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Common indications of diuretics

*all treat volume overload states by increasing urine volume *

HF, CKD, renal failure, idiopathic edema, HTN, diabetes insipidus, glaucoma, nephrolilithis, hypercalcemia


What are the two major board diuretic categories?

- increase urine volume by excretion of Na+
- includes: spironolactone, furosemide, and carbonic anhydrase inhibitors

- increase urine volume by excretion of solute-free water (just water)
- includes: mannitol, desmopressin, conivaptan


Where do diuretics act?

Inside the tubule. MOST diuretics get absorbed in the PCT to actually start its effects


Common adverse responses to diuretics

Rapid loss of ECF by reducing plasma volume

Low blood volume and hyponatremia

Metabolic alkalosis
- too much reduction in ECF without concomitant reduction of bicarbonate

Hypomagnesemia, hyperuricemia, hyperlipidemia

Otoxcity and drug allergies


Where does carbonic anhydrase inhibitors work?

- classic prototype is acetazolamide

Indicated most for edema and glaucoma


How does sodium reabsorption work in PCT

Basolateral Na/K+ ATPase pumps establish Na+ concentration gradient favoring sodium moving INTO PCT from urine (reabsorption)
-however, to move into interstital fluid, requires carbonic anhydrase enzymes to produce H+/HCO3- ions intracellularly from H20/CO2 extracellularly

Secondary active transporters use this sodium gradient to reabsorb proteins, glucose and other ions as well as sodium itself.


What is the physiological responses to carbonic anhydrase inhibtors

Increases delivery of solutes to the macula densa which induces tubuloglomerular feedback
- increases afferent arteriolar resistance which reduces renal blood flow and GFR

**(how it combats diuresis)**


What does the ceiling effect and diuretic threshold effects for loop diuretics mean?

Threshold effect = requires a certain dose to actually work and elict an effect

Ceiling effect = after a certain dose (varies amount patients, there can no more benefit and only harm to the patient

**because of the ceiling effect, you need to monitor what is the appropriate dose for each patient**


What drives the paracellular reabsorption of (Ca2+/Mg2+) cations in the TAL?

ROMK channels (potassium efflux channels in TAL)
- establishes a trans-epithelial voltage differential in the lumen which pushes Ca2+/Mg2+ into the TAL/interstital space


Where do thiazaides act on?



Where do loop diuretics work?

Loops of Henle and TAL


Where do thiazides work?



How does thiazides sometimes cause hyperglycemia?

Off target effect that binds to ATP-sensative K+ channels on pancreatic B-cells and act as a agonist
- this hyperpolarization of these cells prevents insulin release


Diuretic adaptation and resistance

Kidneys are highly adaptive and will induce a “braking phenomenon” where it essentially adapts tot he diuretic effects to prevent too much excretion or reabsorption


Most common type of diuretic combination therapy

Loop diuretics + thiazides (metrolazone usually)
- used to treat refractory loop diuretic treatment
- blocking’s both TAL and DCT syngeriszes the effects

**very high risk of K+ wasting and hypokalemia though**


How does desmopressin and vasopressin differ in function?

Desmopressin = acts only on V2R receptors
- much higher antidiruetic effects with minimal vasoconstriction

Vasopressin = ACEIs on V1aR/V1bR and V2R receptors
- has both high antidiuretic and vasoconstriction effects


Difference between central diabetes insipidus and nephrogenic diabetes insipidus

Central diabetes insipidus:
- inadequate production or secretion of ADH by the posterior pituitary
- wide variety of causes
- first line treatment is ALWAYS vasopressin agonist (unless CAD is present)

Nephrogenic diabetes insipidus
- inadequate response of the kidney to ADH (doesnt respond to it)
- almost always hereditary (mutations in V2)
- can also be drug induced or electrolyte toxicity
- first line treatment varies based on MOA of issue (usually thiazides)


How does diabetes insipidus occur in pregnancy

Increasing levels of circulating vasopressinase (which decreases natural vasopressin sensativity)

DONT give direct vasopressin


What is first line therapy in nephrogenic DI

Thiazides diuretics
- works by reducing RBF/GFR and allows for more reabsorption in the proximal tubule


lithium induced nephrogenic diabetes insipidus

Occurs in 1:3 patients using lithium
- occurs due to reduces cAMP production by reducing V2 receptor agonism by lithium using ENaC receptors in the collecting tubule
- Results in less aquaporins in the collecting ducts and more water secretion
- also increases plasma levels of PTH

Treatment = first line is amiloride to block lithium from using ENaC to enter collecting tubules


What vasopressin antagonists can be used for SIADH

Democlocycline And tolvaptan

**cant use demeclocycline in patients under 12**


What vasopressin antagonists can be used in CHF?

- binds to V1aR receptors and decreases peripheral vascular resistance/increases cardiac output

- adjuvant only for diuretic therapy in CHF patients

***used to combat hyponatremia seen in heart failure due to elevated ADH levels***


Vasopressin antagonists to use in polycystic kidney disease

- blocks V2R receptors and reduces cAMP levels which delays cysts formation
** produces hepatotoxicity however


What is osmotic demyelination syndrome

A acute quick rise in sodium levels after originally being hyponatremic
- the lower the initial hyponatremic, the worse osmotic demyelination syndrome can be

Results in rapid fluctuations of ECF/ICF volumes and causes damage myelin sheaths and causes neurotoxicity symptoms

***alcoholism and SIADH both increases the risk significantly***


How does alcohol effect vasopressin?

Inhibits the release of vasopressin from posterior pituitary which results in excessive diuresis
- lowers efficacy of vasopressin

**in alcohol withdrawal states, vasopressin sensitivity is very heightened and often results in water retention and hyponatremia**


How does carbonic anhydrase Inhibtors (acetazolamide and the rest of the “lamides”) cause their ADRs?

Hyperchloremic metabolic acidosis (non anion gap)
- cause increased chloride reabsorption since HCO3- stays in the lumen of filtrate (negative charges repeal each other)
- H+ ions cannot be reabsorbed easily either

Alkaline urine
- increased HCOs- = alkaline

Potassium wasting
- increase sodium present at the CD causes ENaC channels to increase overall numbers of sodium reabsorption (but still only a certain percentage since channels get saturated). increased Na+ inside CD cells forces potassium out into the the lumen leading to hypokalemia (potassium wasting)

Hepatic encephalopathy
- alkaline urine causes NH4+ to be converted to NH3 (toxic form that secretes out of lumen via gaseous movement)


How does carbonic anhydrase inhibitors treat acute mountain sickness?

In acute mountain sickness, increased hyperventilation as a response to low O2 causes increased CO2 ventilation = alkalosis
- carbonic anhydrase Inhibtors both reduce CO2/H+ loss while increasing HCO3- loss

This combats the alkalosis


How does the prediuresis effect of mannitol and glycerin (osmotic diuretics) work?

The presence of either of these two causes water to leave cells and enter the plasma and eventually the urine as a diuretic

HOWEVER, when water leaves the intracellular space, it briefly enters the extracellular space and then enters the plasma/blood stream. This increases ECF volume and Lowers extracellular electrolyte concentrates (specifically sodium)
- because of this acute increase in ECF, it is contraindicated in CHF and pulmonary edema since it exacerbates these conditions, even if temporarily.
- also contraindicated in renal failure since the kidneys cant filter stuff anyways


How does the TAL work altogether?

1) due to increased concentrated urine with solutes from the descending thin and thick limbs reabsorption of water, Na+/K+ and Cl- are all reabsorbed.
- this occurs via the NKCC2 (Na/K/2Cl) symporter channel
- **uses Na+ natural concentration gradient to move into cells (K+/Cl- use this energy to follow via secondary transport)

2) the increases in intracellular concentration electrolytes forces K+ out of TAL cells (Na+ in high concentrations forces K+ out down its concentration gradient) back into the lumen
- this allows Mg2+/Ca2+ to move into interstitium via paracellular route via the K+ potential energy moving into the lumen (increases K+ in lumen repeals Mg2+/Ca2+ into the interstiitum)


Why is amiloride first line in lithium induced DI?

Li+ can use ENaC sodium channels in the CD to be reabsorbed (continue inducing diabetes insipidus

Amiloride blocks ENaC channels