Lecture 14: Diuretics + Antidiuretics Flashcards
Define diuresis and natriuresis
Diuresis:
Inc. in urine flow rate
Natriuresis:
Inc. excretion of Na + anions
List the four major classes of diuretics
CA inhibitors (CAIs)
Loop diuretics (LDs)
Thiazides diuretics (TZs)
K+ sparing diuretics
What do each class of diuretics inhibit?
CA inhibitors:
Inhibit H+ secretion in PT
Loop diuretics:
Inhibit NKCC2 in thick AL
Thiazide diuretics:
Inhibit NCC in DCT
K+ sparing diuretics:
Inhibit ENaC in CNT/CD
What is an example of carbonic anhydrase inhibitors?
Acetazolamide
What are examples of loop diuretics?
Furosemide
Bumetanide
What are examples of thiazide diuretics?
Hydrochlorothiazide
Chlorthalidone
What are examples of K+ sparing diuretics?
Triamterene
Amiloride
Sprironolactone
What are the max acute decrease in sodium reabsorption that can occur following administration of
CAIs
LDs
TZs
K sparing diuretics
Loop = 25%
Thiazides = 5-8%
CA inhibitors = 5%
K sparing = 1-2%
What is the mechanism for TRIAMTERENE and AMILORIDE blocking ENaC?
How about for Spironolactone?
Directly block ENaC
Spironolactone: competitive inhibition of aldo binding to MR
(Very effective in patients with high aldosterone, not effective in patients with low aldo)
How do diuretics get into tubular fluid?
Enter TF mainly via tubular secretion, where OAT family transporters help
Describe mechanisms for natriuresis
CAIs
LDs
TZs
K-sparing
CAIs =
Inhibit H+ secretion in PT
LDs =
Inhibit NKCC2 in thick AL
TZs =
Inhibit NCC in DCT
K-sparing =
Inhibit ENaC in CNT/CD
Describe mechanism for diuresis
Dec. Na reabsorption = More particles remaining in tubular fluid = Dec. water reabsorption = Inc. urine flow rate
Explain the importance of the diuretic breaking phenomenon
Compensatory mechanism to restore sodium balance with chronic use of diuretics
What does diuretic breaking involve?
Activation of symp division
Activation of RAAS
Other mechanisms
+ load dependence of sodium reabsorption
+ dec. BP = dec. pressure natriuresis
+ dec. natriuretic hormones
+ inc. expression of transporters in tubular epithelial cells
+ hypertrophy of tubular epithelial cells
What is a consequence of even a brief period of negative Na balance?
Dec. total body Na = Dec. ECF = Dec. ECV (The part of the ECF that can activate mechanisms to induce changes in sodium excretion)
What is the key for activating diuretic braking mechanism?
Dec. ECV
What is the effect of dec. ECV on BP?
Dec. ECV = dec. BP
What results from dec. BP after fall in ECV?
(1) arterial BRs = reflex inc. sympathetic tone to kidneys
(2) dec. stretch of afferent arterioles will stimulate renal BRs
Besides drop in BP, what else will reduce stretch of AA in kidney?
Reflex inc. sympathetic tone to kidneys
By constricting AA via alpha1 stimulation
What are consequences of inc. sympathetic tone to kidneys?
1) constriction of AA via alpha1 receptor stimulation
2) inc. renin secretion via stimulation of beta1 receptors on granular cells
3) inc. Na reabsorption in PT by increasing NHE (Na/H exchange)
What factors following diuretic therapy will lead to increased renin secretion?
1) dec. stretch of AA as sensed by renal BRs
2) beta1 sympathetic stimulation
3) dec. Na delivery to macula densa
What are consequences of more sodium reabsorption in PT following diuretic therapy and increased symp tone?
1) reduced Na dlievery to macula densa
2) dec. sodium excretion
What is effect of inc. renin secretion on AngII?
Inc. renin = inc. AngII
What are consequences of inc. AngII following diuretic therapy?
1) inc. Na reabsorption in PT by stimulating more Na/H exchange
2) stimulate AT1 receptor to inc. Aldo secretion
3) inc. Na reabsorption in DCT, CNT/CD
What are effects of increased aldosterone secretion?
Increased Na reabsorption in CNT/CD
What mechanisms contribute to reduction in sodium excretion
AKA restoration of Na balance via diuretic breaking
(1) inc. Na reabsorption in DCT, CNT/CD
(From AngII)
(2) inc. reabsorption in CNT/CD
(From aldo)
(3) inc. Na reabsorption in PT + DCT
(From symp tone)
Where does all regulation of potassium excretion occur?
CNT/CD
How does inc. Na reabsorption in CNT/CD lead to increased K secretion?
Inc. Na reabsorption via ENaC = Inc. electrochemical gradient for K secretion = Inc. K secretion
Describe effect of CAIs, LDs, and TZs on potassium excretion
All inc. sodium delivery to CNT/CD by inhibiting Na reabsorption proximal to CNT/CD = Inc. Na reabsorption in CNT/CD = Inc. electrochemical gradient for K secretion = Inc. K secretion in CNT/CD = Inc. K excretion (common AE of hypokalemia)
What effect does increased flow through CNT/CD have on K?
Further enhances electrochemical gradient by washing away secreted K
Describe effect of K-sparing diuretics on K excretion
Dec. Na reabsorption in CNT/CD by inhibiting ENaC = Dec. electrochemical gradient for K secretion = Dec. K secretion in CNT/CD = Dec. K excretion (Potential AE: hyperkalemia)
What other drugs spare potassium?
ACEIs
ARBs
Trimethoprim
(Related to triamterene)
How do CA inhibitors affect H+ and HCO3?
Dec. H+ secretion in PT by inhibiting CA = Dec. HCO3 reabsorption in PT = Inc. bicarbonate excretion
Common adverse effect: Metabolic acidosis (which limits ability of carbonic anhydrases because if pH is low enough, they aren't needed as much!)
What is effect of LDs and TZs on H+ and HCO3?
Both inc. sodium delivery to CNT/CD by inhibition Na reabsorption proximal to CNT/CD = Inc. Na reabsorption in CNT/CD = Inc. electrochemical gradient for H+ secretion = Inc. H+ secretion in CNT/CD = More new HCO3 made
Common AE = metabolic alkalosis
What are effect of K-sparing diuretics on H+ and HCO3?
Dec. Na reabsorption in CNT/CD by inhibiting ENaC = Dec. electrochemical gradient for H+ secretion = Dec. H+ secretion in CNT/CD = Dec. HCO3 reabsorption in CNT/CD = Inc. HCO3 excretion
(Potential AE: metabolic acidosis)
What are requirements for concentrating urine mechanism?
1) ADH
2) medullary gradient
What does formation and maintenance of medullary gradient require?
NaCl reabsorption in thick AL by NKCC2
Which is the transporter that Loop diuretics block
What effect do loop diuretics have on concentrating mechanism?
Markedly impair concentrating mechanism by completely abolishing medullary gradient
What are requirements for formation of a dilute urine?
1) no ADH
2) delivery of hypo-osmotic TF to CNT/CD
- have NaCl reabsorption in thick AL by NKCC2
- minor way to assure: block NaCl reabsorption by NCC in DCT
What effect do LDs have on diluting mechanism?
Markedly impair diluting mechanisms
Smaller impairment with thiazides
What is mannitol ?
Osmotic diuretic that produces both diuresis and natriuresis
How do osmotic diuretics work?
Dec. water reabsorption in PT = Dec. sodium in tubular fluid in PT = Dec. sodium reabsorption in PT
What is the maximum amount osmotic diuretics can dec. Na reabsorption ?
20%
What are examples of aquaretics?
ADH antagonists (“Vaptans”) = most selective:
Conivaptan
Tolvaptan
Demeclocycline
Lithium
How do aquaretics work?
Produce diuresis ONLY
Vaptans selective for V2 receptor
What are effects of V1A and V2 receptors?
V1A = Gq
Vasoconstriction
V2 = Gs
Anti-diuretic effects, urea permeability
In what conditions does edema most commonly occur?
HF
Cirrhosis
Kidney disease
What are therapeutic uses of diuretics?
Edema
Non-edema: HTN Nephrolithiasis Hypercalcemia Nephrogenic diabetes insipidus
Which diuretics are used for HTN?
Thiazides
What is a difference between chlorthalidone and hydrochlorothiazide?
Chlorthalidone = more potent, longer duration of action in maintaining low BP throughout 24 hours
What is nephrolithiasis?
Kidney stones
Why use a thiazides for kidney stones?
Decrease calcium excretion b/c many patients with these Ca-containing kidney stones got it from inc. calcium excretion
Tx: Thiazide cause mild volume depletion = Inc. Na reabsorption in PT = More calcium reabsorption in PT = Dec. calcium excretion
What usually causes hypercalcemia?
Inc. PTH
What is a possible treatment for hypercalcemia?
Inc. calcium excretion with a loop diuretic:
LD inhibits NKCC2 in thick AL = Dec. lumen positive TEP in thick AL = Dec. paracellular Ca reabsorption in thick AL = Inc. calcium excretion
What is an ADH congener?
Anti-diuretic
What is treatment for central DI ADH deficiency?
Replace ADH with an ADH congener (antidiuretic)
What does nephrogenic DI mean?
Nephrons failing to respond to ADH
How can you treat genetic and acquired nephrogenic DI?
Genetic:
Thiazides
Acquired:
Thiazides
Amiloride
What kind of therapy could be recommended to a patient with severe edema due to HF?
Start patient on LD
Add thiazide for more natriuresis
Add K-sparing diuretic for even more natriuresis
What AEs could be prevented or attenuated by adding K-sparing diuretic to LD/TZ?
Hypokalemia
Metabolic alkalosis
What is the most common use of K sparing diuretics?
In combo therapy with LD or TZ in order to:
Inc. natriuresis
Dec. hypokalemia
Dec. metabolic alkalosis
What is the main instance in which K-sparing diuretics are used alone?
In patients with high aldosterone
What are therapeutic uses of CAIs?
Acute mountain sickness
Glaucoma
What are osmotic diuretics used for?
To shift fluid from IC to EC compartment
Cerebral edema (IC edema)
Dialysis
Crush injuries
Glaucoma
What are aquaretics used for?
Syndrome of inappropriate ADH secretion (SIADH)
Hypervolemic hyponatremia
What is SIADH?
Syndrome of inappropriate ADH secretion
ADH secreted at level that is inappropriate for patient’s volume and osmolality status, resulting in hyponatremia
What are predictable AEs from diuretics?
K+ abnormalities
Acid-base disorders
Ca abnormalities
Hyponatremia
Hypomagnesemia
Hyperuricemia
And others
What predictable AE are caused by CAIs?
Hypokalemia
Metabolic acidosis
Nephrolithiasis
What predictable AEs are caused by LDs?
Hypokalemia
Metabolic alkalosis
Hypocalcemia
Hyponatremia
Hypomagnesemia
Hyperuricemia
Hypovolemic, postural hypotension
What predicable AEs are caused by thiazides?
Hypokalemia
Metabolic alkalosis
Hypercalcemia
Hyperuricemia
Hyponatremia
Hypomagnesemia
Hypovolemic, postural hypotension
What AEs are caused by K-sparing diuretics?
Hyperkalemia
Metabolic acidosis
(Spironolactone: gynecomastic, ED)
What AEs result from mannitol?
Pulmonary edema in patients with decreased LV function
What AEs are not predictable?
Hyperglycemia =
Thiazides, loop diuretics
Hyperlipidemia =
Thiazides, loop diuretics
Ototoxicity =
Loop diuretics
Rashes, etc…. any drug!
In what nephron segment does Bartter’s syndrome effect?
What transporters/channels are abnormal?
Thick AL
NKCC2 ROMK Cl channels Barttin subunit CaSR
What abnormalities are characteristic of Bartter’s syndrome?
What drug does it mimic?
Hypokalemia
Metabolic alkalosis
Hypercalciuria
Impaired concentrating mechanism
Mimics loop diuretics
What nephron segment does Gitelman’s syndrome affect?
What transporters/channels are abnormal?
DCT
NCC
Cl channels (CLC-KB)
What abnormalities are characteristic of Gitelman’s syndrome?
What drug does it mimic?
Hypokalemia
Metabolic alkalosis
Hypocalciuria
Normal concentrating mechanism
Mimics thiazides
What nephron segment does pseudohypo-aldosteronism affect?
What transporters/channels are abnormal?
CNT/CD
Mineralocorticoid receptor
What abnormalities are characteristic of pseudo-hypoaldosteronism?
What drug does it mimic?
Hyperkalemia
Hypovolemic
Mimics K-sparing diuretics
Why is synthetic ADH seldom used as an antidiuretic?
Prominent vasoconstrictor effects!
Name an ADH congener
Desmopressin
What is desmopressin used for?
Central DI
Nocturnal enuresis
Bed-wetting
What is an advantage of desmopressin vs. synthetic ADH?
Desmopressin has minimal V1A agonist activity = minimal vasoconstriction !!!
