Osmotic Diuretics

5. Osmotic Diuretics
Osmotic diuretics, like mannitol (IV), are distributed into the ECF and are freely filtered into the glomerulus. This allows the water to be drawn out from cells. The drug can act on all sites of the nephron permeable to water.

Osmotic diuretics can be used to treat:
-edema
-increased intracranial pressure
-increased intraocular pressure
-adjunct to cisplatin (minimize nephrotoxicity)

Adverse effects of osmotic diuretics include:
-ECF expansion
-headache
-dizziness
-nausea and vomiting
-pulmonary edema
-hyponatremia
-dehydration and hypovolemia
-nephrotoxicity

Contradictions to osmotic diuretics include:
-allergy
-severe dehydration
-severe renal disease
-renal dysfunction
-active cranial bleeding
-progressive heart failure
-pulmonary edema

Potassium Sparing Diuretics

4. Potassium Sparing Diuretics

ENaC Inhibitors
ENaC is a Na+ pump on the apical side of principal cells in the collecting duct. Amiloride blocks Na+ reabsorption causing a decrease in Na+/K+ ATPase activity causing K+ retention. As a result of the reduced K+ electrochemical gradient, there is increased reabsorption of H+, Ca2+, and Mg2+. ENaC polymorphism (T594M) can cause increased sensitivity to the drug.

ENaC inhibitors can be used to treat:
-hypertension
-Li+ induced nephrogenic diabetes
-Liddle Syndrome (pseudohyperthyroidism)

Adverse effects of ENaC inhibitors include:
-hyperkalemia (contradicted in those who have it)

Drug interactions with ENaC inhibitors include:
-ACE inhibitors and ARB (hyperkalemia)
-NSAIDs (hyperkalemia)
-K+ supplements (hyperkalemia)

Mineralocorticoid Receptor Inhibitors
Aldosterone binds to mineralocorticoid receptors, increasing Na+/Cl- reabsorption and K+/H+ secretion. MR inhibitors, such as spironolactone and eplerenone, block ALDO from binding. As a result, there is increased Na+ and Cl- excretion, and increased H+ secretion. Spironolactone can cause antiandrogenic effects like gynecomastia and impotence.

MR inhibitors can be used to treat:
-edema
-hypertension
-primary aldosteronism
-heart failure
-hirsutism (interfere with testosterone)
-hepatic cirrhosis (spironolactone is drug of choice)

Drug interactions with MR inhibitors include:
-Digoxin (decreased clearance with spironolactone)
-CYP3A4 mediated interactions (eplerenone)

Thiazide Diuretics

3. Thiazide Diuretics
Thiazides block the NCC channel in the distal convoluted tubule. This prevents the reabsorption of Na+ and Cl-. Hydrochlorothiazide is a benzothiadiazine derivative while chlorthalidone lacks the benzothiadiazine structure. Chlorthalidone has a longer half-life than hydrochlorothiazide. Thiazides have a moderate diuretic effect. They cause kidney to excrete Na+, Cl-, K+ and titratable acid. However they also cause an increase in Ca2+ reabsorption.

Unlike loop diuretics, the increase in Na+ delivery to the DCT will not cause activation of RAAS. Thus the kidney is unable to compensate for the Na+ excretion, resulting in concentrated urine.

Thiazides can be used to treat:
-congestive heart failure
-hepatic cirrhosis
-nephrotic syndrome
-chronic renal failure
-acute glomerulonephritis
-hypertension
-nephrogenic diabetes

Adverse effects of thiazides include:
-hyponatremia
-hypotension
-hypokalemia
-metabolic alkalosis
-hypomagnesemia
-hypercalcemia
-hyperuricemia (gout)
-hyperglycemia
-hypersensitivity to sulfonamides

Drug interactions with thiazides include:
-Digitalis glycosides (hypokalemia --> arrhythmia)
-Lithium (enhanced Na+ excretion --> lithium toxicity)
-Antihypertensive drugs (hypotension)
-Vitamin D analogs (increase Ca2+)
-Anti-diabetic drugs (hyperglycemia)
-Probenecid (blocks OAT so drug can't get in)
-NSAIDs (block COX-2 --> decreased prostaglandins --> decreased vasodilation --> decreased GFR --> blunted response because not much is filtered)
-Amphotericin B (hypokalemia)
-Glucocorticoids (hypokalemia)
-ACE Inhibitors (increased nephrotoxicity)

Loop Diuretics

2. Loop Diuretics
Loop diuretics block the NKCC channel at the Thick Ascending Loop of Henle. This prevents the reabsorption of Na+, K+, and Cl-. Therefore there is no the potential difference formation, so other solutes (Ca2+ and Mg2+) are also not reabsorbed. In addition to the excretion of Na+, K+, Cl-, Ca2+, Mg2+, there is also increased excretion of titratable acid and decreased excretion of uric acid (gout). Furosemide is a sulfonamide drug. Ethacrynic acid is not. Loop diuretics are highly efficacious as other segments of the nephron are unable to compensate. Furosemide causing venodilation, reducing preload before diuresis occurs. The inhibition of salt transport into the macula densa (low Na+) and the volume depletion (baroreceptor) causes an increase in renin which increases GFR.

Diuretics can evoke compensatory mechanisms such as activation of SNS, RAAS, and decrease BP. These can lead to diuretic resistance or braking phenomenon. For Furosemide, the transporter in the proximal tubule may be blocked so that the drug cannot be secreted into the lumen and travel to the site of action.

Loop diuretics can be used to treat:
-acute pulmonary edema
-congestive heart failure
-nephrotic syndrome
-liver cirrhosis
-chronic kidney disease
-acute kidney injury
-hypertension
-drug overdose
-hypercalcemia

Adverse effects to loop diuretics include:
-hyponatremia
-hypokalemia
-hypomagnesemia
-metabolic alkalosis
-ototoxicity

Contradictions to loop diuretics include:
-pregnancy

Drug interactions with loop diuretics include:
-NSAIDs (block COX-2 --> decreased prostaglandin --> decreased vasodilation --> decreased GFR --> blunted response because not much is filtered)
-ACE inhibitors and ARB (enhanced nephrotoxicity)
-Lithium (enhanced Na+ excretion so lithium toxicity)
-Digitalis glycosides (hypokalemia --> arrhythmia)
-Quinidine (hypokalemia --> torsades de pointe)
-Probenecid (blocks OAT so drug can't get in)
-Aminoglycosides and cisplatin (ototoxicity)
-Amphotericin B (hypokalemia)
-Glucocorticoids (hypokalemia)

Carbonic Anhydrase Inhibitors

1. Carbonic Anhydrase Inhibitors
Carbonic anhydrase converts H2O and CO2 into H+ and HCO3-, allowing Na+ and HCO3- to be reabsorbed into the interstitum. Acetazolamide blocks this conversion and causes HCO3- and Na+ to be excreted. The drug crosses the blood brain barrier and is eliminated in the proximal tubule (site of action). It is a weak diuretic since the Loop and Henle can compensate for the lack of reabsorption. The effects are also self-limiting. Inhibition of carbonic anhydrase will lead to increase solute delivery to the macula densa which will trigger the TGF and decrease GFR. The loss of HCO3- also leads to hyperchloremic metabolic acidosis. The body decreases the amount of HCO3- being filtered leading to enhanced NaCl reabsorption in other parts of the nephron.

Carbonic anhydrase inhibitors can be used to treat:
-open angle glaucoma
-urinary alkalinization
-metabolic alkalosis
-acute mountain sickness (by increasing ventilation)
-epilepsy
-edema
-solubilized uric acid

Adverse effects of carbonic anhydrase inhibitors include:
-metabolic acidosis
-renal stones (calcium phosphate)
-renal K+ wasting
-hypersensitivity with sulfonamide allergies

Contradictions to carbonic anhydrase inhibitors include:
-hypersensitivity with sulfonamide allergies
-acidosis
-renal disease
-cirrhosis (increase ammonium in blood)

Renal Physiology

Anemia

Chapman Points and Visceral Sympathetics 8/8/17

Chapman Points (Anterior)
clavicle and 1st intercostal space - upper respiratory (nasal sinuses, pharynx, tonsils)
2nd intercostal space - bronchi, esophagus, thyroid, heart
3rd and 4th intercostal space - upper and lower lung
1 inch superior and lateral from umbilicus - kidney
umbilicus - bladder
tip of 12th rib - appendix
iliotibial tract - colon

Chapman Points (Posterior)
C2 - upper respiratory (sinuses, pharynx, larynx, tongue)
T2 - bronchi, esophagus, thyroid
T3 - heart
T3 and T4 - upper and lower lung
L3 - kidney
L4 - bladder

Visceral Sympathetics
thyroid T1-T4
lungs T1-T5
heart T1-T6
kidneys T10-T12
bladder T12-L2