Diuretics Flashcards
What is the main function of diuretics?
A substance or drug that tends to increase the discharge of urine.
How can edema develop from NaCl imbalance?
When NaCl intake is greater than output, e.g. in congestive heart failure or renal failure, edema develops.
What is the Na+/K+ ATPase?
It exchanges 3 Na+ for 2 K+, thereby keeping a low Na+ concentration and a high K+ concentration within the cell.
What is the longest and most absorptive part of the nephron?
Proximal Tubule
What is the major determinant of ECF volume?
NaCl
What is mainly absorbed and secreted in the PT?
NaCl and NaHCO3 are absorbed
Organic Acids and Bases are secreted
What is the macula densa and what is its role?
It is a sensor in the TAL of the Loop of Henle. It detects NaCl and decreases in concentration will cause 2 responses:
(1) it decreases resistance to blood flow in the afferent arterioles via vasodilation, which increases glomerular capillary hydrostatic pressure and helps return glomerulus filtration rate (GFR) toward normal, and
(2) it increases renin release from the juxtaglomerular cells of the afferent and efferent arterioles, which are the major storage sites for renin.
What is the primary therapeutic goal of diuretics?
The primary therapeutic goal of diuretic use is to reduce edema
Where do diuretics generally enact their effects?
Except for spironolactone and some ADH antagonists, diuretics generally exert their effects from the luminal side of the nephron.
How do most diuretics reach the urine?
Most other diuretics are tightly protein bound and undergo little filtration. They reach the urine via secretion across the proximal tubule.
What are the carbonic anhydrase inhibitors?
- Acetazolamide
- Dichlorophenamide
- Methazolamide
- Dorzolamide
What is the site of action of the carbonic anhydrase inhibitors?
Proximal Tubule
Acetazolamide MOA
Reversible inhibition of carbonic anhydrase which leads to the inhibition of the reabsorption of HCO3- in the proximal tubule
Acetazolamide PK
Well absorbed orally
Acetazolamide Secretion Mechanism
Renal secretion is via the organic acid transporter
Acetazolamide SE
– Metabolic acidosis
– Hypokalemia
– Calcium phosphate stones
Acetazolamide Contraindications
Cirrhosis (increased urine pH
reduces NH3 secretion and thereby increases serum NH3)
Acetazolamide Indications
– Diuretic agent: weak, but ok as backup
– Glaucoma: reduction of intraocular pressure
– Urinary alkalinization: drug overdose/some stones
– Acute mountain sickness
How does acetazolamide lead to the increased serum levels of NH3?
Acetazolamide increases the excretion of HCO3- which will alkalinized the urine. The alkalinization of urine causes the NH3 in the collecting duct (CD) to not be protonated to NH4+ which would trap it in the CD. It can therefore just diffuse back as NH3.
Dichlorophenamide Class and Action
CA Inhibitor
30X more potent than acetazolamide
Methazolamide Class and Action
CA Inhibitor
5X more potent than acetazolamide
Dorzolamide Class and Action
CA Inhibitor
Topical variant used for ocular disease like glaucoma to avoid systemic effects
Mannitol MOA
Osmotic diuretic
Where does mannitol enact its effects?
Major osmotic effects in proximal tubule and descending limb of the loop of Henle; collecting ducts too, if ADH is present - water permeable parts of the nephron
How does mannitol reach the kidney?
Filtration via the glomerulus
Mannitol PK
NOT orally absorbed-must be injected IV to reach the kidneys
Mannitol SE
– Major toxicity due to increased plasma osmolality. This moves water out of cells into ECF potentially worsening heart failure. In addition, Na+ follows water movement out of cells leading to hyponatremia.
– Acute pulmonary edema
– Dehydration
What exacerbates the SE of mannitol?
Anything that would impair filtration
Mannitol Contraindications
– Congestive heart failure
– Renal failure
– Pulmonary edema
Mannitol Indications
– Maintain or increase urine volume
– Reduce intracranial pressure
– Reduce intraocular pressure (glaucoma)
What is the main transporter on the apical side of the TAL in the Loop of Henle?
- Na+/K+/Cl- cotransporter into the cell
What is the role of K+ with the Na+/K+/Cl- cotransporter in the TAL of the LoH?
K+ diffuses back into the lumen creating (+) charge in lumen which aids in the absorption of other cations like Ca and Mg
What are the Loop Diuretics?
Furosemide
Bumetanide
Torsemide
Ethacrynic Acid
Loop Diuretics MOA
Act primarily by blocking the Na+/K+/2Cl- co- transporter in the apical membrane of the thick ascending limb of Henle’s loop.
- Increase urinary water, Na+, K+, Ca2+, and Mg2+ excretion.
What is the most effective diuretic class?
The Loop Diuretics. They can cause excretion of up to 20% of the filtered Na+.
What is a secondary effect of the loop diuretics?
Also cause dilation of the venous system and renal vasodilation – effects that may be mediated by prostaglandins.
Furosemide MOA
– Inhibits the Na+/K+/Cl- cotransporter
What can cause metabolic acidosis with hypokalemia?
Acetazolamide
What are the effects of furosemide?
– Reduces reabsorption of Na+, K+, Cl- as expected, but also Ca2+ & Mg2+ due to loss of (+) luminal charge
– Renal vasodilation improves renal blood flow
Fusosemide PK
– Oral absorption is rapid but variable for each patient
– Half-life is short (1-1.5 hrs) so duration is only 2-3 hrs
What is the secretion mechanism for Furosemide?
Renal secretion mechanism; organic acid transporter
Furosemide SE
– Hyponatremia/hypokalemia/hypomagnesemia – Dehydration – Metabolic alkalosis – Mild hyperglycemia – Ototoxicity
Furosemide Indications
– Acute pulmonary edema – Edema associated with CHF – Acute hypercalcemia – Acute hyperkalemia – Hypertension
Bumetanide Class and Action
Loop Diuretics
– About 40X more potent than furosemide
– Shorter half-life than furosemide: ~ 1 hr
Torsemide Class and Action
Loop Diuretics
– Longer half-life than furosemide: ~ 3 hrs
– Longer duration of action, too: ~ 5-6 hrs
– Better oral absorption than furosemide
Ethacrynic Acid Class and Action
Loop Diuretics
– Last resort; used only when others exhibit hypersensitivity
– No CA inhibition
– Nephrotoxic and ototoxic
What is the DT important in absorbing?
Ca2+
How is Ca2+ absorbed in the DT?
- There is an apical Ca2+ channel
- Na/Ca antiport on the basolateral side the brings Ca to the blood
Hydrochlorothiazide MOA
Inhibition of Na+/Cl- cotransporter in distal tubule. This increases Ca2+ absorption as the Na+ gradient on the basolateral side becomes stronger and the Na+/Ca2+ antiport becomes more active
Hydrochlorothiazide PK
– Good oral absorption and renal elimination
– Half-life of 2.5 hrs
Hydrochlorothiazide SE
– Hyponatremia & hypokalemia – Hyperglycemia – Hyperlipidemia (LDL) – Dehydration – Metabolic alkalosis – Hyperuricemia – Weakness, fatigue, paresthesias & hypersensitivity
Hydrochlorothiazide Indications
– Hypertension
– Congestive heart failure
– Reduce Ca2+ excretion to prevent kidney stones
Chlorothiazide Class and Action
Thiazide
– 1/10th the potency of Hydrochlorothiazide
– Half-life of 1.5 hrs
Metolazone Class and Action
Thiazide
– 10X more potent than Hydrochlorothiazide
– Half-life of 4-5 hrs
Indapamide Class and Action
– 20X more potent than Hydrochlorothiazide
– Half-life of 10-22 hrs; metabolized extensively by the liver
Chlorthalidone Class and Action
– Same potency as Hydrochlorothiazide
– Half-life of 44 hrs
What are the channels on the principal cells in the CD like?
– Na+ absorption exceeds K+ secretion causing net (–) charge in the tubular lumen – Net (–) charge repels Cl- and attracts K+ into lumen
What is the most commonly used class of diuretics?
Thiazides
What is the function of ADH in the CD?
– ADH regulates water channels and water reabsorption
What is the function of aldosterone in the CD?
– Aldosterone regulates expression of
Na+/K+ ATPase & channels
What is the function of intercalated cells in the CD?
• Luminal membrane:
Proton pumps actively transport H+ into the lumen
• Basolateral membrane:
HCO3-/Cl- passive countertransporter
How do CA inhibitors lead to hypokalemia?
Increased HCO3- in tubule lumen leads to increased lumen negative potential which enhances K+ efflux
How do thiazides and loop diuretics cause hypokalemia?
Increased Na+ & Cl- leads to increased lumen negative potential. The lumen-negativepotential enhances K+ efflux from the principal cells.
What is an absolute contraindication of K+ sparing diuretics?
They should never be given in the setting of hyperkalemia or in patients on drugs or with disease states likely to cause hyperkalemia. These include diabetes mellitus, multiple myeloma, tubulointerstitial renal disease, and renal insufficiency.
What are the K+ sparing diuretics?
Spirolactone and Eplerenone
Amiloride
Triamterene
Spirolactone MOA
Competitive inhibition of the aldosterone receptor
What are some off target effects of spironolactone?
Anti-androgenic effects
• Decrease testosterone synthesis
• Competitive inhibition of DHT receptor
Spironolactone PK
Slow onset of several days as it requires liver metabolism to several active metabolites
Spironolactone SE
– Hyperkalemia
– Metabolic acidosis
– Gynecomastia, amenorrhea, impotence, decreased libido
– GI upset, including association with peptic ulcers
– CNS effects: headache, fatigue, confusion, etc.
Spironolactone Indications
– Primary hyperaldosteronism
– Secondary hyperaldosteronism
– Liver cirrhosis
– Hypertension
Eplerenone Class and Action
K+ Sparing Diuretic
Eplerenone is also a competitive antagonist of aldosterone binding to MR. Eplerenone is considerably more expensive than spironolactone, but it does not inhibit testosterone binding and therefore it does not induce gynecomastia or other related anti-androgenic side effects.
How does spironolactone cause metabolic acidosis?
- Decreased lumen negative potential
- Reduced driving force for H+
- Decreased expression of H+ pumps
Amiloride MOA
Blocks Na+ channels in the principal cells
How does amiloride spare K+?
Blocking Na+ influx decreases the driving force for K+ efflux so K+ is “spared”
Amiloride PK
– Half-life of 21 hrs
– Secreted into the tubule via the organic base transporter
– Excreted unchanged by the kidney
Amiloride SE
– Hyperkalemia (NSAIDs can exacerbate this)
– GI upset: nausea, vomiting, diarrhea
– Muscle cramps
– CNS effects: headache, dizziness, etc.
Amiloride Indications
– Edema
– Hypertension
– Usually used in combination with other diuretics to reduce K+ loss
Triamterene MOA
Blocks Na+ channels in the principal cells. Blocking Na decreases the driving force for K+ efflux so K+ is “spared”
Triamterene PK
– Half-life of 4 hrs
– 10X less potent than AMILORIDE
– Liver metabolizes the drug to its active form
– Active metabolite secreted using the organic base transporter
What are the ADH antagonists?
Demeclocycline
Lithium
Tolvaptan
Tolvaptan MOA
It is a selective antagonist of the vasopressin V2 receptor.
Tolvaptan PK
Orally with half life of 6-8 hours
What are the V2 receptor antagonists?
Tolvaptan, mozavaptan, and lixivaptan
What is a V2 and V1a receptor antagonist?
Conivaptan
ADH Antagonist SE
Hypernatremia, thirst, dry mouth, hypotension, dizziness
ADH Antagonist Indications
SIADH
Euvolemic or hypervolemic hyponatremia Congestive heart failure
What is the main effect of CA inhibitors?
Increased NaHCO3 excretion
What is the main effect of Loop Agents?
Increased excretion of all ions with NaCl especially
What is the main effect of thiazides?
Increased NaCl excretion with increased Ca2+ reabsorption
What is the main effect of K+ sparing agents?
Increased NaCl excretion with increased K+ reabsorption
Which diuretic drugs would be indicated to reduce edema/ascites in patients with hepatic cirrhosis?
Spironolactone
What is the best treatment for CHF?
Combination of thiazides and loop agents with ACE inhibitors - without ACE inhibitors they may cause too much K+ loss
What is used to treat chronic right heart failure?
Oral loop diuretics are indicated
What is used to treat acute left heart failure?
Rapid, aggressive therapy with IV loop diuretic
What is used to treat hyponatremia?
ADH antagonists
What can be used to treat kidney stones?
Thiazides can decrease calcium concentrations in the urine by promoting Ca2+ reabsorption in the distal convoluted tubule.
What can be used for hypercalcemia?
Loop Agent
What is done to patients refractory to a loop or thiazide?
Combination therapy of Loop + Thiazide Diuretic - normally causes too much K+ wasting
Which thiazide-like diuretic is most likely to be efficacious in patients with severe renal insufficiency?
Metolazone
