Diuretics

Question 1

What are the potential effects diuretics have on electolytes?

Answer 1

hyponatremia or dehydration

hypo/hyperkalemia through K+ wasting or sparing effects

Ca+ loss or reabsorption (loop diuretics)

hypomagnesemia

Hypokalemic metabolic alkalosis

Hyperchloremic metabolic acidosis

hyperuricemia (competing with uric acid for OAT)

Question 2

How do diuretics end up excreting too much potassium in the principle cells of the collecting ducts?

Answer 2

The diurtic blocks Na+ transport upstream of the collecting duct which causes increased delivery of sodium to the collecting ducts.

Increased ENaC reabsorption (by aldosterone) which created an electro-negative chemical gradient in the lumen of the duct leading to K+ excretion (negative pulls the pos. K+ in)

Question 3

Mechanisms of Diuretic K+-sparing effect in the collecting tubules (principle cells)?

Answer 3

Na+ reabsorption is coupled with K+ secretion

ENaC is blocked (blocking the effects of aldosterone - Na+ and water reabsorption) promoting Na+ / water excretion and K+ reabsorption.

Question 4

clinical uses of diuretics

Answer 4

Edematous states - CHF, hepatic failure w/ fluid retention, plasma protein decrease (hepatic disease, severe burns), cerebral edema, idiopathic cyclic edema, premenstrial edema, and acute kidney injury.

Non-edmatous states - hypertension, diabetes insipidus

drug intoxication - not first line, alkalizes urine

Question 5

mountain sickness

Answer 5

Acetazolamide

Question 6

Hypercalciuria

Answer 6

thiazides - causes calcium reabs

Question 7

hypercalcemia

Answer 7

Furosemide - enhance renal calcium excretion

Question 8

Potassium wasting diuretics

Answer 8

CA inhibitors

Loop diuretics

thiazide diuretics

Question 9

K+ sparing diuretics

Answer 9

ENaC Inhibitors

Mineralocorticoid receptor antagonists

Question 10

CARBONIC ANHYDRASE INHIBITORS - kinetics, MOA

Answer 10

Acetazolamide - et al

Potent reversible inhibitor

There are some that treat glaucoma (eye drops)

IV and Oral, cross BBB, excreted proximal tubule (site of action) mostly unchanged; ∼8–12h

Blocking CA prevents formation of CO2 and H2O from carbonic acid increases Na+, HCO3- and water excretion.

Question 11

Effects of Carbonic Anhydrase Inhibitors

Answer 11

Acetazolamide

Weak diuretics, self-limited

-due to compensatory effects of metabolic acidosis where the body decreases filtered HCO3- which in turn enhanced NaCl reabsorption

Increase Urine pH and decrease body pH (mild acidosis)

Hemodynamic effects => decreased renal blood flow and GFR (by way of TG feedback)

Question 12

Clinical Applications of CA Inhibitors

Answer 12

Acetazolamide

Glaucoma, open-angle: ↓ Rate of aqueous humor
formation

Urinary alkalinization: Solubilization of uric acid, cystine stones

Metabolic alkalosis

Acute mountain sickness: ↑ Ventilation

Epilepsy: antiseizure activity- mild acidosis

Edema - low efficacy

Question 13

Adverse Effects of and Contraindications of CA Inhibitors

Answer 13

AEs ===> Metabolic acidosis, renal stones, renal K+ wasting, paresthesia, somnolence, ataxia, headache

hypersensitivity - sulfonamide allergy

contraindications:
Hypersensitivity, acidosis, severe renal disease, cirrhosis/severe hepatic disease

(They decrease excretion of ammonium which leads to hyperammonemia, as does cirrhosis, too much NH3 => cerebral encephalopathy.)

Question 14

Drug interactions of CA inhibitors

Answer 14

CA inhibitors may reduce the excretion rate of weak organic bases, such as amphetamines and quinidine

Drugs that block secretion of CA inhibitor into the proximal tubule

Topiramate, zonisamide => contribute to formation of renal stones and metabolic acidosis.

Question 15

LOOP DIURETICS - Pharmkin, MOA

Answer 15

Furosemide; oral, IV, IM; short half life

MOA - blockade of the Na+-K+-Cl- symport in the thick ascending limb. (this symport brings the ion out of the urine and into the cell/blood/interstitium) Increases Na+ excretion and decreases medullary osmolarity increasing urine output. (blocking kidney’s ability to concentrate urine)

Highly efficacious diuretic - TAL reabsorbs 25% of all filtered Na+ load.

Furosemide rapidly reduces preload - mediated by prostaglandins.

requires intact kidneys

Question 16

Effects of Loop Diuretics

Answer 16

Profound ↑ Na+-Cl– excretion

Marked ↑ Mg2+ and Ca2+ excretion

↑ K+ and H+ secretion in collecting tubultes

↓ Uric acid excretion

Increase body pH

Stimulate renin release (powerful)

Question 17

Furosemide resistance

Answer 17

Resistance is through compensatory mechanism like activation of ANA or RAAS

Decreased BP decreases pressure natriuresis

system may also increase renal epithelial cell transporter expression or make more cells (renal cell epithelial hypertrophy)

all leading to increase sodium reabsorption elsewhere in the nephron and diuretic resistance

called the diuretic braking phenomenon.

Blocking secretion of loop diuretic into the proximal tubule

Short half-life can lead to a post-diuretic Na+ retention

Question 18

Clinical Applications of Loop Diuretics

Answer 18

Acute pulmonary edema
↑ venous capacitance + natriuresis →↓ LV pressure → relieves pulmonary edema

Chronic congestive heart failure
↓ ECF volume ⇒ minimizes venous and pulmonary congestion

Nephrotic syndrome (edema secondary to salt and water retention)
avoid intravascular volume depletion

Ascites of liver cirrhosis - adjunct use

Chronic kidney disease - higher doses required

Acute Kidney Injury - not for prolonged therapy

Can be used for but not perferred — hypertension, OD, hyperCa2+

Question 19

Adverse Effects of loop diuretics

Answer 19

Furosemide

abnormalities of electrolytes – hyponatremia, hypokalemia, hypomagnesemia,

ototoxicity, hyperuricemia

hypersensitivity

avoid in pregnancy

Question 20

Drug Interactions involving Loop Diuretics

Answer 20

Furosemide

thiazide - synergistic

anti-HTN - enhanced effects

ACE inhibitors or ARBs - NEPHROTOXICITY by vasodilation

Lithium - enhanced Na+ excretion can lead to lithium toxicity

Digitalis glycosides => hypokalemia => arrhythmias

quinidine/ QT prolonging drugs + diuretic-induced hypokalemia = increased risk of torsades de pointe

Antidiabetic agents - impaired glucose control

probenecid, NSAIDs - blunted effects of diuretic

gucocorticoids, amphotericin B, - hypokalemia

aminoglycosides and cisplatin - ototoxicity and nephrotoxicity

Question 21

THIAZIDE DIURETICS – Pharmanokinetics, MOA

Answer 21

Na+-Cl– Cotransporter (NCC) Inhibitors

Hydrochlorothiazide
-oral, 2 hour onset, 6-12 duration
Chlorthalidone
-oral (2hr), IV (15min); short half life

↑ Na+ and Cl– excretion and moderate diuresis

transporter is upregged by aldosterone. Found in DCT

Thiazide action depends in part on renal prostaglandin

Question 22

Effects of Thiazide Diuretics on Na+, Cl–, K+, H+

Answer 22

↑ Excretion of Na+ and Cl-
(Moderate)

↑ Excretion of K+ and H+ (Flow-dependent enhancement of ion secretion, RAAS activation, inc Na+ load to DCT)

Question 23

Effects of Thiazide Diuretics on uric acid, Ca2+, Mg2+

Answer 23

Inhibition of Na+-Cl− cotransporter

Decrease uric acid secreation

decrease Ca2+ excretion

increase Mg2+ excretion

attenuate kidney’s ability to excrete dilute urine but not to concentrate

Question 24

Clinical uses for thiazide diuretics

Answer 24

Edematous states – CHF, hepatic cirrhosis, nephrotic syndrome, chronic renal failure, acute glomerulonephritis

Hypertension - causes modent dec in intravascular vol.
=> Hydrochlorothiazide, most used
=> Chlorthalidone, much longer half-life

Moderate restriction of dietary Na+ intake (60-100mEq/d)

Nephrolithiasis: ↓ Ca2+ excretion

Nephrogenic diabetes insipidus

Question 25

Potential Adverse Effects of thiazide diuretics

Answer 25

Extracellular volume depletion

hypotension

hyponatremia

hypokalemic metabolic alkalosis

hypomagnesemia

hypercalcemia

hyperuricemia/gout

hyperglycemia and hyperlipidemia

hypersensitivity

generally not given to pregnant patients

Question 26

Drug interactions of thiazide diuretics

Answer 26

Digitalis glycosides and dofetilide => hypokalemia => arrhythmia

Lithium - increase Li+ reabsorption and toxicity

synergystic with loop diuretics and anti-hypertensive drugs

Vit D analogs - pot. enhancment of hypercalcemic effects

blunt the effects of the antidiabetic agent

probenecid - competition

Question 27

Drugs that may decrease the effectiveness of thiazide diuretics

Answer 27

NSAIDs
-blunted diuretic response

Bile acid sequestrants
=> hypokalemia and nephrotoxicity

(↓ Absorption of thiazide diuretics)

Question 28

ENaC Inhibitors

Answer 28

Renal Epithelium Na+ Channel inhibitors - Amiloride

Oral, 2hr onset, 24 hr action

blocks channel => messes potential difference (Na+,K+-ATPase function) => K+ sparing and Na+ ditching

H+, Ca2+, and Mg2+ also reabs (decrease body pH)

Question 29

Therapeutic uses for ENaC Inhibitors

Answer 29

ENaC inhibitor + thiazide diuretic for enhanced diuresis and to counteract K+ loss

adjunct

hypertension or edema

Li+ induced nephrogenic diabetes insipidis (prevents the transportation of Li+ into the principle cell and thus promotes it’s excretion)

Liddle syndrome - ENaC inhibitor + sodium restriction for Tx of hypertension and hypokalemia

Question 30

Adverse Effects of ENaC Inhibitors

Answer 30

hYPERKALEMIA

Risk factors – old age, high dose, renal impairment, hypoaldosteronism

Drug Interactions –
ACEI / ARB: ↓aldosterone secretion → ↑ K+ reabsorption → risk of hyperkalemia

NSAIDs: ↓ PG-dependent renin release → leads to ↓ANG II-mediated aldosterone secretion → ↑ K+ reabsorption → risk of hyperkalemia

K+ supplements or Salt-substitutes

Question 31

Mineralcorticoid Receptor Inhibitors

Answer 31

Spironolactone or Eplerenone

Oral, Eplerenone has CYP3A4 metabolism, spironolactone undergoes enterohepatic circulation

competitively inhibit binding of aldosterone to the MR

Spironolactone has antiandrogenic effects (gynecomastia, impotence, low libido) Eplerenone does not have these effects

Question 32

Therapeutic Uses of Spironolactone and Eplerenone

Answer 32

Edema and hypertension (w/ thiazide or loop diuretic)

Resistant hypertension due to primary aldosteronism (adrenal adenoma, bilateral adrenal hyperplasia)

heart failure due to left ventricular systolic dysfucntion - shown to reduce mortality

hepatic cirrhosis - spironolactone

refractor edema associated with secondary aldosteronism

Acne / hirsutism in women

Question 33

Adverse Effects of mineralcorticoid antagonists

Answer 33

Both - hyperkalemia, not for use in pregnancy

Spironolactone - gynecomastia, impotence
avoid in pregnacy in first trimester

Question 34

Drug Interactions of MR Inhibitors

Answer 34

Drugs that increase serum potassium:
K+ supplements, ACEI / ARBs, NSAIDs, k+ diuretics

Spironolactone - decreases digoxin clearance and toxicity

Eplerenone - CYP3A4 inhibits (Grapefruit)

Question 35

Mannitol

Answer 35

osmotic diuretic

distributed in EC fluid; onset in 1-3 hours, reduction of EC fluid in 15-30 minutes, ICP in 1.5-6 hours.

Extracts water from ECF and increases urine volume and promotes electrolyte excretion

Given by bolus - to avoid accumulation in brain

Question 36

Therapeutic Uses of Mannitol

Answer 36

Acute increase in intracranial pressure with edema or intraocular pressure

Adjunct to cisplain to minimize nephrotoxicity

(increases osmotic pressure of plasma → water shift out of brain parenchyma / eye tissue)

Question 37

AEs or cautions of Osmotic Diuretics

Answer 37

ECF expansion => HF complication is pulmonary edema

hypernatremia - in patients with severe renal inpairment

Dehydration and electrolyte imbalance

Nephrotoxicity - especially in high doses

Question 38

Contraindications of Mannitol use

Answer 38

Allergy

severe dehydration

severe renal disease

renal dysfunction following mannitol administration

active cranial bleeding

progressive heart failure

severe pulmonary edema / congestion