9/11- Pharmacology and the Kidney I: Diuretics Flashcards
What hormone primarily regulates the serum sodium level?
A. ADH (anti-diuretic hormone)
B. ALdosterone
C. Renin
D. WCH (water controlling hormone)
What hormone primarily regulates the serum sodium level?
A. ADH (anti-diuretic hormone)
B. ALdosterone
C. Renin
D. WCH (water controlling hormone)
Clinical manifestations of excess salt (volume overload) in the body include:
A. Increased thirst
B. Peripheral edema
C. ?
D. ?
Clinical manifestations of excess salt (volume overload) in the body include:
A. Increased thirst
B. Peripheral edema
C. ?
D. ?
- Increased thirst is more for hypernatremia
Define:
- Natriueresis:
- Aquaresis:
- Diuresis:
- Diuretic:
- Natriueresis: increased renal excretion of sodium
- Aquaresis: excretion of water without electrolyte loss
- Diuresis: increased urine excretion
- Diuretic: substance that increases the excretion of urine (caffeine, alcohol, cranberry juice)
Body volume disturbances reflect what? Dysnatremias reflect what?
Body volume disturbances reflect sodium content changes
- Volume depletion: loss of Na and water
- Volume overload: retention of Na and water
Dysnatremias reflect water balance
- Hyponatremia- too much ADH
- Hypernatremia- in access to water, DI
What are the proximal tubule transport mechanisms?
NaHCO3 reabsorption is most relevant to diuretic action in the PCT
- Na-H exchanger in luminal membrane (Na in; H out)
- H couples with HCO3- in lumen before CA converts it to H2O and CO2
- CO2 is taken up over apical membrane to reverse reaction, creating HCO3 and H inside cell
—- H can then be pumped out by Na-H exchanger
—- HCO3 pumped over basal membrane
What is the mechanism of Acetazolamide? Effects?
Carbonic anhydrase inhibitor in the proximal tubule
Effects:
- Na bicarbonate diuresis
- Hyperchloremic metabolic acidosis
Clinical uses of Acetazolamide?
- Glaucoma: Decreases the rate of aqueous humor formation with decrease in intraocular pressure
- Urinary alkalinization: uric acid and cysteine are more soluble in alkaline urine
- Metabolic alkalosis: diuretic induced
- Acute mountain sickness: acidosis leads to increased ventilation.
Toxicity of Acetazolamide?
(Recall: CA inhibitor)
- Hyperchloremic metabolic acidosis
- Hypokalemia (renal K wasting)
How do diuretics induce renal K wasting?
Increased distal Na delivery drives K secretion
- High aldosterone
What is the mechanism of Mannitol? Effects?
Osmotic diuretic
- Prevents water reabsorption in the proximal tubule and tDLH (freely water permeable)
- Opposes ADH action in the collecting tubule
Effect = increased urine volume
- Reduced Na reabosrption (Increase in urine flow rate decreases the contact time between fluid and tubular epithelium)
What are the clinical uses of osmotic diuretics?
- Cerebral edema: decreased ICP - alter Starling forces so that water leaves cells and reduce intracellular volume
- Acute congestive glaucoma: reduction of intraocular pressure
- Increase urine volume to prevent an oliguric phage of an AKI in setting of Hemolysis or Rhabdomyolysis.
(Not typically liked/used by nephrologists)
Toxicity of osmotic diuretics?
- Extracellular volume expansion along with hyponatremia: extracts water from cells
(This effect can complicate CHF and may produce florid pulmonary edema)
- Dehydration and hypernatremia: can ultimately lead to excessive free water losses
What diuretics work in the proximal tubule?
- Acetazolamide
- Osmotic diuretics (mannitol)
What are the transport mechanisms in the loop of Henle?
Apical:
- Na-K-2Cl cotransporter
- K channel
Basal:
- Na-K exchanger
- K-Cl cotransporter
What are the main diuretics that work in the LoH?
What channel/process do they block?
Loop diuretics: Furosemide
- Inhibits Na-K-2Cl co-transporter in TALH (thick)
What are the effects of loop diuretics?
- Very potent diuretic
- Induce NaCl diuresis
- Decrease positve lumen, the driving force for Mg2+ and Ca2+ absorption, cause an increase in Mg2+ and Ca2+ excretion
- Cause K+ wasting
- Induce renal prostaglandin synthesis that increases renal blood flow and vasodilation
Clinical Uses of loop diuretics?
- Acute pulmonary edema
- Edematous conditions: heart failure, cirrhosis, nephrotic syndrome
- Hypercalcemia and Hyperkalemia
- SIADH
Hypertension:
- Refractory cases
- Associated with renal insufficiency or heart failure
- Hypertensive emergencies
How do loop diuretics help with SIADH?
- In LoH, Na reabsorption without water concentrates the medulla (hypeosmolar medulla provides urine concentrating ability)
- Loop diuretics block Na reabsorption in LoH, getting rid of hyperosmolar medulla and blocks responses to ADH
Toxicity of loop diuretics?
- Hypokalemic metabolic alkalosis
- Hypomagnesemia
- Hyperuricemia (hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule)
- Ototoxicity (hearing loss; dose-related)
What are the transport mechanisms in the distal convoluted tubule?
Apical:
- Na-Cl cotransporter
- Ca transporter
Basal:
- Na-K- ATPase
- Na-Ca exchanger
- Cl channel
What is hydrochlorothiazide (HCTZ) (broad class)?
Thiazide diuretic
What channel do thiazide diuretics block?
Inhibits Na-Cl cotransporter in the DCT
What are the effects of thiazide diuretics?
(Blocks Na-Cl contransport)
- Induce NaCl diuresis
- Icrease Ca reabsorption:
— In the PCT, thiazide-induced volume depletion -> enhanced Na and passive Ca reabsorption
—- In the DCT, lowering IC Na by thiazide -> more Na/Ca exchange in teh basolateral membrane
- Renal K wasting
What are some clinical uses of thiazide diuretics?
- HTN
- Heart failure
- Renal stones due to idiopathic hypercalcuria
- Nephrogenic diabetes insipidus
How do thiazide diuretics help in diabetes insipidus?
- The absence of ADH (central DI) or resistance to ADH actions in the kidney (nephrogenic DI)
—- Causes rapid loss of water and an increase in osmolality
- Thiazide-induced Na losses -> more Na reabsorption in the proximal tubule and decreases urine formation
Toxicity of thiazide diuretics?
Hypokalemic metabolic alkalosis
Hyperuricemia
Hyponatremia
- Hypovolemia-induced elevation of ADH
- Reduction in the diluting capacity of the kidney
- Increased thirst
Hyperglycemia
- Impaired insulin release
- Diminished tissue utilization of glucose
Hyperlipidemia
What are the ion transporters at play in the collecting duct?
Apical:
- Na channel (into cell)
- K channel (into lumen)
- H2O (into cell)
Basal:
- ALD action (Mineralocorticoid receptor, MR)
- ADH receptor
- Na-K-ATPase
INTERCALATED CELLS
Apical:
- H-ATPase (pumping H into lumen)
Basal:
- HCO3-Cl exchanger (HCO3 out, Cl into cell)
____ diuretics inhibit the effects of aldosterone at the late distal and cortical collecting tubules
K-sparing diuretics inhibit the effects of aldosterone at the late distal and cortical collecting tubules
What are the mechanisms of action/blocked transporters of K-sparing diuretics?
1. Direct antagonism of mineralocorticoid receptors (aldosterone)
- Spironolactone
- Eplerenone
2. Inhibition of Na entry thru ion channels in the luminal membrane
- Amiloride
- Triamterene
What are the effects of K-sparing diuretics?
- Increase urine NaCl excretion
- Hyperkalemia
- Metabolic acidosis
What are clinical uses of K-sparing diuretics?
- Primary and secondary hyperaldosteronism
- Heart failure
- Cirrhosis
What is toxicity of K-sparing diuretics?
- Hyperkalemia
- Hyperchloremic metabolic acidosis: like type IV renal tubular acidosis (similar to type IV RTA)
- Gynecomastia: spironolactone-adrogen receptor (dihydrotestosterone) (painful breasts)
How can you measure diuretic effectiveness?
- Depletion of extracellular volume to treat hypertension or edematous states is easily measured as a decrease in body weight
- Check Daily Weights
- “I’s & O’s” are usually inaccurate and net changes over time are rarely available
- Plasma electrolytes are limited in value
Describe diuretic resistance- what could cause it?
- Normal Response: Compensation
- Inadequate Dose
- Inadequate control of salt intake
- Drug interactions (e.g., NSAIDs)
- Reduced bioavailability: (CHF, CKD, Hypoalbuminemia)
How do you deal with diuretic resistance?
- Assess Compliance with Salt restriction and medicine intake. If necessary, measure the amount of salt and diuretic in the urine
- Discontinue NSAIDs
- Adjust the dose of the diuretic in patients with renal impairment
- Switch to intravenous administration to overcome problems associated with impaired absorption
- Switch to a continuous intravenous infusion of a loop diuretic to avoid postdiuretic salt retention
- Combine loop diuretics with other diuretics, preferably a thiazide diuretic
What diuretics work at the:
- Proximal tubule
- LoH
- DCT
- Collecting tubule
Proximal tubule
- Carbonic anhydrase inhibitors
- (Osmotic agents)
LoH
- Furosemide
- Bumetanide
- Ethyacrinic acid
DCT
- Thiazides
Collecting tubule
- Aldosterone receptor antagonists (spironolactone)
- Epithelial sodium channel inhibitors (amiloride)
