Diuretic Drugs

Question 1

Diuresis

Answer 1

Increase in urine volume above normal levels

Question 2

Natriuresis

Answer 2

Increase in urinary [Na+] above normal levels

Question 3

Saluresis

Answer 3

Increase in urinary [NaCl] above normal levels

Question 4

Kaliuresis

Answer 4

Increase in urinary [K+] above normal levels

Question 5

Goals of diuretic therapy

Answer 5

1) Change extracellular fluid characteristics
- decrease volume of ECF (by decreasing serum [Na+]
- change ionic composition of ECF
2) Modify urine characteristics
- maintain normal or accelerated urine flow
- alter rate of drug or toxicant elimination by change in urine flow or pH

Question 6

The most effective diuretics change…

Answer 6

active ion transport in the nephron

Question 7

Efficacy of drugs affecting glomerular filtration rate

Answer 7

low

Question 8

Drugs acting on what and where are most effective

Answer 8

Na/K/2Cl cotransport in the thick ascending limb of Henle’s loop

Question 9

Highly effective natriuretics –>

Answer 9

hypokalemic alkalosis

Question 10

General characteristic of diuretic drugs

Answer 10

• oral or parenteral routes
• actively secreted into the kidney tubules
• some undergo hepatic biotransformation (site 4 drugs)
• predominately eliminated in the urine
• most are weak acids

Question 11

Site 1

Answer 11

-Carbonic anhydrase inhibitors

Question 12

Acetazolamide

Answer 12

• site 1 carbonic anhydrase inhibitor
• non-competitive inhibition of CA in PT–> decreases sodium-bicarbonate reabsorption–> increase in HCO3 in urine–> increased urinary pH
• Increased HCO3 delivery to distal tubule–> increase in luminal electronegativity–> increase in H+ and K+ excretion
• produces mild natriuresis with hyperchloremic metabolic acidosis
• should be co-administered with bicarbonate
• used to treat glaucoma
• yields short-term urinary alkalinization–> facilitates excretion of acidic toxicants and dissolves some types of crystals
• not for long term use
• side effects include formation of calcium phosphate uroliths

Question 13

Site 2

Answer 13

“Loop” diuretics

Question 14

Furosemide

Answer 14

• Block NKCC2 transport protein–> inhibit Na/K/Cl cotransport in TAL–> concentrate urine–> increased flow of hypertonic urine w/ Na+, Cl-, K+, Mg2+, and H+ in a large volume of water.
• P.O. or parenteral
• half of administered dose undergoes phase II glucuronidation, rest excreted unchanged
• Binds plasma protein and is secreted into nephron through organic acid transport pathways
• Site of action = lumen of nephron, elimination via urine
• Indications = edema, hypervolemia, acute renal failure, to accelerate excretion of toxicants, reduce hyper-kalemia and calcemia, and hyperthyroidism, Horses reduces exercise-induced pulmonary hemorrhage.
• decreases blood pressure can cause hypoglycemia in dogs and ototoxicity in cats.
• Adverse effects: hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, dehydration (shock), hyponatremia

Question 15

Drug interaction with loop diuretics

Answer 15

Ototoxic drugs
NSAID: compete for active acid transport into tubule
Glucocorticoids: enhance K+ depletion
Digitalis: hypokalemia increase digitalis activity and risk of cardiac arrhythmias

Question 16

Site 3

Answer 16

Thiazides

-In general less effective in promoting natriuresis than loop diuretics

Question 17

Hydrochlorothiazide

Answer 17

Block NCC transporter in early DT–> decreases NaCl reabsorption–> increase delivery of Na+ to late DT –> increased excretion of Na+, Cl-, K+, Mg2+, H+ and water AND after long term therapy–> increased Ca2+ reabsorption

Question 18

Site 4 Drugs

Answer 18

K+-Sparing diuretics

• little short term effect on K+ exretion
• Action to decrease K+ excretion is manifested when K+ loss is increased due to thiazide or loop diuretic treatment or cases of hyperaldosteronism
• weak natriuretic effects
• Given p.o.
• plasma protein bound
• undergo hepatic biotransformation to become active and excreted in the urine

Question 19

Triamterene

Answer 19

• organic base
• Directly blocks epithelial Na+ channels in principal cells of LDT and CD
• Action NOT dependent on aldosterone
• faster onset and shorter duration of action (12-16 hrs)
• actively secreted into proximal tubule by organic base transporter
• Indications: treatment of hypokalemia due to prolonged thiazide or loop diuretic therapy or excess mineralocorticoid activity, edematous condition secondary to hyperaldosteronism
• Contraindications: preexisting hyperkalemia or hyperkalemic metabolic acidosis, renal disease (can mask K+ balance)

Question 20

Spironolactone

Answer 20

• lipophilic steroid hormone analog
• Antagonist of mineralocorticoid receptors and inhibits aldosterone-mediated induction of epithelial Na+ channels–> decreased distal Na+ re-absorption–> reduces electrochemical driving force for K+ secretion
• dependent on aldosterones presence
• slower onset and longer duration of action (2-3 days)
• only diuretic drug that does not act within the tubular lumen to produce diuresis

Question 21

Non-specific diuretics

Answer 21

water and osmotic diuretics

Question 22

Mannitol

Answer 22

• inhibition of water reabsorption
• creates osmotic gradient to reduce water reabsorption–> disrupts renal counter-current exchange in loop of Henle
• causes rapid movement and increased volume of water–> dilutes [Na+] decreasing contact time–> increased [Na+] excretion
• Net effect: increased H2O exrestion&raquo_space;> excretion of Na+ and other ions
• Given IV due to poor GI absorption, freely filtered at glomerulus, no metabolism, excreted in urine
• Indications: renal failure (increases urine volume and flow), toxicant elimination, cerebral edema, glaucoma, pulls water out of interstitial fluid compartments
• Contraindications: volume-expanded or edematous states, preexisting dehydration