Diuretics and Kidney SketchyPharm Flashcards
What are the metabolic effects of acetazolamide and what type of urine / osmolyte imbalances will it cause? What type of drug is it?
Normal anion gap hyperchloremic metabolic acidosis -> by blocking bicarbonate reabsorption, NaCl reabsorption is favored, and base is lost.
Urine - becomes alkalinized, due to high concentration of bicarbonate
Electrolytes: causes hypokalemia due to increased distal convoluted tubule ENaC absorption to compensate (think of banana on ground next to red #2 car)
It is a sulfa drug (like most diuretics)
Give two uses for CA inhibitors which involve decreased fluid production?
Idiopathic intracranial hypertension / pseudotumor cerebri - Decreased CSF production
Glaucoma - Decreased aqueous humor production
-> typically dorzolamide
Other than rare use in glaucoma, what are the primary clinical indications of acetazolamide? What will be made worse by this?
- Cystinuria and hyperuricemia -> cystine and uric acid are more soluble in alkaline urine
- Treatment of metabolic alkalosis in edematous states (fluid overload, good to correct this) -> induction of a Type 2 renal tubular acidosis
- Altitude sickness -> corrects respiratory alkalosis caused by hyperventilation by inducing acidosis.
Calcium phosphate stones will be made worse by this -> less soluble in higher pH
What are the three most important indications of mannitol?
- Cerebral edema
- Prevention of dialysis disequilibrium syndrome (rapid removal of osmolytes from plasma causes cerebral edema)
- Intoxications - enhances urinary excretion of toxins / drugs
What are the acute and chronic effects of mannitol on plasma osmolality? Volume status overtime?
Acutely - hyponatremia - pulls water into ECF, diluting sodum
Chronically - Hypernatremia - dehydration due to decreased free water clearance
ECF volume - diuresis of sodium and water leads to hypovolemia (drop in total body Na)
What are the contraindications of mannitol?
- Heart failure - expands ECV, even more likely to cause pulmonary congestion / pulmonary edema
- Anuria - severe intracellular hyponatremia due to expanded ECV.
How do loop diuretics interact with the COX system?
They actually stimulate COX2 synthesis -> PGE2 release -> vasodilatory effect on afferent arteriole
- > think of the proslugger bat
- > makes them an even better diuretic
What is one scary and possibly irreversible side effect of loop diuretics?
Ototoxicity - deafness. Think of gong in sketchy
-> NKCC2 is present in cochlear stria vascularis, results in edema of ear if blocked
What metabolic acid state do loop diuretics induce?
Metabolic alkalosis - probably due to contraction alkalosis (think of guy squeezing out water from tube in sketchy) -> increased angiotensin II (stimulates Na/H exchanger) and aldosterone (stimulates H+ secretion for K+ reuptake in alpha intercalated cell).
Can loop diuretics or thiazide diuretics cause an arthritis?
Yes! Both cause hyperuricemia -> gout.
This is because uric acid reabsorption is increased in low volume states.
How is calcium reabsorbed in the distal convoluted tubule (DCT, that is, NOT collecting duct)? What controls this?
Entirely through the transcellular route, via apical TRPV5 channels and basolateral Ca+2-ATPase and NCX.
TRPV5 channels are upregulated by PTH and calcitriol. NCX also upregulated by PTH (basolateral Na/Ca exchanger)
What are the acquired causes of nephrogenic diabetes insipidus?
Hypercalcemia, hypokalemia
-> impairs cAMP mechanisms, abnormal AQP2 number
Remember hypokalemia lecture mentioned impaired renal concentrating ability
Remember hypercalemic lecture (polyuria)
What are the treatments for central and nephrogenic diabetes insipidus?
Central - ADH or desmopressin
Nephrogenic - hydrochlorothiazide - NCC channel in DCT is responsible for making iso-osmotic filtrate hypo-osmotic (down to 50mOsm / L). Knocking this out will make all the urine lost only iso-osmotic (300 mOsm/L) -> improves quality of life
What are rarer but important possible side effect of thiazide diuretics?
Hypercalcemia - never give if hypercalcemic, as can worsen problem via volume contraction and increased reabsorption as well
Acute interstitial nephritis (they are sulfa drugs)
Hyperlipidemia and hyperglycemia (think of candy and butter on high platform in sketchy)
Why do you have to be careful when treating nephrogenic DI due to lithium use with thiazide diuretics?
Thiazide diuretics increase lithium levels, as do NSAIDs, ACE inhibitors, and calcium channel blockers (i.e. verapamil)
Think lithium Liftium.
What process forces K+ wasting in the collecting duct and in what cell does it primarily occur?
Primarily occurs in the principle cells, via ENaC / ROMK
Negative intraluminal potential generated from Na+ reabsorption via ENaC activity stimulates K+ excretion
What transporters does aldosterone normally increase the speed or number of?
Principle cell: Na/K ATPase, ENaC, ROMK
Alpha-intercalated cell: H+ ATPase
Think of all the things with keys in them on the right side of the K+ sparing diuretics sketchy
What are the drug targets of spironolactone, amiloride, triamterene, and eplerenone?
Spironolactone / eplerenone - aldosterone antagonists - good for Conn syndrome
Amiloride / Triamaterene - ENaC inhibitors - good for Liddle’s syndrome (ENaC gain of function)
Which K+ sparing diuretics have proven mortality benefit in heart failure and how?
Spironolactone / eplerenone - reduce the aldosterone-mediated cardiac remodelling
What K+ sparing diuretic can be used for the treatment of Li+-induced diabetes insipidus and how?
Amiloride - prevents Li+ entry into cells (Enters via ENaC).
-> think of the almonds cart the ADH sketch
What type of renal tubular acidosis can K+ sparing diuretics cause?
Hyperkalemia (Type IV) renal tubular acidosis (hypoaldosteronism)
What is the mechanism of action of spironolactone in the treatment of PCOS?
Inhibits testosterone synthesis via inhibition of 17,20-desmolase / 17a hydroxylase - useful for the treatment of hirsutism and reduction in circulating androgens (which drives the inhibition of conversion to estrogens, inhibiting FSH release and causing ovarian failure)
What is the role of ADH in limiting blood loss during injury?
- Induces secretion of Factor 8 and von Willebrand factor from vascular endothelium -> promotes clotting
- Vasoconstriction
What are three signals for ADH secretion?
- Hyperosmolality
- Volume depletion
- Angiotensin II
-> inhibited by alcohol
What are the ADH receptor subtypes?
V1 = vasoconstriction, Gq (think of the Q hole on the left)
Most important effects at physiological levels:
V2 = AQP2 channels to the membrane via cAMP!!, Gs
V2-like: factor 8 / von Willebrand
What is the primary agent used to treat central DI, and its advantages over ADH?
Desmopressin - synthetic ADH agonist (DDAVP)
- > less affinity for V1 receptors, diminishing vasoconstriction.
- > think of V2 engine
- > more resistant to degradation, only need twice daily
What can desmopressin be used for, other than central DI?
- Nocturnal enuresis - think of the wet mattress on the back of the buggy
- von Willebrand disease - induced vWF release from endothelial cells via V2 receptors
- mild hemophilia A (factor 8 deficiency) - induces factor 8 release as well as vWF, which stabilizes factor 8.
What are the adverse reactions of desmopressin?
- Vasoconstriction -> contraindicated in coronary artery disease
- Water intoxification - really bad in high blood pressure and heart failure
- Hyponatremia - due to overdilution of blood, manifests as headache and nausea before CNS effects. Avoid in renal failure
What are the treatments for SIADH?
- Water restriction
- Loop diuretics
- IV hypertonic saline
- Demeclocycline - interferes with ADH
- Tolvaptan / conivaptan - V2 receptor antagonists
What might exogenous vasopressin (not desmopressin) be specifically useful for?
Treatment of esophageal varices -> V1 receptor can constrict these veins. -> think of the blue golf club guy with ADH backpack next to the V1 receptors
