11 Diuretics Flashcards
Where is most sodium and chloride reabsorbed in the nephron?
Proximal Tubule
Function of proximal tubule
Reabsorption!
- Na+ and Cl- (50-75%)
- K+
- HCO3- (80-90%)
On what part of the nephron is chloride actively reabsorbed?
Ascending Limb of Loop of Henle
On what part of the nephron is water impermeable?
Ascending Limb of Loop of Henle
Function of Ascending Limb of Loop of Henle
- Na+ and Cl- reabsorbed (20-30%)
- active chloride reabsorbed
- impermeable to H2O: no reabsorption
- compensates for inc Na+ delivery from proximal tubule by increasing reabsorption
On what part of the nephron is K+ secreted?
Distal Tubule and Collecting Duct
On what part of the nephron does regulation of Na+ and K+ exchange by aldosterone occur?
Distal Tubule and Collecting Duct
On what part of the nephron is water permeability regulated by ADH (Vasopressin)?
Distal Tubule and Collecting Duct
Function of Distal Tubule and Collecting Duct
- Na+ reabsorbed (8-9%)
- K+ secreted from blood to tubule lumen to urine
- Aldosterone regulation of Na+/K+ exchange
- Water permeability regulated by ADH
What drugs are renal vasodilators?
Dopamine
Fenoldapam
Atriopeptins
Work at glomerulus
Where do renal vasodilators such as dopamine, fenoldapam, and atriopeptins exert their action?
Glomerulus
What group of drugs selectively dilates the renal vasculature that modifies the proximal tubular function?
Renal Vasodilators: Dopamine, Fenoldapam, Atriopeptins
What group of drugs decrease filtration fraction?
Renal Vasodilators: Dopamine, Fenoldapam, Atriopeptins
Inc renal blood flow without changing GFR
FF = GFR / RBF
Dec FF reduces protein concentration and hydroosmotic forces in peritubular capillaries
Renal Vasodilator Characterisitcs
Dopamine, Fenoldapam, Atriopeptins
Mech:
- inc RBF w/o reducing GFR, which dec FF, which reduces protein conc and hydroosmotic forces in the peritubular capillaries
- Na+ and H2O leak back into tubule for excretion
Weak as diuretic due to compensatory Na+ reabsorption in distal nephron
Use:
- Limited clinically– hypertensive crisis and shock
What type of drug is mannitol?
Osmotic Diuretic
Where on the nephron does mannitol exert effect?
Whole nephron but mostly proximal tubule
What drug acts in the tubular lumen as a non-reabsorbable solute to increase urinary excretion of Na+, Cl+, K+, and H2O?
Mannitol
What is mannitol used for?
Edema
Glaucoma–reduce intraocular pressure
Acute renal failure
Characteristics of Mannitol
- freely filtered at glomerulus
- not reabsorbed by tubule
- metabolically inert
Mech:
- act in tubular lumen as non-reabsorbable solute to limit reabsorption of water from tubule
- urine volume and Na+ excretion proportional to osmotic load
- increases urinary excretion of Na+, K+, Cl-, H2O, and mannitol
Tx:
- edema
- Glaucoma
- Acute renal failure
What type of drug is acetazolamide?
Carbonic Anhydrase Inhibitor
What drug inhibits carbonic anhydrase in the proximal and distal tubule?
Acetazolamide–carbonic anhydrase inhibitor
What does acetazolamide do to the pH of urine?
Alkalinizes the urine
Prevents carbonic anhydrase from providing H+ ions to the lumen in exchange for Na+ for the reabsorption of HCO3-
What are the side effects of acetazolamide?
Metabolic acidosis
Hypokalemia
What drug can be used to alkalinize the urine (ex. to decrease drug toxicity)?
Acetazolamide
What drug can be used to treat mountain or altitude sickness?
Acetazolamide
What can acetazolamide be used to treat?
Glaucoma
Akalinize the urine
Mountain or altitude sickness
Anticonvulsant
Characteristics of Acetazolamide
Carbonic Anhydrase Inhibitor
- weak diuretic
- inhibited by acidosis (limited clinical use)
Mech:
- filtered and secreted by OAT on tubular lumen
- inhibit CA in proximal and distal tubule
- CA provides H+ ions for bicarb reabsorption
- increases excretion of Na+, K+, HCO3-, and H2O (less excretion of Cl-)
AEs:
- metabolic acidosis (reduces renal response to drug)
- hypokalemia
Tx:
- glaucoma
- alkaline the urine
- mountain or altitude sickness
- anticonvulsant
What type of drugs are furosemide, bumetanide, and ethacrynic acid?
Loop Diuretics
What drug inhibits the Na+/K+/2Cl- symporter?
Loop Diuretics: furosemide, bumetanide, ethacrynic acid
Where on the nephron do furosemide, bumetanide, and ethacrynic acid exert action?
Cortical and medullary segments of ascending limb of Loop of Henle
What are disadvantages to using loop diuretics such as furosemide, bumetanide, ethacrynic acid?
Hypokalemia Alkalosis Hypovolemia Hyperuricemia Hyperglycemia (furosemide only) Ototoxicity
Characteristics of furosemide, bumetanide, and ethacrynic acid
Loop Diuretics
- high efficacy (20-30% filtered Na+ load excreted)
- rapid onset/short duration
Mech:
- filtered and secreted by OAT
- inhibits Na+/K+/2Cl- symporter
- act on cortical and medullary segments of ascending limb of loop of Henle
- increases excretion of Na+, K+, Cl-, and H2O (also Ca2+)
- inc RBF and GFR
- large urine volume
AEs:
- hypokalemia
- alkalosis
- hypovolemia
- hyperuricemia (inc urate reabsorption @PT)
- hyperglycemia (furosemide only)
- ototoxicity
Tx:
- edema of cardiac, hepatic, or renal origin
- acute pulmonary edema
- hypertension
What type of drugs are hydrochlorothiazide and metolazone?
Thiazide and Thiazide-like Diuretics
Where do thiazide and thiazide-like diuretics exert action on the nephron?
Cortical segments of distal tubule
What drugs inhibit the Na+/Cl- symporter?
Hydrochlorothiazide and Metolazone: Thiazide and Thiazide-like Diuretics
What drug exerts effect on cortical segment of the distal tubule to create a hypertonic urine?
Hydrochlorothiazide and Metolazone: Thiazide and Thiazide-like Diuretics
What are the disadvantages to using hydrochlorothiazide or metolazone?
Hypokalemia Alkalosis Hyperuricemia Hyperglycemia Dec in GFR
What can hydrochlorothiazide or metolazone be used to treat?
Edema due to CHF
Hypertension
Hypercalciuria
Characteristics of Hydrochlorothiazide and Metolazone
Thiazide or Thiazide-like
- intermediate efficacy (8-10% of filtered Na+ load excreted)
- moderate onset/long duration
Mech:
- filtered and secreted by OAT
- inhibits Na+/Cl- symporter
- acts on cortical segment of distal tubule
- increases excretion of Na+, K+, Cl-, and H2O
- urine is hypertonic
- enhances urate reabsorption (PT)
- dec renal Ca2+ excretion
AEs:
- hypokalemia
- alkalosis
- hyperuricemia
- hyperglycemia
- dec in GFR
Tx:
- edema due to CHF (chronic disease)
- hypertension
- hypercalciuria
What is used for hypercalciuria?
Hydrochlorothiazide or Metolazone
What are the 2 classes of K+ sparing diuretics?
Aldosterone Antagonists: Spironolactone, Eplerenone
Sodium Channel Inhibitors: Amiloride, Triamterene
What drugs are Na+ channel inhibitors?
Amiloride and Triamterene
What drugs are aldosterone antagonists?
Spirinolactone and Eplerenone
What drugs can be used to increase Na+ excretion without K+ loss?
K+ sparing diuretics:
Aldosterone antagonists: Spirinolactone, Eplerenone
Sodium channel inhibitors: amiloride and triamterene
Why are K+ sparking drugs used in combination with loop diuretics?
K+ sparing can cause hyperkalemia
Loop diuretics can result in hypokalemia
Where on the nephron do K+ sparing diuretics exert its effect?
Distal tubule Cortical Collecting Duct
Characteristics of Spironolactone and Eplerenone
K+ sparing: Aldosterone Antagonist
- weak diuretic (2-3%)
- act on distal tubule as competitive antagonist of aldosterone
- urine volume inc
- inc Na+ / dec K+ excretion
AEs:
- hyperkalemia
- gynecomastia (spirinolactone is weak progesterone agonist)
Uses:
- hypertension
- refractory edema
- primary aldosteronism
- use with thiazide or loop diuretic to enhance diuretic effect and reduce potassium loss
Characteristics of amiloride and triamterene
K+ sparing: Na+ channel inhibitor
- weak diuretic (2-3%)
- inhibit entry of Na+ into principal cells (prevents Na+/K+ exchange on basolateral membrane)
- urine volume inc
- inc Na+/ dec K+ excretion
AEs:
- hyperkalemia
- mild azotemia (high Nitrogen levels)
- Triamterene dec RBF and GFR (high dose)
Tx:
- edema or hypertension
- use with thiazide or loop diuretic to enhance diuretic effect and reduce potassium loss
Which what drugs can mild azotemia (high levels of Nitrogen) occur?
Potassium sparing diuretic:
- Sodium channel inhibitors: amiloride and triamterene
What is often the cause of edema?
Edema is often secondary to cardiac or hepatic disease. Treat primary condition
Which diuretic has greatest intrinsic activity?
loop > thiazides > potassium-sparing
Which diuretic is cheapest to prescribe?
thiazides < loop < potassium sparing
Which diuretic has a faster onset of action?
Loop > Thiazide
Diuresis derives fluid from what fluid compartments first?
Intravascular Space Edematous tissue (ECF) Body compartments (peritoneal or pleural space)
Which diuretic has the greatest ceiling effect? Diseased conditions that exhibit ceiling effect?
Loop > Thiazide > K+ sparing
Diminished nephron response in nephrotic syndrome, cirrhosis, and heart failure
Exceeding ceiling dose yields possible adverse effects
What does K+ loss parallel? How can this be corrected? Is this fatal?
- K+ loss parallels Na+ excretion
- can inc intake of K+ supplements or dec output with K+ sparing diuretics
- hyperkalemia = fatal; hypokalemia is rarely life-threatening
Foundation of Diuretic Antihypertensive therapy
Reduce renal tubular Na+ and H2O reabsorption
- Lower BP
- Prevent Na+ and H2O retention and enhance BP lowering by other antihypertensive drugs
Drugs: hydrochlorothiazide, furosemide
How do diuretics decrease BP?
=> Deceases vascular volume
=> Decreases venous return (preload)
=> Decreases Cardiac output
=> Decreases BP
Also relaxes arteriolar smooth muscle
Diuretics in Chronic Heart Failure
- inc salt and water excretion. reduce ECF volume and preload
- reduce symptoms of CHF and improve exercise capacity
Furosemide and thiazides:
- reduce symptoms of CHF
- do not improve survival from CHF so used in combo with ACE inhibitors, etc.
Spironolactone and Eplerenone:
- inhibit renal and cardiac effects of aldosterone
- weak diuretics so small effect on salt and water excretion and CHF symptoms
- act on heart to inhibit hypertrophy and fibrosis caused by aldosterone
- proven to improve survival from CHF
Drugs used in chronic heart failure target compensatory reflexes. What types of drugs are these?
Sympathetic nervous system:
- Beta blockers
Renin/angiotensin/aldosterone activation:
- ACE inhibitors
- ARBs
- Spironolactone, Eplerenone
What Starling Forces are imbalanced by disease that results in edema?
Edema = fluid entering interstitial space
Decreased oncotic pressure due to:
- malabsorption
- nephrotic syndrome
- liver failure
- malnutrition
Increased capillary hydrostatic pressure due to:
- venous obstruction
- cirrhosis
- CHF
- constriction/restriction
- renal failure
- pregnancy
Foundation of diuretic edema therapy
Increase salt and water excretion by reducing renal tubular sodium and water reabsorption
- Reduce intravascular volume
- Reduce ECF and edema
Drugs: hydrochlorothiazide, furosemide
