Cardio Exam 1 - L2a Volume Control Diuretics

What fraction of fluid is inside the cells and what fraction of fluid is in the plasma? What is this important for?

2/3 inside cell, 1/3 in plasma & interstitial fluid

Conservation regulators for fluid balance?

(1) ADH

(2) Renin-angiotensin-aldosterone

Excretion regulators for fluid balance?

Natriuretic peptides

ADH is also known by what name?

vasopressin

ADH is produced by what part of the brain?

hypothalamus

ADH is released by what part of the brain?

posterior pituitary

ADH signals to what part of the body?

kidney tubules

ADH is released in response to?

Increased plasma osmolality OR severe hypovolemia

What are the two main ADH receptors?

V₁ and V₂

V₁ receptors are found on what cells?

Vascular smooth muscle cells

V₁ receptors are responsible for which actions?

• stimulate vasoconstriction

• Signaling for Gq

• “squeezing vessels”

V₂ receptors are found on what cells?

Collecting duct principal cells

V₂ receptors are responsible for what actions?

• signaling Gs → ↑ cAMP → PKA → P’ plate aquaporin 2 → insert aquaporin 2 vesicles into apical membrane → reabsorb H2O

• “saving water”

Explain how ADH regulates water consumption in the body

↑ ADH = ↑ water permeability, concentrated urine

• ADH binds to the V₂ receptor to activate AC and cAMP

• Water enters AQP2 from urine (lumen) on the apical side into the principal cell

• Water leaves AQP3 or AQP4 from principal cell into blood (interstitium) on the basolateral side

ULTIMATELY water leaves urine to be reabsorbed into the blood

What do natriuretic peptides, mainly ANP and BNP, ultimately function to do?

promotes vasodilation and sodium & water secretion when there is too much volume

What are the three main natriuretic peptides?

(1) ANP

(2) BNP

(3) CNP

Where is ANP released from?

Released from atrial myocytes when they are stretched by increased blood volume

What receptors do ANP act on?

NPR-A and NPR-C

Where is BNP released from?

Released from ventricular myocytes in response to stretch/pressure overload

What receptors do BNP act on?

NPR-A and NPR-C

Where is CNP released from?

Produced in vascular endothelium, more involved in vascular tone than volume regulation

What receptors do CNP act on?

NPR-B and NPR-C

What class of diuretics work on the proximal tubule?

• carbonic anhydrase inhibitors

• osmotic diuretics

What class of diuretics work on the thick ascending limb?

Loop diuretics

What class of diuretics work on the cortical collecting duct?

K+ sparing diuretics

What class of diuretics work on the distal convoluted tubule?

Thiazide diuretics

Explain the MOA of carbonic anhydrase inhibitors

• Inhibits carbonic anhydrase II and IV

  • HCO₃ and Na reabsorbed together increases water absorption

• ↓ HCO₃ reabsorption

• ↑ urine pH, becomes more alkaline

  • blood becomes more acidic

• Mild diuresis because Na can be reabsorbed later in the nephron

What are notable drugs categorized as carbonic anhydrase inhibitors?

• acetazolamide

• dorzolamide

• brinzolamide

What are clinical uses of carbonic anhydrase inhibitors?

(1) Glaucoma

• decreases aqueous humor (fluid in eye) to decreases pressure in eye

(2) Acute mountain or altitude sickness

• disease patho: vessels will try to dilate more to let in more oxygen, body goes through alkalosis (rapid decrease in CO₂ in blood causes body fluid pH to be too high)

• prevent secretion of HCO₃ by choroid plexus into the CSF → makes blood more acidic by preventing HCO₃ reabsorption → stimulates the body to breath more because in alkalosis

Limited use in HTN

• carbonic anhydrase inhibitors are weak diuretics

Adverse effects of carbonic anhydrase inhibitors?

(1) Metabolic acidosis

• due to HCO₃ loss

(2) Hypokalemia

• delivery of Na⁺ to distal part of nephron leading to K⁺ wasting

(3) Renal stones

• due to alkaline urine favors formation of calcium phosphate stones

MOA of osmotic diuretics?

• “water magnet” - holds water in tubule and prevents it from being reabsorbed

• Inert sugar alcohol that is filtered not reabsorbed

• creates intraluminal osmotic force that limits reabsorption of water across water-permeable nephron segments

• No receptors/transporters needed

• Leads to water loss and some Na+ loss

  • ↑ urine output

• greatest effect in proximal tubule

What notable drug is categorized as an osmotic diuretic?

Mannitol (IV)

Clinical uses of osmotic diuretics?

Reduce cerebral intravascular volume in patients with elevated intracranial pressure (head trauma, neurosurgery)

Adverse effects of osmotic diuretics?

(1) Hypernatremia

• H₂O loss w/o Na+ loss

(2) Natriuresis

• ↑ urine volume → need to monitor electrolytes

Contraindications for osmotic diuretics?

Contraindicated in active intracranial bleeding because increased plasma volume can increase bleeding

MOA for loop diuretics?

• Inhibition of NKCC2 on apical membrane in the thick ascending loop of henle 

  • Reduces reabsorption of Na, Cl, K (since it contains all has a very strong effect) 

  • Reduces reabsorption of Ca, Mg

  • Impairs concentrating function of the kidney (the urine isn’t mainly water)

• ‘High Ceiling’ Diuretics’

What notable drugs fall under loop diuretics?

• furosemide

• bumetanide

• torsemide

• ethacrynic acid

Clinical uses for loop diuretics?

(1) Edema states [FIRST LINE]

• CHF, cirrhosis, nephrotic syndrome, pulmonary edema

(2) Hypercalcemia

•  increases Ca excretion → loops lose Ca

(3) Hyperkalemia

In general: Loops are ‘High Ceiling’ Diuretics that lead to substantial diuresis

Explain half life and duration of action for loop diuretics

Has longer duration of action even though they have a short half life

• moves large amounts of salt when present

Adverse effects of loop diuretics?

(1) Volume depletion and hypotension 

(2) Electrolyte disturbance 

• Hypokalemia (increases risk of arrhythmia) 

• hypocalcemia , hypomagnesemia 

• Metabolic alkalosis due to volume contraction  

(3) Ototoxicity

• altered electrolytes in endolymph (inner ear fluid)

• Caution with other ototoxic drugs (ex. aminoglycosides) 

(4) Hyperuricemia

• loops can compete with uric acid for secretion and increase risk of gout attacks

  • fyi: gout caused by uric acid crystal build up in joints

Explain how concurrent loop and NSAID use can lead to a weaker diuretic response

• NSAIDs reduce the natriuretic/antihypertensive effects of loops

• inhibits cyclooxygenase (COX)

  • COX: ↑ prostaglandin synthesis, ↑ renal vasodilation, ↑ renal blood flow, ↑ natriuresis and diuresis

What can concurrent loop and NSAID use in states of compromised renal perfusion lead to?

acute kidney injury (AKI)

MOA of thiazide diuretics?

• competitive antagonist of the NCC co-transporter on the apical surface of distal tubules

• Decrease reabsorption of Na+ and Cl- (‘low ceiling diuresis’)

• Increased reabsorption of Ca (Thiazides “tighten” Ca)

• Moderate diuresis

What are notable drugs under thiazide diuretics?

• Hydrochlorothiazide (HCTZ)

• Chlorthalidone

• Indapamide

• Metolazone

Clinical uses for thiazides?

(1) HTN

• leads to modest naturiuresis and intravascular volume depletion as well as reduced peripheral vascular resistance due to relaxation of arteriolar smooth muscle

(2) Nephrolithiasis/kidney stones and calcium oxalate stones in urinary tract

• thiazides promote Ca²⁺ uptake by TRPV5 channel

(3) CHF

• use of metolazone with loop diuretics-combined prevention of Na+ reabsorption in TAL (loops) and DCT (thiazides)

(4) Nephrogenic diabetes insipidus

• inability to concentrate urine due to impaired ADH response

• can paradoxically produce modest decrease in urine flow by reducing GFR and intravascular volume

HCTZ vs Chlorthalidone dosing?

HCTZ: short half life = multiple times a day dosing

Chlorthalidone: longer half life, better at preventing nocturnal hypertension

Explain why thiazide diuretics are considered a ‘low ceiling’ diuretic

moderate diuresis → even at higher doses no extra effect on diuresis (increasing dose only increases ADRs)

AEs for thiazide diuretics

(1) Metabolic effects

• hyperuricemia/gout due to competition for uric acid secretion 

• Hyperglycemia due to to impaired insulin release with hypokalemia

(2) Electrolyte disturbances

• Decreased K, Mg, Na

• Increased Ca (thiazides tighten Ca) 

• Efficacy may be diminished with use of NSAIDs which decreases renal PGs and reduces renal blood flow

MOA of collecting duct diuretics and associated drugs?

Targets principal cells to reduce Na+ reabsorption by:

(1) Inhibit synthesis of ENaC by blocking mineralocorticoid receptor translocation (MRAs)

• spironolactone & eplerenone (more selective for mineralocorticoid)

(2) Competitive functional inhibitors of ENaC

• Amiloride and triamterene

Clinical uses of Mineralocorticoid Receptor Antagonists?

(1) HTN

• 20% of patients have higher aldosterone (usually obese) 

• ↑ ENaC channels

(2) CHF

• lower doses to prevent myocardial remodeling from aldosterone

(3) Hypokalemia and hypokalemic alkalosis 

• MRAs make blood more acidic

(4) Polycystic ovary syndrome

• inhibit androgen receptor 

(5) Cirrhosis/ascites

• edema associated with mineralocorticoid excess and impaired plasma protein production in liver failure 

AEs for Mineralocorticoid Receptor Antagonists?

(1) Hyperkalemia

• inhibition of Na uptake reduces force that drives normal K+ secretion (also cause potassium sparing diuretics) 

(2) Gynecomastia and impotence

• inhibit the androgen receptor (spironolactone >> eplerenone)

Clinical uses for ENaC competitive inhibitors?

(1) HTN

• used in combo with other diuretics to prevent hypokalemia

(2) Liddle syndrome

• rare form of hypertension that results from gain-of-function mutations in ENaC

(3) Lithium toxicities

• amiloride can block ENaC reabsorption of lithium and prevent diabetes insipidus and risk of renal cancers

AEs for ENaC competitive inhibitors?

(1) Hyperkalemia

• similar to mineralocorticoid receptor antagonists

(2) Metabolic acidosis

• less Na uptake by ENaC diminishes H+ secretion → acidosis