Diuretics Flashcards
1
Q
Carbonic anhydrase inhibitors
A
Acetazolamide
Brinzolamide
Dorzolamide
Methazolamide
2
Q
Loop diuretics
A
Bumetanide
Ethacrynic acid
Furosemide
Torsemide
3
Q
Thiazide diuretics
A
Bendroflumethiazide Chlorothiazide Clorthalidone Hydrochlorothiazide Hydroflumethiazide Indapamide Methyclothiazide Metolazone Polythiazide Trichlormethiazide
4
Q
Potassium-sparing diuretics
A
Mineralocorticoid antagonists (Aldosterone antagonists): eplerenone spironolactone
Inhibitors of renal Na channels:
Amiloride
Triamterene
5
Q
Agents that alter water excretion
A
Osmotic diuretics:
mannitol
isosorbide
ADH antagonists: conivaptan
6
Q
Proximal tubule transporters
A
- NaHCO3, NaCl, glucose, amino acids, and other organic solutes are reabsorbed in the PCT
- K reabsorbed via paracellular pathway
- H2O passively reabsorbed
- NaHCO3 reabsorbed by the action of the Na/H exchanger in the luminal membrane
- Carbonic anhydrase is here forming H2CO3
- Na/K ATPase in basolateral membrane pumps reabsorbed Na into the interstitium to maintain low intracellular Na
- In straight segment, acid secretory systems secrete uric acid, NSAIDs, abx into the luminal fluid from the blood
7
Q
Thin descending loop of Henle
A
Water is reabsorbed
8
Q
Thin ascending loop of Henle
A
-Water impermeable, and impermeable to ions/solutes
9
Q
Thick ascending limb
A
- Reabsorbs Na and is impermeable to H2O
- NaCl reabsorption into the interstitial space dilutes the fluid
- Na/K/2Cl cotransporter establishing the ion concentration gradient in the interstitium
- K leak channels create a positive charge that pushes cations (Mg, Ca) to be reabsorbed paracellularly
10
Q
Distal convoluted tubule
A
- 10% of NaCl is reabsorbed
- impermeable to water, NaCl reabsorption further dilutes
- NaCl transported by thiazide-sensitive transporter
- Ca is passively reabsorbed in PTH influenced channels
11
Q
Collecting tubule
A
- ENaC channels to reabsorb Na
- Most important site of K secretion and where all of the diuretic induced K changes occur
- Diuretics that act upstream increase Na delivery that enhances K secretion
- Basolateral Na/K ATPase pumps Na out of cell and into interstitium while K into the cell to go into urine
- Aldosterone and ADH work here
- H is secreted by proton pumps into the urine
12
Q
Aldosterone
A
-Increases expression of ENaC and basolateral Na/K ATPase, increasing Na reabsorption and K secretion
13
Q
ADH
A
- Controls the permeability of CCT to H2O by controlling the number of AQP2 (aquaporin) that are in apical membrane
- W/o ADH, CD is impermeable to water
- ADH regulated by serum osmolarity and volume status
- Alcohol decrease ADH release and increases urine production
14
Q
Carbonic Anhydrase Inhibitors (acetazolamide) Pharmacokinetics
A
- Well absorbed orally
- Excretion by proximal tubule
- Excreted drug is unchanged
- No hepatic metabolism
15
Q
Carbonic Anhydrase Inhibitors (acetazolamide) MOA
A
- Inhibition of carbonic anhydrase eliminating NaHCO3 reabsorption in the proximal tubule
- Decreases H formation inside PCT, Increases Na and HCO3 in the lumen increasing diuresis
- Urine pH increased and body pH is decreased
- Diuretic efficacy decreases significantly over several days
- major clinical application is targeting carbonic anhydrase at other sites
16
Q
Carbonic Anhydrase Inhibitors (acetazolamide) toxicity
A
- Metabolic acidosis and bicarbonaturia form chronic reduction in HCO3 stores
- Renal stones may occur because Ca becomes less soluble as pH more alkaline
- K wasting due to increased Na in tubule
- Drowsiness and paresthesias w/ large doses
- Hypersensitivity reactions are rare but happen (fever, rashes, bone marrow suppression due to sulfonamide group)
17
Q
Carbonic Anhydrase Inhibitors (acetazolamide) contraindications
A
- Pts w/ cirrhosis: increase of urine pH decreases urinary excretion of NH4+ and may cause hyperammonemia and hepatic encephalopathy
- Pts w/ hyperchloremic acidosis or severe COPD, worsen metabolic or respiratory acidosis
18
Q
Carbonic Anhydrase Inhibitors (acetazolamide) clinical indications
A
- Rarely used as diuretics
- Glaucoma: reduces aqueous humor formation and decreases intraocular pressure, topical formations
- Urinary alkalization (enhance excretion of uric acid, cystine), metabolic alkalosis (excessive use of diuretics in severe heart failure), acute mountain sickness, and adjuvants in epilepsy
19
Q
Loop diuretics (Furosemide and ethacrynic acid) Pharmacokinetics
A
- Rapidly absorbed orally, but some have IV forms
- Eliminated by the kidney by glomerular filtration and tubular secretion
- Act on luminal side of the tubule
- Loop diuretic half-life is associated with renal function
- Coadministration with other weak acids results in reduction in loop diuretic secretion
20
Q
Loop diuretics (Furosemide and ethacrynic acid) MOA
A
- Inhibition of the luminal Na/K/2Cl cotransporter in the thick ascending limb of the loop of Henle stopping all of the ion transport here
- Increase the excretion of K and titratable acid due to the delivery of Na and H to the DCT and CCT (body pH increases)
- Induce synthesis of prostaglandins
- Cause increase of RBF in vascular beds
- Some are weak inhibitors of carbonic anhydrase
21
Q
Loop diuretics (Furosemide and ethacrynic acid) toxicity
A
- Can cause hyponatremia, reduce GFR, circulatory collapse, thrombohemolytic episodes, and hepatic encephalopathy in pts w/ liver disease
- Hypokalemic metabolic alkalosis due to increased K and H secretion (corrected by K+ replacement)
- Hyperuricemia can cause gout
- Dose-related hearing loss in pts w/ diminished renal function
- hypomagnesemia with pts with dietary mg deficiency
- Allergic reactions (rash, eosinophilia) and dehydration
22
Q
Loop diuretics (Furosemide and ethacrynic acid) Contraindications
A
- Furosemide, bumetanide, and torsemide are sulfonamides that can cause rxs in pts w/ sulfonamide sensitivity
- deleterious in hepatic cirrhosis, borderline renal failure, heart failure
- Avoid in postmenopausal osteopenia women due to Ca wasting
- Drug interactions with aminoglycosides (enhanced ototoxicity), lithium, and digoxin (electrolyte disturbances)
23
Q
Loop diuretics (Furosemide and ethacrynic acid) Clinical indications
A
- Most efficacious diuretic
- Acute pulmonary edema, edematous states
- HTN and heart failure
- Treatment of mild hyperkalemia
- Treatment of acute renal failure by increasing rate of urine flow and enhancing K excretion
- Anion overdose: Br-, Fl-, I- reabsorbed in the thick ascending loop
- Hypercalcemic states
24
Q
Thiazide diuretics (hydrochlorothiazide) Pharmacokinetics
A
- All given orally
- Chlorothiazide is only one in parenteral administration. Must be given in large doses
- Chlorthalidone is longest acting thiazide with a 47 hour half life
- Secreted in the PCT by organic acid secretory system (competes with uric acid secretion - elevates serum uric acid levels)
25
Thiazide diuretics (hydrochlorothiazide) MOA
- Inhibits the Na/Cl cotransporter and inhibits NaCl reabsorption from the luminal side of epithelial cells in the DCT
- Enhance reabsorption of Ca2+, unmask hypercalcemia due to hyperparathyroidism, carcinoma, sarcoidosis
- Some weak inhibitors of carbonic anhydrase
26
Thiazide diuretics (hydrochlorothiazide) toxicity
- Hypokalemic metabolic alkalosis and hyperuricemia similar to loop diuretics
- Impaired carbohydrate tolerance: cause hyperglycemia, unmask latent DM during tx
- Hyperlipidemia: increase in total serum cholesterol and LDL except for indapamide
- Hyponatremia: deficiency of Na in the blood due to hypovolemia elevated ADH and reduced diluting capacity of the kidneys and increased thirst
- Hypercalcemia and hyperuricemia
- Weakness, fatiguability, paresthesias, allergic actions, and impotence
- Sulfonamide hypersensitivity
27
Potassium sparing diuretics
- Mineralcorticoid receptor antagonists (spironolactone)
| - Na channel inhibitor prototype (amiloride)
28
Spironolactone and eplerenone pharmacokinetics
- Both given orally
- Inactivation occurs in the liver and several days are needed before results are seen
- Eplerenone is a spironolactone analog with greater selectivity for the Mineralocorticoid receptor
29
Amiloride and triamterene Pharmacokinetics
- Oral preparations
| - Triamterene is metabolized extensively in the liver and has a shorter half-life than amiloride
30
Spironolactone and eplerenone MOA
- Mineralocorticoid receptor (MR) antagonists that are competitive inhibitors of aldosterone binding to the MR
- MR is nuclear hormone receptor responsible for regulating the expression of ENaC and Na/K ATPase pumps in the late distal tubule and CCT
- Reduce Na reabsorption to the interstitium in the CCT and reduce K secretion (as well as H, Ca, Mg)
- Only diuretics that do not require access to the tubular lumen to induce diuresis
31
Amiloride and triamterene MOA
- Directly inhibit Na entry by blocking ENaC channels in the apical membrane of the CCT
- Reduce Na reabsorption to the interstitium in the CCT and reduce K (H, Ca, Mg) secretion
32
K sparing diuretics Toxicity
- Mild, moderate or even life-threatening hyperkalemia
- -- risk is increased by renal disease or by B-blockers and NSAIDs (renin reduction) or by ACEIs and ARBs (angiotensin II activity reduction)
- --Usually combine with other diuretics that increase K+ secretion
- Metabolic acidosis - reduced H+ secretion
- Gynecomastia, importance, and BPH (eplerenone has less antiandrogenic effects)
- Triamterene may cause kidney stones; w/ indomethacin can cause acute renal failure
33
K sparing diuretics contraindications
- Patients with chronic renal insufficiency vulnerable to severe or fatal hyperkalemia
- Concomitant use of K sparing diuretics with B-blockers, NSAIDs, ACEIs or ARBs
- Strong inhibitors of CYP3A4 can increase serum levels of eplerenone
34
K sparing diuretics clinical indications
- Most useful in mineralocorticoid excess or hyperaldosteronism, either primary hyper secretion (Conn's syndrome, ectopic androcorticotropic hormone production) or secondary hyperaldosteronism (HF, hepatic cirrhosis, nephritic syndrome, diminished effective intravascular volume)
- Thiazides and loop diuretics can cause secondary hyperaldosteronism - increase renal wasting of K+; K+-sparing diuretics can blunt K+ secretory response
- MR antagonists are used to treat heart failure
35
Osmotic agents (mannitol) pharmacokinetics
- Poorly absorbed, must be given parenterally (oral causes diarrhea)
- Not metabolized, excreted w/in 30-60 minutes
36
Osmotic agents (mannitol) MOA
- Causes increase in osmotic pressure of glomerular filtrate, which inhibits tubular reabsorption and electrolytes and increases urinary output
- Opposes ADH effect in the CCT
- Increase in water diuresis increases urine flow rate and decreases contact time between fluid and tubular epithelium - reduces Na+ reabsorption
- Natriuresis leading to excessive water loss and hypernatremia
37
Osmotic agents (mannitol) toxicity
- Extracellular volume expansion - mannitol extracts water from cells - leads to expansion of EC volume and hyponatremia
- Dehydration, hyperkalemia, and hypernatremia
38
Osmotic agents (mannitol) contraindications
-Severe renal disease (anuria), severe dehydration, severe pulmonary edema or congestion
39
Osmotic agents (mannitol) clinical indications
- Increase or maintain urine volume - prevent anuria from delivery of large pigment loads to kidneys due to hemolysis or rhabdomyolysis, removal of toxins
- Reduction of intracranial or intraocular pressure
40
ADH hormone agonists
- Increased water reabsorption
- Vasopressin and desmopressin mediate vasoconstriction of vascular smooth muscle and increase water permeability and reabsorption in the CCT (AQP2 channels)
- Treatment for pituitary diabetes insidious and to treat polyuria, polydipsia, hypernatremia, and nocturnal enuresis
41
ADH antagonists (conivaptan)
- Used for heart failure and SIADH
- Parenterally administered, t1/2 5-10 hr
- Antagonist of ADH receptors (V1a, V2) in the CCT
- Can cause hypernatremia and nephrogenic diabetes insipidus
42
Loop and thiazide diuretic combo
- If they fail or become refractory to usual dose of loop diuretics
- Na and H2O reabsorption at TAL (blocked by loop diuretics) or DCT (blocked by thiazides) can increase when other is blocked, inhibit both produce more than an additive diuretic response
- Combination block Na reabsorption from PCT, TAL, DCT (thiazides produce sodium excretion in PCT)
- Combo not recommended for outpatient usage - profuse diuresis
- K wasting is very common
43
K-sparing diuretics and loop agents or thiazides
- Hypokalemia is common in loop agents and thiazides but can be managed with dietary NaCl restriction or KCl supplementation
- The addition of K-sparing diuretics can lower K secretion
- Combo is generally safe but should be avoided in its with renal insufficiency or tx with angiotensin antagonists
44
Edematous states treated with diuretics
- Heart failure: pulmonary or interstitial edema occur when the plasma volume increases due to decreased cardiac output stimulating retention of salt and water; this leaks from the vasculature
- Kidney disease: most cause retention of salt and water. Severe loss of renal function - diuretics little benefit; mild renal disease - tx when retain sodium; beneficial in glomerular diseases (SLE, DM) retain salt and water; hyperkalemia with early stage renal failure - loop and thiazides
- Hepatic cirrhosis: edema and ascites, aggressive use can be disastrous
45
Non edematous states treated with diuretics
- HTN: Thiazides are typically used. Loop diuretics used w/ renal insufficiency or heart failure. Often used in combo w/ vasodilators (hydralazine, minoxidil) that cause significant salt and water retention
- Nephrolithiasis: Thiazide diuretics enhance Ca reabsorption in the DCT, reduce urinary Ca concentration
- Hypercalcemia: loop diuretics reduce Ca reabsorption and promote Ca diuresis (alone causes volume contraction); w/ saline maintain effective Ca diuresis
- Diabetes insipidus: Either central (deficiency ADH) or nephrogenic (inadequate responsiveness to ADH); supplementary ADH effective in central DI; thiazides reduce polyuria and polydipsia in both CIs
46
Thiazide diuretics contraindications
diminish effects of anticoagulants, agents used to tx gout, insulin, increase effects of loop diuretics
caution in DM
efficacy reduced with NSAIDs and COX-2 inhibitors - inhibition of prostaglandins
excessive use dangerous in hepatic cirrhosis, borderline renal failure, or heart failure
47
Thiazide diuretics clinical indications
HTN and heart failure
Nephrolithiasis due to idiopathic hypercalcuria
Nephrogenic diabetes insipidus
48
Hydrochlorothiazide (HCTZ) MOA in nephrogenic diabetes insipidus
inhibits Na/Cl transporter in DCT
Administration increases diuresis, reducing ECF
Reduction in volume - less volume filtered at glomeruli and decreased GFR
Decreased GFRcauses increase in PT Na and H2O reabsorption (tubuloglomerular feedback)
Leads to less sodium and water delivery to CD, decreases urine output
