Week 1: PHM-Diuretics Flashcards
Which 2 classes of diuretics combine at the thick descending & ascending limbs acting synergistically?
Loop and Thiazine; ex of how adding 2+ diuretics from different classes have synergistic action as long as sites of action differ
What is the site and MOA of carbonic anhydrase inhibitors?
Site: PCT MOA: Inhibit CA in lumen and in tubular cells. Decrease sodium bicarbonate reabsorption and causes HCO3 diuresis (may even lead to metabolic acidosis) *Normally, intraluminal/cellular mechanisms turn HCO3 into carbonic acid, which will dissociate into H2O and CO2 to be reabsorbed intracellularly by CA to regulate Na and H2O
How can CA inhibitors lead to Ca stones?
CA inhibitors alkalinize the urine; uric acid and cysteine and relatively insoluble in acidic urine and stones may form but their solubility can be enhanced by pH increase *excessive alkalization can lead to Ca stones*
Why are CA inhibitors used to treat alkalosis induced by excessive use of other diuretics?
CA inhibitors induce hyperchloremic metabolic acidosis
What diuretic class is used as prophylaxis/Tx of acute mountain sickness?
CA Inhibitors
In severe cases, rapidly progressive pulmonary and cerebral edema can occur.
But CSF formation and pH decrease so drugs like acetazolomide can ↑ ventilation and ↓ Sx
When are CA inhibitors contraindicated?
Liver Disease!
Urinary alkalinization->ammonia diversion in urine into systemic circulating, inducing worsening hepatic encephalopathy
What are 3 side effects/toxicities of CA Inhibitors?
1) Phosphaturia and Hypercalciuria
2) K Wasting: ↑ Na presented to CT (w/ HCO3) partially reabsorbed; lumen’s (-) electrical potential ↑ enhanced K secretion
3) Drowsiness and paresthesia: w/ higher doses from potential inhibition of CA in CNS
What are 3 ex’s of CA Inhibitors?
Which 2 are used for glaucoma Tx?*
1) Acetazolomide
2) Dichlorphenamide*
3) Methazolamide*
What is a PK consideration for CA Inhibitors?
efficacy ↓ after several days use
↓ HCO3 in glomerular filtrate; HCO3 depletion
->enhanced NaCl reabsorption by remainder of nephron
What is the site and MOA of loop diuretics?
Site: cortical and medullary thick ascending limb
MOA: inhibits NKCC2
↓ reabsorption of NaCl and ↓ lumen (+) potential that comes from K recycling
↓ in (+) potential also causes ↑ Mg and Ca excretion
What 2 things can loop diuretics stimulate?
1) Briefly stimulates RBP and ↓ peripheral venous compliance
2) Stimulates PGN synthesis in lung and kidney
*PG2 can enhance diuretic effect*
What drug class can interfere w/ loop activity especially in 2 comorbid conditions*?
NSAIDs ↓ PG synthesis in kidney
Interferes w/ loop activity’s diuretic effects for pts w/ nephrotic syndrome* and hepatic cirrhosis*
What are the 1st and 2nd line indications for loop diuretics?
1st: acute pulmonary edema; Tx for CHF to ↓ venous and pulmonary congestion
K, Mg, Ca excretion ↑ bc NKCC inhibited
2nd (or in combo w/ thiazide diuretics): HTN or severe HF in pts who are diuretic resistant
What class can help in acute and chronic renal failure patients but can’t prevent or shorten duration?
Loop Diuretics
What are 4 side effects of Loop Diuretics?
1) Hypochloremic metabolic alkalosis: ↑ Na delivery to distal tubule-> ↑ urinary excretion of K and H
2) Hypokalemia
3) Hypomagnesemia
4) Hyperuricemia: may precipitate gout attacks
*shouldn’t be used in pts w/ hx*
What is a possible dose related side effect of Loop Diuretics?
Hearing loss
From alts in electrolyte composition in inner ear fluid; usually reversible
What is a cross-reactivity risk w/ Loop Diuretics?
Pts w/ sulfonamide allergy
What are 4 ex’s of Loop Diuretics?
Which one can be used for sulfa allergic?*
1) Furosemide
2) Bumetanide
3) Torsemide
4) Ethacrynic Acid*
Why is the hypocalcemia generated w/ Loop Diuretics not a concern?
Bc Ca actively reabsorbed in DCT
What might loop diuretics enhance in hypercalcemic disorders? Does this offer Tx potential?
↑ Ca excretion
May be used to Tx mild hyperkalemia
What is the site and MOA of Thiazide diuretics?
Site: DCT
MOA: Inhibits NaCl reabsorption from luminal side of epithelial cells in DCT by blocking NaCl transporter
Which class is a “ceiling diuretic?”
Thiazide Diuretics
↑ dose above normal doesn’t further diurese
How do Thiazide Diuretics affect Ca levels?
↓ renal excretion of Ca
(+) in treating Ca containing urinary stones
In what clinical condition are Thiazide diuretics indicated?
Diabetes Insipidus
What are the primary indications and uses of Thiazide Diuretics?
Primarily results in contraction of ECF volume
- (+) in HTN and mild CHF Tx
- Edema assoc w/ liver and renal diseases
Adjunct to loop diuretics
Which class is 1st line Tx for Nephrogenic Diabetes Insipidus? 3 effects and clinical manifestations
Thiazide Diuretics
1) Paradoxically reduce polyuria
2) Plasma vol ↓, leading to enhanced proximal reabsorption of NaCl and H2O; ↓ fluid delivery to distal segments
3) ↑ expression of Na transporters in DCT and collecting tubules
Clinical: Excretion of large vols of dilute urine; hyponatremia, lethargy, anorexia, N/V, muscle cramps
What are 2 rare side effects of Thiazide Diuretics?
Photosensitivity and generalized dermatitis
What are 8 metabolic consequences of Thiazide Diuretics?
1) Metabolic alkalosis
2) Hyponatremia (from ↑ ADH and thirst)
3) Hypokalemia
4) Hypomagnesemia
5) Hypochloremia
6) Uric acid and Ca retention
7) Hyperglycemia
8) Hyperlipidemia
What are 3 possible causes of hyperglycemia from Thiazide Diuretics?
1) Impaired pancreatic rel of insulin
2) ↓ tissue use of glucose
3) ↓ glucose tolerance, even unmasking DM
*Seen in doses > 50 mg, not in doses 12.5 mg
What are 4 ex’s of Thiazide Diuretics?
What are 2 special indications?
1) Hydrochlorothiazide
2) Chlorothiazide
3) Chlorothalidone*
4) Metolazone*
*Chlorothalidone: ↓ stroke and heart attacks in HTN (over HCTZ)
*Metolazone: CHF pts resistant to loop diuretics, add-on to loop
What is the site and MOA of ADH Antagonists?
Site: Collecting Duct
MOA: Inhibits ADH effects
can ↓ peripheral vascular resistance and ↑ CO
When are ADH Antagonists not inidicated?
HTN or HF settings
What are 2 ex’s of ADH Antagonists?
What is a special consideration for 1?
1) Conivaptan *must be infused IV
2) Tolvaptan
What are 2 indications for ADH Antagonists?
1) Hypervolemic and euvolemic hyponatremia
(not corrected w/ fluid resuscitation)
2) SIADH mgmt when H2O restriction has failed
What is a side effect and consideration for ADH Antagonists?
1) Severe hypernatremia
*Too rapid correction of Na can cause osmotic demyelination-> dysphagia, lethargy, seizures, even death
What is an ex of an osmotic diuretic?
Mannitol
What are 2 considerations for the osmotic diuretic Mannitol?
Rapid distribution in ECF and H2O extraction from cells
1) prior to diuresis, acute ↑ in ECF vol and hyponatremia can complicate HF and produce pulmonary edema
2) excessive use w/o adeq H2O replacement can lead to severe dehydration and hypernatremia
What are 2 side effects of osmotic diuretics?
1) N/V, headache from initial hyponatremia
2) Hyperkalemia: H2O extracted from cells, intracellular K ↑ leading to cellular losses and ↑ in extracellular compartments
What are 5 indications and responses for osmotic diuretics?
1) ↓ extracellular vol and pressure
2) ↑ H2O excretion rather than Na, compared to other classes
3) ↓ intraocular pressure
4) prevents acute renal failure after severe trauma or complicated surgical procedures, resulting in large pigment load on kidneys (from hemolysis/rhabdomyolysis)
5) promotes renal excretion of toxins
When are osmotic diuretics not useful?
Conditions w/ Na retention
What are 4 ex’s of K sparing Diuretics?
1) Spironolactone
2) Eplerenone
3) Triamterene
4) Amiloride
What are 2 side effects of K Sparing Diuretics?
1) Hyperkalemia: esp in aldo receptor antagonists, risk ↑ w/ renal disease
2) Hyperchloremic metabolic acidosis by inhibiting H and K secretion
What are side effects specific to the K sparing diuretic spironolactone (not eplerenone!)?
Endocrine abnormalities on steroid receptors: androgen and progesterone
1) Gynecomastia
2) Hirsutism
3) Impotence
4) Benign prostatic hyperplasia
5) Menstrual irregularities
What is the site of action and 2 MOA’s for K sparing diuretics?
Site: Cortical collecting tubule
MOA 1: competitive aldosterone antagonist (↓ EF): Spironolactone and Eplerenone
MOA 2: interferes w/ Na influx through epithelial Na ion channels in luminal membrane of collecting ducts
Triamterene and Amiloride
What are 2 general PD effects of K sparing diuretics?
What about for spironolactone and amiloride?
1) Na/K exchange sites are not stimulated
2) Prevents Na reabsorption and K/H secretion
Spironolactone: prevents protein synthesis that normally responds to aldo
Amiloride: directly blocks ENac
When is the K sparing diuretic Spironolactone indicated?
Most effective in primary and secondary hyperaldosteronism
*Prevents aldosterone binding to its receptor*
Also cirrhotic edema (ascites) Tx
Vs. hypokalemia (in combo w/ Loop or Thiazide)
What might evoke secondary hyperaldosteronism?
HF, Hepatic Cirrhosis, Nephrotic Syndrome
What is the K sparing diuretic Eplerenone and its effects?
Spironolactone analogue w/ greater SP for aldo receptors and fewer AE
Interferes w/ fibrotic and inflammatory effects of aldosterone, slows progression of albumineria in diabetes
How do Triamterene and Amiloride work and when are they indicated?
Directly interfere w/ Na entry
Can counteract K wasting of Thiazide
(all K sparing diuretics)
Used in combo w/ Thiazide for HTN Tx
What are the 3 sites of action for osmotic diuretics?
1) Proximal Tubule: ↓ Na reabsorption by osmotic gradient, ↑ urine vol
2) Descending LOH: ↑ medullary blood flow, inhibits passive reabsorption of H2O
3) Collecting Duct: via osmotic effects, opposes ADH action
Which class of diuretics is indicated for Diabetes Insipidus? How do the two types of DI compare? In which one is administration of ADH or an analogue uniquely effective?\*
Thiazide Diuretics
- Central DI*: deficient production of ADH (adjunct Tx)*
- Nephrogenic DI*: inadequate responsiveness to ADH (1st line)
