Pharm: Diuretics Flashcards
What is the definition of a diuretic?
a substance/drug that increases the discharge of urine
What was the original parent compound for diuretic drugs?
Sulfanilamide (an antibiotic) that causes metabolic acidosis and alkaline urine (NaHCO3 diuresis)
What are the diuretics empirically derived from sulfanilamide and how do they work?
Acetazolamide (CA inhibitor)
Dichlorphenamide (CA inhibitor)
Disulfamoylchloraniline (most commonly used diuretic today)
How does the kidney control ECF volume?
Adjusting NaCl and H2O excretion by altering nephron permeability, regulating ion channels
What happens if NaCl intake > output?
Edema develops
This happens in heart failure, renal failure
What does natriuretic mean?
Increased Na+ excretion
-In addition to diuretics increasing urine output, many also increase Na+ excretion (natriuretic)
What are the anatomical input(s) and output(s) to the kidney?
Input: renal artery
Outputs: renal vein and ureter
List the components of the nephron in order that filtered fluid traverses the nephron
Glomerulus Proximal convoluted tubule Loop of henle (thin descending and ascending, thick ascending) Distal convoluted tubule Collecting ducts
What are the major substances reabsorbed and secreted in the proximal convoluted tubule?
Reabsorbed: NaHCO3, NaCl
Secreted: organic acids and bases
Is the thin descending limb H2O permeable or impermeable?
Permeable
Water is reabsorbed from the lumen leading to concentration of the tubular fluid
What is the major ion transporter in the thick ascending limb?
Na+/K+/2Cl- cotransporter pumps these cations out of the lumen
Describe the structure and function of the juxtaglomerular apparatus
Cells from distal convoluted tubule and glomerular afferent arteriole containing osmoreceptors (macula densa) and mechanoreceptors (JG cells) that regulate the RAA system via renin release
What ion is reabsorbed in the distal convoluted tubule and what regulates this reabsorption?
Ca2+ is reabsorbed in the DCT in the presence of PTH
What regulates the H2O permeability of the collecting duct?
In the presence of ADH, the collecting ducts are permeable to H2O due to aquaporin insertion
What regulates NaCl permeability of the collecting duct?
Aldosterone
What are the ions secreted in the collecting ducts?
K+ and H+ are secreted in the collecting ducts
Location of action of acetazolamide
Proximal convoluted tubule
Location of action of mannitol
Proximal convoluted tubule
Location of action of furosemide
Thick ascending limb
Location of action of thiazides
Distal convoluted tubule
Location of action of K+ sparing diuretics
Collecting ducts
Location of action of ADH antagonists
Collecting ducts
Diuretics primarily prevent Na+ ________________
Diuretics primarily prevent Na+ entry into the tubule cells
Where do diuretics have to get to in order to be effective?
They must reach the tubular fluid in order to be effective
Describe how diuretics reach the tubular fluid
Mannitol is filtered across the glomerulus
Most others are secreted via organic acid/base transporters in the proximal tubule
What primarily drives Na+ reabsorption throughout the tubule epithelial cells?
The Na/K ATPase pump on the basolateral membrane keeps a low [Na+] and a high [K+] inside the cells
Describe the pathway for Na+ and HCO3- absorption in the proximal convoluted tubule
Transporters: Na/H antiport on lumenal side, Na/HCO3- on basolateral side
1) Na enters cells via antiporter down gradient and is pumped out via Na/K pump
2) HCO3- is converted to CO2 and H2O in the tubules by CA, which then can diffuse into the cell
3) CO2 and H2O combine to form H+ and HCO3- via intracellular CA
4) HCO3- pumped out of cell into blood
What is the mechanism of action of acetazolamide?
Reversibly inhibits carbonic anhydrase, thus inhibiting the reabsorption of HCO3- in the proximal tubule
Describe the pharmacokinetics of acetazolamide
Good oral absorption
Effect begins ~30 minutes, lasts 12 hours
Renal secretion via OAT
What adverse events are associated with acetazolamide?
Metabolic acidosis (due to chronic excretion of HCO3-)
Hypokalemia (acute effect)
Calcium phosphate stones (due to high pH in tubule)
Drowsiness, paresthesias and hypersensitivity
What are the contraindications for acetazolamide?
Cirrhosis because serum NH3 is elevated by both liver failure and increased tubule pH
What is the relationship between ammonia excretion and urine pH?
Inversely related
Increased urine pH (like due to acetazolamide treatments) will decrease ammonia excretion, thus increasing serum ammonia
What are the CA inhibitors other than acetazolamide?
Dichlorphenamide: 30x potency
Methazolamide: 5x potency
Dozolamide: topical ocular use
What are the indications for acetazolamide treatment?
Diuretic therapy (used in combination) Glaucoma (reduce intraocular pressure) Urinary alkalinization (treat overdose, stones) Acute mountain sickness
What is the mechanism of action for mannitol?
Osmotic diuretic (holds water in tubule) that acts in the water permeable segments of the nephron (proximal tubule, descending loop, collecting ducts +ADH)
Describe the pharmacokinetics of mannitol
Not orally absorbed, so given IV to reach kidney
Half life is 1.2 h
What condition worsens adverse effects associated with mannitol?
AEs predominate if filtration is impaired because mannitol cannot reach the tubule without filtration
What are the adverse effects associated with mannitol
Caused by increased plasma osmolarity, water leaves cells, Na follows
- Acute pulmonary edema
- Dehydration
- Headache, nausea, vomiting
What are the contraindications for mannitol?
CHF, renal failure, pulmonary edema
*CHF and RF reduce glomerular filtration, pulmonary edema would be exacerbated
What are the clinical indications of mannitol?
- Maintenance/Increase of urine volume (Renal failure, drug overdose)
- Reduce intracranial/intraocular pressure (doesn’t cross BBB or enter eye, so it pulls fluid out)
Describe the ionic movements in the thick ascending limb
Transporters: Na/K/2Cl cotransporter moves cations in from lumen, Na/K ATPase basolateral, K+/Cl- cotransport basolateral
1) ATPase maintains Na gradient to drive NaKCl cotransporter
2) K+ enters from both sides and diffuses back into lumen through channel creating a positive lumenal charge
3) Positive lumenal charge repels Mg and Ca promoting paracellular diffusion
What is the mechanism of action of the loop diuretics?
Block the Na/K/2Cl cotransporter which increases urinary water, Na, K, Ca, and Mg excretion
- Also dilates venous system and renal vasodilation mediated by PGs
What is the main loop diuretic?
Furosemide (Lasix)
Describe the pharmacokinetics of furosemide
Rapid oral absorption with a short half life, short duration
Renal secretion via OAT
What adverse effects are associated with furosemide?
- Hyponatremia, hypokalemia, hypomagnesemia
- Dehydration
- Metabolic alkalosis
- Mild hyperglycemia
- Ototoxicity
- Hypersensitivity
What are the clinical indications for furosemide?
- Acute pulmonary edema
- Edema w/ CHF
- Acute hypercalcemia, hyperkalemia
- Hypertension
What are the loop diuretics other than furosemide and how do they differ?
Bumetanide (40x potency, shorter half life, liver metabolism) Torsemide (longer half life, duration, better oral absorption, liver metabolism) Ethacrynic acid (different structure, used w/ hypersensitivity, BAD AEs)
Describe the ionic movements in the distal convoluted tubule
Transporters: lumenal Na/Cl symporter, basolateral Na/K ATPase and Na/Ca antiporter
- Na gradient drives Na/Cl symporter
- Ca absorption regulated by PTH
What is the mechanism of action of hydrochlorothiazide?
Inhibition of the Na/Cl cotransporter on the lumenal side of the distal tubule
How does the Ca2+ reabsorption differ between loop diuretics and hydrochlorothiazide?
Loop diuretics decrease Ca2+ reabsorption whereas hydrochlorothiazide increases Ca2+ reabsorption
Describe the pharmacokinetics of hydrochlorothiazide
Good oral absorption, renal elimination
Short half life (2.5 h)
How do thiazide diuretics cause hypercalcemia?
Inhibition of Na/Cl cotransporter decreases intracellular [Na+], producing a bigger gradient for the Na/Ca antiporter on the basolateral membrane. More Ca gets pumped out of the cells (reabsorption), leading to hypercalcemia
What are the adverse effects of hydrochlorothiazide?
Hyponatremia, hypokalemia Dehydration Metabolic alkalosis Hyperuricemia Hyperglycemia Hyperlipidemia (LDL) Weakness, fatigue, paresthesia, hypersensitivity
What are the clinical indications for hydrochlorothiazide?
Hypertension
CHF
Prevent kidney stones by reducing Ca2+ excretion
What are the thiazide drugs other than hydrochlorothiazide and how to the differ?
Chlorothiazide: 1/10 potency, short half life
Metolazone: 10x potency, long half life
Indapamide: 20x potency, longer half life, liver metabolism
Chlorthalidone: same potency, Longest half life
Describe the ionic movements in the principal cell of the collecting tubule
Na and water reabsorbed with ADH present
K secreted via K+ channels
Basolateral Na/K ATPase
*Aldosterone regulates Na/K ATPase and channel expression
Describe the ionic movements in the intercalated cells of the collecting tubule
H+ secreted into tubular lumen by proton pump
HCO3- reabsorbed into circulation by HCO3-/Cl- countertransport on basolateral membrane
How do CA inhibitors cause hypokalemia?
Increased tubular HCO3- makes lumen potential more negative. This electrogradient increases K+ efflux from principal cells into the tubule and thus increased K+ excretion, hypokalemia
How do loop and thiazide diuretics cause hypokalemia?
Increased tubular Na+ and Cl- creates a more negative lumen potential, which promotes K+ efflux from principal cells
How do loop and thiazide diuretics cause metabolic alkalosis?
Lumen negative potential (increased Na and Cl-) enhances H+ efflux from the intercalated cells. More HCO3- is therefore reabsorbed, leading to alkalosis
In what situations should K+ sparing diuretics be avoided?
Hyperkalemia
Patients on drugs (ACEi’s) or with diseases (DM, renal insufficiency) that could cause hyperkalemia
What is the mechanism of action for spironolactone?
Competitive inhibition of aldosterone receptor
-Also anti-androgenic, decreases testosterone synthesis
What affect does spironolactone have on potassium levels and pH?
Sparing of K+ and H+ due to aldosterone inhibition
-The negative lumenal charge is prevented because Na remains in lumen
Describe the pharmacokinetics of spironolactone
Slow onset, takes days for effect
Liver metabolism to several active metabolites
What adverse events are associated with spironolactone?
Hyperkalemia (K+ sparing) Metabolic acidosis (H+ sparing) Gynecomastia, amenorrhea, impotence, decreased libido GI upset, ulcers CNS: headache, confusion, fatigue
What is the mechanism of action of eplerenone?
Aldosterone antagonist
How does eplerenone differ from spironolactone?
Same MOA, but does not inhibit testosterone binding, so it has decreased side effects
Much more expensive
What are the clinical indications for spironolactone?
Primary and secondary hyperaldosteronism Liver cirrhosis (drug of choice) Hypertension
What is the mechanism of action of amiloride and triamterene?
Blocks Na+ channels in the principal cells, thus decreasing the driving force for K+ efflux
K+ sparing
Describe the pharmacokinetics of amiloride
Long half life (21h)
Secreted into tubule via OBT
Excreted unchanged by kidney
What are the adverse effects of amiloride?
Hyperkalemia (exacerbated by NSAIDs)
GI upset: NVD
Muscle cramps
CNS: headache, dizziness
What are the clinical indications of amiloride?
Edema
Hypertension
Used in combo with other diuretics to minimize K+ loss
How does triamterene differ from amiloride?
10x less potent than amiloride with a much shorter half life
Which drugs are the ADH antagonists?
Demeclocycline: tetracycline antibiotic
Lithium: psych drug for mania
Vaptans
What are the vaptans and how do they differ?
V2 (kidney) receptor antagonists: tolvaptan, mozavaptan, lixivaptan
V1a (vascular smooth muscle) and V2 antagonist: conivaptan
What adverse effects are associated with ADH antagonists?
hypernatremia, thirst, dry mouth, hypoteension, dizziness
What are the indications for ADH antagonists?
SIADH
euvolemic or hypervolemic hyponatremia
CHF
Which diuretic drugs most profoundly increase urinary NaCl?
Loop agents + thiazides combo
Loop agent monotherapy
Which diuretic drugs most profoundly increase urinary NaHCO3- ?
Carbonic anhydrase inhibitors
Which diuretic drugs most profoundly increase urinary K+?
Loop + thiazide combo
How does edema form?
If filtration exceeds lymphatic drainage, edema forms
Unbalanced starling forces
Describe the mechanism of renal disease causing systemic edema
2 Pathways:
1) Urinary loss of albumin decreases plasma oncotic pressure
2) reduced GFR leads to renal Na retention, water retention
How does hepatic cirrhosis cause systemic edema?
Increased pressure in sinusoids leads to exudate, ascites
Decreased albumin production decreases oncotic pressure, RAA system activated, Na retention
What diuretic therapies are recommended for CHF?
Spironolactone to prevent hypokalmeia induced heart problems ACE inhibitors (increase K) may be used with thiazide or loop diuretics
How does diuretic treatment differ between chronic right heart failure and acute left heart failure?
Right: oral loop diuretics
Left: IV loop diuretics (Emergent situation)
What is the most common electrolyte disorder in hospitalized patients? How is this treated?
Hyponatremia
*Corrected with AVP receptor antagonists (vaptans)
What are some causes of diuretic resistance?
NSAID use
CHF or chronic renal failure
Nephrotic syndrome
Hepatic cirrhosis
*Overcome via increased dose, decreased interval, add another drug
What drugs interact with K+ sparing diuretics?
ACE inhibitors
NSAIDs
What drugs interact with loop diuretics
Aminoglycosides Anticoagulants (increased effect) Beta blockers Digoxin NSAIDs Quinidine Sulfonureas Steroids
What drugs interact with Thiazides?
Anticoagulants (decreased effect) Beta blockers Carbamazepine Digoxin NSAIDs Quinidine
