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)

9/11- Pharmacology and the Kidney I: Diuretics Flashcards by Kathryn Kudlaty

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)

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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

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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)

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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

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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

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What is the mechanism of Acetazolamide? Effects?

Carbonic anhydrase inhibitor in the proximal tubule

Effects:

Na bicarbonate diuresis
Hyperchloremic metabolic acidosis

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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.

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Toxicity of Acetazolamide?

(Recall: CA inhibitor)

Hyperchloremic metabolic acidosis
Hypokalemia (renal K wasting)

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How do diuretics induce renal K wasting?

Increased distal Na delivery drives K secretion

High aldosterone

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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)

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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)

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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

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What diuretics work in the proximal tubule?

Acetazolamide
Osmotic diuretics (mannitol)

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What are the transport mechanisms in the loop of Henle?

Apical:

Na-K-2Cl cotransporter
K channel

Basal:

Na-K exchanger
K-Cl cotransporter

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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)

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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)