A27. Potassium excreting (wasting) diuretics

Question 1

What are diuretics?

Answer 1

Diuretics increase diuresis (excretion of salt and water)

Question 2

List the classes of Potassium excreting (wasting) Diuretics.

Answer 2

1. Carbonic anhydrase inhibitors: work on PCT. rarely used.
2. Loop diuretics: act on TAL. main indication is edema.
3. Thiazides:act on DCT. mainly indicated in HTN, mild edema.

Question 3

List the Carbonic anhydrase inhibitors.

Answer 3

1. Acetazolamide
2. Dorzolamide

Question 4

List the Loop Diuretics.

Answer 4

1. Furosemide
2. Torsemide
3. Bumetanide
4. Piretanide
5. Ethacrynic acid
6. Indacrinone
7. Ticrynafen

Question 5

List the Thiazide diuretics.

Answer 5

1. Hydrochlorothiazide (most important)
2. Indapamide
3. Clopamide (less important)
4. Chlorthalidone (longer duration) (less important)

Question 6

What are the contraindications of taking Carbonic Anhydrase?

Answer 6

1. Allergy: from sulfonamides, other sulfa drugs.
2. Pregnancy
3. Liver cirrhosis: ammonia is not excreted in alkaline urine!

Question 7

What is the MOA of Thiazide diuretics?

Answer 7

Thiazide diuretics inhibit Na+/Cl- cotransporter in the DCT. What happens:

1. The driving force of the Sodium-calcium exchanger driven by sodium concentration gets higher and more Ca2+ leaves the cells to be reabsorbed.
2. The decreased Na reabsorption from collecting duct will lead to osmotic diuresis (moderate).

Question 8

What are the indications for Carbonic Anhydrase (Acetazolamide)?

Answer 8

1. Broad-spectrum anti-epileptic: bc metabolic acidosis increases epileptic threshold. (MOA also seen in Sulthiam, Topiramate).
2. Urine alkalinization: useful to excrete weak acid drugs, can accelerate the excretion. However, in order to maintain the excretion you need to also provide additional bicarbonate to the pt.
3. Meniere syndrome: high pressure in semicircular canals → vertigo. furosemide is more likely to be used.
4. Acute mountain disease: hypoxia → hyperventilation → respiratory alkalosis. Can treat this with some induced metabolic acidosis. (don’t use the paper bag trick, hypoxia will be more severe)
5. Treat metabolic alkalosis from other medications: including some of the other potassium-wasting diuretics. Generally NOT used for edema but maybe also glaucoma, intracranial hypertension (decreases CSF).

Question 9

What are the side effects of taking Carbonic Anhydrase?

Answer 9

1. Hyperchloremic metabolic acidosis with normal anion gap
2. Hypokalemia: important side effect. Must check K+ level often with diuretics. lose sodium, and so in the distal nephron the body tries to save some Na by exchanging it for some potassium.
3. Secondary hyperaldosteronism - sodium concentration gets lower, and so aldosterone secretion increases. (note CHF also causes secondary hyperaldosteronism)
4. Calcium phosphate kidney stone due to alkaline urine
5. Interstitial nephritis
6. Type 2 renal tubular acidosis due to prox tubule bicarb reabsorption.

Question 10

What are the side effects of taking Loop diuretics?

Answer 10

• Side effects: o Hypokalemia: esp in CHF when you use a lot • May cause metabolic alkalosis o Transient deafness.. warning on meds - don’t mix loop diuretics with ototoxic agents (aminoglycosides)! although the mechanisms are totally different.. o hyponatremia, hypovolemia, hypotension

Question 11

What is the MOA of Loop diuretics?

Answer 11

Loop diuretics inhibit Na/K/2Cl symporter in the TAL. What happens:

1. Lose salt, and so water follows with it. This disrupts the concentration gradient.
2. Despite presence of ADH in collecting duct, it cannot compensate and won’t save much water. This causes massive diuresis.
3. Changes PCT luminal potential from positive to negative, and so the K+ reabsorption in the PCT is lost. K+ remains in filtrate and is excreted.
4. Macula densa senses low Na+ flow, increases prostaglandin synthesis which dilates renal vessels and increase RBF (the only diuretics that do this! important if renal function is damaged).

Question 12

What are the indications for taking Thiazides?

Answer 12

Indications: o CHF: regularly-used daily administration from NYHA stage 2. • drug helps to keep volume lower, heart may work better • dose is 25-100mg of hydrochlorothiazide (need to know) o hypertension: for mild/moderate HTN • 12.5mg hydrochlorothiazide (sheet says 6.25-25mg). oral admin. • decreases blood volume, but only in the first 2 weeks of tx • afterwards the diastolic pressure remains lower due to vasodilation. overall lower sodium level, including intracellularly. sodium gradient between extracellular and intracellular space ↑. *smooth muscle therefore loses some calcium and relaxes, causing vasodilation. • seems more efficient in older patients than younger ones. β blockers better for young pts. • if you can combine ACE-I and thiazide → pharmacodynamic synergism, can balance potassium concentration → less side effects. can also combine with ARB • indapamide is only used for HTN o idiopathic nephrogenic hypercalciuria: thiazides → calcium reabsorption enhanced, less Ca2+ in urine • thiazide diuretic is not final solution, but can save some calcium o nephrogenic diabetes insipidus: seems like it would worsen this condition, but actually helps • resistance to ADH → hypernatremia → strong thirst. pts drink more, urinate more. • thiazides decrease sodium → feels less thirsty, lower urine output o osteoporosis: increased calcium reabsorption

Question 13

What are the side effects of taking Thiazides?

Answer 13

• side effects: o hypokalemia: kidney attempts to save some Na+ by exchanging for K+ o metabolic alkalosis (“contraction alkalosis” – hypovolemia → aldosterone → H+ excretion + HCO3- reabsorption o hypotension o hyponatremia: more Na than H2O is lost o hypersensitivity: sulfa (rare) o *increased cholesterol level: not good for LDL. o *impaired glucose tolerance: Diabetes mellitus patients should probably not have thiazides. o impotency in men o rarely: interstitial nephritis, hemolytic anemia, acute pancreatitis, pulmonary edema, jaundice • but known bc so many people are on thiazides

Question 14

Pharmacokinetics of Thiazides?

Answer 14

interactions: lithium. thiazides decrease clearance of Li → serum [Li] ↑. Because Li causes nephrogenic DI, must avoid using thiazide diuretics as a treatment.

Question 15

Pharmacokinetics of Loop diuretics?

Answer 15

o Sulfonamide types: something about uric acid excretion

• Furosemide: very common

▪ acute from LV failure: 40 mg IV, repeat in 1 hour

▪ chronic: 20mg oral daily

• Others: less important, don’t really need to know.. maybe just 1 name

▪ Torsemide,Piretanide,Bumetanide

o Etacrynic acid types: inhibits uric acid reabsorption. more uric acid excretion (useful in gout)

• Ethacrynic acid: also need to know this one. good if allergy to furosemide (Kaplan)
• Indacrinone, Ticrynafen Interactions: NSAIDS. COX inhibition interferes with PG ↑ effect, and this leads to ↓ diuretic action

Question 16

What are the indications for starting loop diuretics?

Answer 16

1. *Acute left ventricular failure: furosemide is life-saving pulmonary edema drug. IV 40mg → pt immediately feels better. diuresis increases within few minutes • furosemide has some other not-well understood mechanism to cause massive venodilation → preload ↓ → volume in heart ↓ → weak LV can still pump
2. CHF: can be good, although regular use of loop diuretic probably not good. thiazide diuretic is preferred for chronic bc they are weaker and keep sodium level lower in the long run. furosemide can be used intermittently for thiazide-resistant edema.
3. Hypertension: but be careful with this. furosemide is short-acting. usually only used if the kidneys are impaired and so pt cannot have a thiazide diuretic. o Acute renal failure: • ATN → obstruction → anuria. If you can wash through the nephron before the complete occlusion, maybe you can prevent dialysis. However literature says there’s no good evidence that this works, but still it’s attempted. It does improve renal blood flow so maybe could help in that way.
4. Chronic renal failure: • uremia: worst problem is hyperkalemia. so helps excrete K+, furosemide is strongest potassium-excreting agent. • sometimes need higher doses, up to 500mg o Hypercalcemia: promptly reduced by furosemide. should also give extra water to the pt o Excretion of other alkaline metals: especially Barium. doesn’t work with lithium. • Halogenides can also be excreted, as well as iodide. o Hypervolemia: o Gout: only ethacrynic acid, not furosemide o Meniere o [Sketchy said use for ascites, but someone’s notes had Kato saying CI in cirrhosis]

Question 17

What is the MOA of Carbonic Anhydrase?

Answer 17

1. 1. HCO3- combines with H+ → H2CO3 → H2O + CO2.
2. 2. Carbonic anhydrase can speed up this process 1000x. Net result is sodium-bicarbonate reabsorption. By blocking CA, more bicarbonate is excreted. More sodium excretion follows with it, and so more of a diuretic effect occurs. [specifically due to less bicarbonate in the cell → inhibition of Na/H exchanger that reabsorbs some sodium] o Urine pH also increases, can be higher than 8. o metabolic acidosis develops, less and less bicarbonate is available so the diuretic effect decreases as more bicarbonate is lost. As you reach low concentrations, most bicarbonate is reabsorbed before the collecting duct, and so the diuretic effect is basically gone. More pronounced metabolic acidosis → less diuretic effect. Urine eventually becomes acidic again. o chloride is reabsorbed (hyperchloremic metabolic acidosis)

Question 18

How do diuretics increase diuresis?

Answer 18

1. extra-renal: don’t directly influence renal processes, but change blood flow, GFR, ADH secretion. • e.g. caffeine, alcohol. not used as medications o renal: directly influence renal functions / reabsorption processes • sodium excreting drugs: larger group • water excreting drugs

Question 19

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Answer 19

Main categories and drug names • Na excreting drugs: • K+ wasting diuretics: o Carbonic anhydrase inhibitors - work on PCT. rarely used • Acetazolamide, Dorzolamide o Loop diuretics - act on TAL. main indication is edema • Furosemide, Torsemide, bumetanide, piretanide • Ethacrynic acid, indacrinone, ticrynafen o Thiazides - act on DCT. mainly indicated in HTN, mild edema • Hydrochlorothiazide, Indapamide, Clopamide, Chlorthalidone • K+ sparing diuretics - act on collecting tubules. Used in combo with K+ wasting diuretics o Direct Na transporter inhibitors: • Amiloride, triamterene o Aldosterone receptor antagonists • Spironolactone, eplerenone, canrenone • Water excreting drugs: • Osmotic diuretics o Mannitol, glycerin • ADH antagonists o Tolvaptan, conivaptan

Question 20

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Answer 20

Physio review: • Glomerulus: 180L filtered per day • PCT: 66% of sodium reabsorbed here o Na/H pump o Bicarbonate reabsorption o most diuretics are weak acids, excreted before they can exert all their actions bc they usually act from the luminal side. • most diuretics excreted by weak acid transporter here can compete with uric acid! increase uric acid level in blood. **so gout is often a contraindication. o Glucose transporter (SGLT2) is here, some drugs act on this • thin descending limb: urine concentration region o water permeable, but ions are not permeable • thick ascending limb: 20% Na reabsorbed o Na/K/2Cl symporters to reabsorb the ions. essential to maintain concentration gradient. o has slightly positive lumen potential, and this is enough to drive out Ca2+ and Mg2+ • DCT: 10% Na reabsorbed o connecting to afferent arteriole with macula densa. senses sodium concentration to control renal blood flow (less sodium → prostaglandins → dilate renal arteriole to increase flow) - important bc drugs that block Na/K/2Cl transporter can “deceive” macula densa o reabsorption: has NaCl transporter, PTH-sensitive Ca2+ transporter, and HCO3- transporter • collecting tubule: 3% Na reabsorbed o Na reabsorption and Na/K ATPase • activity is aldosterone dependent! aldosterone increases sodium reabsorption, K excretion. aldosterone is the only hormone that gets rid of potassium. o ADH-dependent water reabsorption. ADH → concentrated urine.

Question 21

What are the indications of Dorzolamide?

Answer 21

1. This is a less important carbonic anhydrase drug.
2. Local drug, not used as a diuretic.
3. Used as an eyedrop for glaucoma bc aqueous humour production is CA-dependent.