Diuretic Drugs Flashcards
Diuresis
Increase in urine volume above normal levels
Natriuresis
Increase in urinary [Na+] above normal levels
Saluresis
Increase in urinary [NaCl] above normal levels
Kaliuresis
Increase in urinary [K+] above normal levels
Goals of diuretic therapy
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
The most effective diuretics change…
active ion transport in the nephron
Efficacy of drugs affecting glomerular filtration rate
low
Drugs acting on what and where are most effective
Na/K/2Cl cotransport in the thick ascending limb of Henle’s loop
Highly effective natriuretics –>
hypokalemic alkalosis
General characteristic of diuretic drugs
- 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
Site 1
-Carbonic anhydrase inhibitors
Acetazolamide
- 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
Site 2
“Loop” diuretics
Furosemide
- 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
Drug interaction with loop diuretics
Ototoxic drugs
NSAID: compete for active acid transport into tubule
Glucocorticoids: enhance K+ depletion
Digitalis: hypokalemia increase digitalis activity and risk of cardiac arrhythmias
Site 3
Thiazides
-In general less effective in promoting natriuresis than loop diuretics
Hydrochlorothiazide
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
Site 4 Drugs
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
Triamterene
- 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)
Spironolactone
- 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
Non-specific diuretics
water and osmotic diuretics
Mannitol
- 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»_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
