metolazone still works. His mnemonic: “metolazone could make a rock pee”. (FLAG, see the last topic: do not treat “thiazides do not work in kidney failure” as absolute.) |
| ★ Interactions | Non-steroidal anti-inflammatory drugs block prostaglandins and weaken the natriuretic action. Digitalis toxicity rises with potassium loss: keep potassium above 4.0 milliequivalents per liter. |
| Term | What you need to know |
|---|---|
| ★ Potassium-sparing: agents and mechanism | Amiloride and triamterene block luminal sodium channels in the collecting duct, inhibiting 2 to 3% of sodium chloride reabsorption and decreasing the gradient for potassium secretion. Modest increase in urine flow. Combination products with hydrochlorothiazide exist. |
| Potassium-sparing: use | Same indications as the others but much less natriuretic and diuretic effect; most often combined with another diuretic or an antihypertensive. A loop plus a potassium-sparing drug offsets the potassium loss. |
| ★ Potassium-sparing: adverse effects | Hyperkalemia (the major difference from other diuretics); caution with angiotensin-converting enzyme inhibitors, angiotensin blockers and potassium supplements; glucose intolerance in diabetes; megaloblastic anemia (triamterene); azotemia (amiloride). Salt substitutes are usually potassium chloride, a hidden potassium source. |
| FLAG: boxed warning | FDA boxed warning, not on the slide: amiloride and triamterene both carry a boxed warning for hyperkalemia. |
| Aldosterone: normal action | Aldosterone binds its receptor, moves to the nucleus and drives protein synthesis: more sodium channels, more sodium-potassium pump activity, more energy production in the distal tubule. |
| ★ Aldosterone antagonists: agents and mechanism | Spironolactone, eplerenone. They bind the steroid receptor but do not move to the nucleus, so they work best when aldosterone is high. Block 2 to 3% of sodium chloride reabsorption and reduce potassium loss; modest effect on lipids, glucose and uric acid. |
| ★ Aldosterone antagonists: indications | Primary aldosteronism, hypertension, heart failure, edematous conditions, cirrhosis (secondary hyperaldosteronism), nephrotic syndrome. Heart failure is the big one: advanced (class III or IV) failure; see FLAG. |
| ★★ Aldosterone antagonists: adverse effects | Hyperkalemia and mild acidosis; nausea, vomiting, gastrointestinal upset; sex-hormone effects of spironolactone (it blocks the androgen receptor; see FLAG) → gynecomastia in men; menstrual irregularities in women (the slide also lists testicular atrophy). Eplerenone has less effect on androgen receptors: switch to it if the patient complains of breast development or menstrual problems. |
| Term | What you need to know |
|---|---|
| ★ Agents and mechanism | Acetazolamide, dichlorphenamide, methazolamide. Inhibit carbonic anhydrase: bicarbonate absorption in the proximal tubule falls by 80 to 90%, less hydrogen ion production, less hydrogen/sodium exchange. Bicarbonate is trapped in the tubule and passed out (alkaline urine, a mild acidification of the patient). |
| Weak and self-limiting | Short term sodium and potassium excretion rises about 5%, but after 3 to 5 days the effect shrinks to 1 to 3% because the rest of the nephron compensates. The wimpiest diuretic. |
| ★ Other uses | Glaucoma (less bicarbonate in the ciliary body: dorzolamide, brinzolamide), epilepsy (metabolic acidosis, central nervous system effects), mountain sickness (acidifies the blood so the patient breathes faster). |
| ★ Adverse effects | Metabolic acidosis (the opposite of the contraction alkalosis of other diuretics), potassium depletion, drowsiness. |
| Term | What you need to know |
|---|---|
| Causes | Ischemic heart disease and myocardial infarction (50 to 60% of cases), hypertension, idiopathic dilated cardiomyopathy; other cardiomyopathies (alcoholic, viral, hypertrophic); drug induced. |
| ★ Systolic dysfunction | Decreased contractility (loss of muscle mass, left ventricular hypertrophy, dilated cardiomyopathies), assessed as a reduced ejection fraction (the slide says below 45%; current practice says 40% or less). |
| ★ Diastolic dysfunction | Impaired relaxation: thicker, stiffer ventricles; ischemia impairs removal of calcium back into the sarcoplasmic reticulum; less filling means less cardiac output. Symptoms with a preserved ejection fraction. |
| Compensatory response | More preload (sodium and water retention), vasoconstriction, tachycardia and more contractility (sympathetic activation), left ventricular hypertrophy. A vicious cycle that therapy has to interrupt. |
| Precipitants of decompensation | Lack of compliance (diet or medicines), uncontrolled hypertension, arrhythmias, inadequate therapy, inappropriate medicines or fluid overload; also acute anginal chest pain, pulmonary infection, emotional stress. |
| Non-drug therapy | Restrict dietary sodium and fluid (the slide gives 1 to 3 grams of sodium and under 2 liters of fluid a day); physical activity may improve function. |
| Term | What you need to know |
|---|---|
| ★★ Diuretics in heart failure | Loops are the mainstay; thiazides are not potent enough for most patients. They cut sodium and water retention and so preload, for symptomatic benefit only: no evidence they slow progression or lower mortality, and not mandatory (some patients take them as needed). Daily weights detect fluid overload. |
| ★ Angiotensin-converting enzyme inhibitors: what they do | Lower preload, afterload and sympathetic activation; reduce left ventricular hypertrophy, dilation and remodeling; slow progression; lower mortality. Hemodynamics, exercise tolerance, symptoms, admissions, progression and survival all improve. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have to be mandatory. |
| Angiotensin-converting enzyme inhibitor problems | Renal function impairment, hypotension, raised serum potassium, cough, angioedema. Loops lower potassium, angiotensin-converting enzyme inhibitors raise it: monitor. |
| ★★ Beta blockers: only three | Beta blockers were classically considered contraindicated in heart failure. The ones with a mortality benefit are carvedilol, metoprolol succinate (the extended-release form) and bisoprolol; the others have not shown it. |
| ★ Beta blockers: low and slow | Patient stable before starting; in hospital preferred; very low starting doses; titrate up slowly (the slide says over 6 to 8 weeks total); monitor for worsening heart failure signs and symptoms. Heart rate and contractility fall, so a rushed start can decompensate the patient. |
| Beta blockers: benefit and place | Better exercise tolerance, a higher ejection fraction, slower progression, fewer hospitalizations, less need for transplant, lower mortality. First line in class II to IV heart failure; patients should be on an angiotensin-converting enzyme inhibitor AND a beta blocker irrespective of symptoms. |
| Term | What you need to know |
|---|---|
| Structure and source | Lactone ring and steroid nucleus are essential for activity; the sugar molecules influence absorption, half-life and metabolism. |
| ★ Mechanism | Inhibits the sodium-potassium ATPase → intracellular sodium rises → calcium enters through the sodium/calcium exchanger → force of contraction rises (the older, inotropic mechanism). The newer one is neurohormonal: less sympathetic and more parasympathetic activity, baroreflex resensitized, renin-angiotensin-aldosterone system down, so the heart rate falls (more parasympathetic effect on the atrioventricular node) and cardiac output rises. |
| ★ Narrow therapeutic index | There is little gap between an effective and a toxic level, and it is one of the few heart failure drugs whose level is checked. Target range on the slide: 0.5 to 1 nanogram per milliliter; higher concentrations are associated with worse outcomes in heart failure. He will probably not quiz the number. |
| ★★ Benefit: symptoms, NOT survival | Better symptoms, exercise tolerance and quality of life; fewer hospitalizations; NO SURVIVAL BENEFIT; no evidence of slowed disease progression. So it is not mandatory like angiotensin-converting enzyme inhibitors and beta blockers. |
| ★ Place in therapy | Symptomatic patients already on optimal angiotensin-converting enzyme inhibitor/beta blocker and diuretic therapy; can be used for rate control in atrial fibrillation with heart failure; considered in symptomatic systolic dysfunction. (FLAG: the slide says “first line” for the atrial fibrillation case; that is overstated.) |
| ★ Toxicity | Gastrointestinal: anorexia, nausea. Visual: blurred vision, photophobia, xanthopsia, yellow-green halos around lights. Central: delirium, fatigue, confusion, dizziness, abnormal dreams. Cardiac: nodal slowing (longer PR interval, shorter QT interval, depressed ST segment), bradycardia, digoxin-induced afterdepolarization (the tracing shows premature ventricular beats and ST depression). |
| ★★ Contraindications and risk factors | Advanced atrioventricular block; severe bradycardia or sick sinus syndrome; premature ventricular beats and ventricular tachycardia; Wolff-Parkinson-White syndrome. Toxicity is more likely with hypokalemia, hypomagnesemia and hypercalcemia: loops and thiazides lower potassium and magnesium, so a patient on digoxin plus a diuretic needs electrolyte monitoring. (FLAG: slide 71 prints hyperkalemia; see the last topic.) |
| ★ Antidote: digoxin immune Fab | An antibody fragment made by immunizing healthy sheep with digoxin coupled to human serum albumin; its affinity for digoxin is higher than digoxin's affinity for the sodium-potassium ATPase, so it rapidly reverses toxicity. It can unmask what digoxin was treating (atrial fibrillation or heart failure decompensation). |
| Term | What you need to know |
|---|---|
| ★ Aldosterone antagonists in heart failure | Spironolactone lowers mortality in advanced (class III or IV) heart failure (the slide says “grade”) by neurohormonal inhibition and slowed left ventricular remodeling. Not eligible if potassium is above 5 or serum creatinine above 2.5. Gynecomastia in men (about 10%; may respond to a lower dose); eplerenone: little or no gynecomastia. |
| Milrinone and inamrinone | Phosphodiesterase type 3 inhibitors (cyclic adenosine monophosphate up): direct stimulation of contraction plus balanced arterial and venous dilation → lower afterload, higher cardiac output. Approved for short-term intravenous use in acute decompensated heart failure; long-term use carries higher mortality and morbidity than placebo. Adverse: thrombocytopenia (milrinone less), ventricular arrhythmias. |
| ★ Dobutamine and dopamine | Dobutamine: selective beta-1 agonist, intravenous; stimulates force of contraction more than rate; short-term use to stabilize patients. Dopamine: intravenous, acts through dopamine and beta receptors. Unlike milrinone they are not vasodilators, so they suit a hypotensive decompensation; milrinone suits a hypertensive one. |
| ★ Ivabradine | Blocks the hyperpolarization-activated cyclic nucleotide-gated channel (pacemaker current in the sinoatrial node): lowers heart rate without affecting contractility. For patients maxed out on beta blockers who are in normal sinus rhythm with a heart rate above 70; fewer hospitalizations and heart failure deaths. Adverse: atrial fibrillation risk, symptomatic bradycardia, visual impairment (phosphenes, halos, may resolve). Contraindications resemble beta blockers: hypotension, heart block, pacemaker. |
| ★ Sacubitril-valsartan | Sacubitril is a neprilysin inhibitor (neprilysin normally degrades natriuretic peptide, bradykinin and other vasoactive peptides): vasodilation, natriuresis, diuresis, less myocardial growth and fibrosis. Formulated with valsartan, an angiotensin receptor blocker. Reduces cardiovascular death and hospitalization. Never with an angiotensin-converting enzyme inhibitor: 36-hour washout. Common adverse: hypotension, hyperkalemia, cough, renal insufficiency. |
| FLAG: sacubitril-valsartan | FDA boxed warning, not on the slide: fetal toxicity. A history of angioedema is also a contraindication. |
| ★ Sodium-glucose cotransporter 2 inhibitors | Dapagliflozin, empagliflozin. For stable chronic heart failure with reduced ejection fraction: reduce mortality and hospitalizations. Originally for diabetes: the kidneys stop reabsorbing glucose. Risks: hypotension and fungal infections of the genitourinary tract (the slide says “fungal urinary tract infections”). A “necessary add-on” for heart failure patients. |
| Term | What you need to know |
|---|---|
| FLAG: digoxin and potassium | Slide 71 lists hyperkalemia as a digoxin contraindication, and he said “hyperkalemic” once. Slides 19 and 29 (and the pharmacology) say the opposite: hypokalemia, hypomagnesemia and hypercalcemia raise toxicity risk. Learn hypokalemia. |
| FLAG: descending limb | The descending limb is permeable to water (the slide: “water leaves lumen”); he misspoke once. The thick ascending limb is the impermeable one. |
| FLAG: thiazides and calcium | Slide 24 lists hypercalcemia among thiazide indications. Thiazides raise serum calcium and lower urinary calcium: they treat calcium stones, not hypercalcemia (loops with saline do). |
| FLAG: thiazides at low clearance | Slide 28: thiazides are ineffective below a creatinine clearance of 30 to 40. Learn metolazone works at low clearance; do not memorize “thiazides never work in kidney disease” (newer trials show chlorthalidone works in advanced kidney disease). |
| FLAG: uric acid with thiazides | Slide 23 says thiazides increase uric acid excretion acutely; slide 26 and the clinical picture are hyperuricemia and gout. Learn hyperuricemia. |
| FLAG: aldosterone antagonists and class | Slide 37 says heart failure “class IV”; slide 73 says “grade III or IV.” Learn advanced (class III or IV) heart failure. The slide 36 lines on a 30 to 60 minute lag and on calcium excretion are not carried here. |
| FLAG: spironolactone and androgen receptors | Slide 38 calls spironolactone a “partial agonist at testosterone receptors” with “weak androgenic effects” (he repeated the partial agonist wording). Spironolactone actually BLOCKS (antagonizes) the androgen receptor, which is why it causes gynecomastia and menstrual irregularities. Hirsutism is not an adverse effect of it (the slide lists it, but spironolactone is used to treat hirsutism): do not learn it as one. |
| FLAG: antidiuretic hormone and water | Slide 10 says water movement in the distal tubule is controlled by aldosterone. Aldosterone drives sodium and potassium handling; antidiuretic hormone controls the collecting duct water channels (slides 11, 30, 34). |
| FLAG: ejection fraction and weight numbers | Reduced ejection fraction is now 40% or less (slide 46 says below 45%). The weight gain of more than 1 pound a day (slide 52) is a teaching figure: learn daily weights, and rapid gain means fluid. |
| FLAG: dopamine and the kidney | Slide 77 says dopamine infusions maintain renal function. Low-dose dopamine has not been shown to protect the kidneys; do not rely on that claim. |
| FLAG: carbonic anhydrase notes | Slide 21 (thiazides have some carbonic anhydrase activity and phosphodiesterase inhibition at high doses) and slide 42 (head injury, less swelling) are not examined points: he said not to worry about the carbonic anhydrase action. |
| Other boxed warnings (not on the slides) | FDA boxed warnings not on the slides: furosemide, bumetanide, ethacrynic acid (profound diuresis); amiloride, triamterene (hyperkalemia); sacubitril-valsartan (fetal toxicity); angiotensin-converting enzyme inhibitors (fetal toxicity); abrupt beta blocker withdrawal (metoprolol). |