Diuretics DSA Flashcards
List the carbonic anhydrase inhibitors
Acetazolamide
Brinzolamide
Dorzolamide
Methazolamide
List the loop diuretics
Bumetanide
Ethacrynic acid
Furosemide (Lasix)
Torsemide
List the thiazide diuretics
Bendroflumethiazide Chlorothiazide Chlorthalidone Hydrochlorothiazide Hydroflumethiazide Indapamide Methyclothiazide Metolazone Polythiazide Trichlormethiazide
List the potassium-sparing diuretics
Mineralocorticoid antagonists (aldosterone antagonists)
- eplerenone
- spironolactone (Aldactone)
Inhibitors of renal sodium channels
- amiloride
- triamterene
List agents that alter water excretion
Osmotic diuretics
- Mannitol
- isosorbide
Antidiuretic hormone antagonists
-conivaptan
What do diuretics do?
Increase sodium excretion and the amount of urine produced by kidney
Used to adjust volume and/or composition of body fluids in a variety of clinical situations: HTN, heart and renal failure, nephrotic syndrome, and cirrhosis)
Compare and contrast diuretic vs natriuretic
Diuretic increases urine volume
-can exert their effects on a variety of targets, such as specific membrane transport proteins, enzymes, and hormone receptors
Natriuretic causes an increase in renal sodium excretion
What are reabsorbed in the proximal tubule?
Sodium bicarbonate (NaHCO3, 85%), NaCl (65% Na), glucose (100%), amino acids (100%) and other organic solutes into blood via specific transport systems in early PCT Potassium (65%) via paracellular pathway Water (65%) passively
What initiates the NaHCO3 reabsorption in the PCT?
Na/H exchanger (NHE3) located in luminal membrane of proximal tubule epithelial ecll
In the PCT, what catalyzes the formation of H2CO3 from CO2 and water?
Membrane-bound and cytoplasmic forms of carbonic anhydrase
What does the Na/K ATPase in the basolateral membrane do in all portions of the nephron?
Pumps reabsorbe Na into interstitium to maintain low intracellular Na concentration
What do acid secretory systems do in the straight segment of the proximal tubule (late proximal tubule)?
Secrete organic acids (uric acid, NSAIDS, diuretics, antibiotics, etc) into the luminal fluid from the blood
Diuretics are delivered to the luminal side of the tubule where most of them act
What is reabsorbed from the thin descending limb of loop of Henle?
Water
Describe reabsorption in the thin ascending limb of loop of Henle
Relatively water impermeable
Impermeable to other ions/solutes
What does the thick ascending limb of loop of Henle reabsorb?
Na (25% of filtered Na)
Impermeable to water
NaCl reabsorption into the interstitial space dilutes the tubular fluid
What is the NaCl transport system in the luminal membrane of the thick ascending loop of Henle?
Na/K/2Cl cotransporter (NKCC2 or NK2CL)
Establishes ion concentration gradient in the interstitium (both renal cortex and medulla)
In the loop of Henle, what does the increase in K concentration in the cells cause?
Causes back diffusion of K into the tubular lumen, allowing a lumen-positive electrical potential to drive reabsorption of cations (Mg2+, Ca2+) via paracellular pathway
Therefore, inhibition of salt transport in the thick limb reduces the lumen-positive potential and causes an increase in urinary excretion of divalent cations in addition to NaCL
Describe reabsorption in the distal convoluted tubule
10% NaCl reabsorbed. Further dilutes tubular fluid
Transported via thiazide-sensitive Na and Cl cotransporter (NCC)
Relatively impermeable to water
Ca2+ is passively reabsorbed by calcium channels (regulated by PTH)
Describe reabsorption and secretion in the collecting tubule (CCT)
Responsible for 2-5% of NaCl reabsorption through epithelial sodium channel (ENaC)
Most important site of K secretion by kidney and site at which virtually all diuretic-induced changes in K balance occur
Where do diuretics act in relation to CCT?
Upstream of CCT
Will increase Na delivery, which will enhance K secretion
Describe the Na/K ATPase pump in CCT
Basolateral. Pumps Na out of cell and into interstitium/blood while pumping K into the cell, where it can exit down the concentration gradient into the lumen/urine
Describe the H-ATPase pump in the CCT
H is secreted by proton pumps into the lumen and increases urine acidity
What does aldosterone do in the CCT?
Increases expression of both ENaC and basolateral Na/K ATPase pumps, leading to increase in Na reabsorption and K secretion, which causes retention of water, increase in blood volume, and increase in blood pressure
What dos antidiuretic hormone (ADH/vasopressin) do in the CCT?
Controls permeability of CCT to water by controlling expression levels of functional aquaporin-2 (AQP2) water channels that insert into the apical membrane
- In absence of ADH, CCT (and collecting duct) is impermeable to water, and dilute urine is produced
- ADH levels are regulated by serum osmolality and volume status
- Alcohol decreases ADH release and increases urine production
What is the protypical carbonic anhydrase (CA) inhibitor?
Acetazolamide
Describe the pharmacokinetics of carbonic anhydrase (CA) inhibitors
Well absorbed following oral administration
Excretion of drug is by secretion in proximal tubule segment (dosing must be reduced in renal in sufficiency)
Excreted drug is unchanged (no hepatic metabolism)
Describe the pharmcodynamics (MOA) of carbonic anhydrase (CA) inhibitors
Cause inhibition of membrane-bound and cytoplasmic forms of carbonic anhydrase, resulting in nearly complete abolition of NaHCO3 reabsorption in proximal tubule (primary site of action)
Describe the results of carbonic anhydrase inhibition
Decreased H formation inside PCT cell, decreased NHE3 activity, increased Na and HCO3 in lumen, and increased diuresis
Up to 45% of whole kidney HCO3 reabsorption is inhibited
Urine pH is increased, and body pH is decreased (increase in urine pH from HCO3 diuresis is apparent within 30 min)
Diuretic efficacy decreases significantly with use over several days (HCO3 depletion leads to enhanced NaCl reabsorption by remainder of nephron, defeating purpose of diuretic action)
As a result of systemic toxicity and eventual NaCl reabsorption, major clinical applications involve targeting CA at other sites other than kidney
Describe the toxicity of carbonic anhydrase (CA) inhibitors
Metabolic acidosis and bicarbonaturia predictably occur from chronic reduction of body HCO3 stores Renal stones can occur because calcium salts are more insoluble as urine pH become more alkaline Potassium wasting (hypokalemia) due to increased Na in CCT, which enhances K secretion (can be counteracted with simultaneous administration of KCl) Drowsiness and paresthesias with large doses Hypersensitivity reactions (fever, rashes, bone marrow suppression due to sulfonamide group) are more rare than above effects
Describe contraindications of carbonic anhydrase (CA) inhibitors
Pts with cirrhosis: increase of urine pH decreases urinary excretion of ammonia (NH4) and may contribute to development of hyperammonemia and hepatic encephalopathy
Pts with hyperchloremic acidosis or severe COPD: cause a worsening of metabolic or respiratory acidosis
Describe clinical indications of carbonic anhydrase (CA) inhibitors
Due to low efficacy of inhibitors as single agents and coupled with the fact that long-term use is often compromised by development of metabolic acidosis, these agents are rarely used as diuretics
Glaucoma
Most common indication for use of CA inhibitors
Reduces aqueous humor formation and decreases intraocular pressure
Topical formulations used
Urinary alkalinization (to enhance excretion of uric acid, cystine, and other weak acids), metabolic alkalosis (due to excessive use of diuretics in pts with severe heart failure), acute mountain sickness, and as adjuvants in epilepsy
What are the prototypes of loop diuretics?
Furosemide
Ethacrynic acid
Describe the pharmacokinetics of loop diuretics
Rapidly absorbed after oral administration. IV also available for some
Eliminated by kidney by glomerular filtration and tubular secretion
Since loop agents act on luminal side of tubule, their diuretic activity correlates with their secretion by proximal tubule, and therefore, loop diuretic half life is correlated with kidney function
Coadminsitration with other weak acids (NSAIDs, probenecid) may result in reduction in loop diuretic secretion due to competition for weak acid secretion
Describe the MOA of loop diuretics
Cause inhibition of luminal Na/K/2Cl cotransporter (NKCC2) in thick ascending limb of loop of Henle, bringing ion transport in this section of nephron to a virtual standstill (Na, K, Cl by blocking cotransporter. Mg and Ca by abolishing lumen-positive electrical potential)
Describe the effects of loop diuretics
Increase excretion of K and titratable acid due to delivery of Na and H to DCT and CCT (total body pH increases)
Induce synthesis of renal prostaglandins (NSAIDS interfere with actions of loop diuretics by reducing prostaglandin synthesis, which may be significant in pts with nephritic syndrome or hepatic cirrhosis)
Cause increases in renal blood flow in vascular beds
Some are weak inhibitors of CA
Describe toxicity of loop diuretics
Overzealous use can cause serious depletion of total body Na, leading to hyponatremia, reduced GFR, circulatory collapse, thrombohemolytic episodes, and hepatic encephalopathy in pts with liver disease
Hypokalemic metabolic alkalosis can occur due to increased secretion of K and H (can be corrected by K replacement)
Hyperurecemia can precipitate attacks of gout (uric acid is reabsorbed in proximal tubule)
Dose-related hearing loss (ototoxicity), which is most common in pts who have diminished renal function (exacerbated with concomitant aminoglycoside treatment due to sulfonamide allergy)
Hypomagnesemia can occur in pts with dietary magnesium deficiency (reversed by oral magnesium preparations)
Allergic reactions (skin rash, eosinophilia) and dehydration
What are the contraindications for loop diuretics?
Furosemide, bumetanide, and torsemide are sulfonamides and may cause allergic reactions in pts with sulfonamide sensitivity
May be deleterious in pts with hepatic cirrhosis, borderline renal failure, or heart failure
Avoid in postmenopausal osteopenic women due to hypocalcemic effects
Drug interactions with aminoglycosides (enhanced ototoxicity), lithium (may increase or decrease serum concentrations of lithium), and digoxin (increased toxicity due to electrolyte disturbances)
What are the clinical indication of loop diuretics?
Among most eficacious diuretic agents available
Acute pulmonary edema and other edematous states
HTN and heart failure
Treatment of mild hyperkalemia because loop diuretics enhance urinary secretion of K (enhanced by simultaneous NaCl and water administration)
Treatment of acute renal failure by increasing rate of urine flow and enhancing K excretion (diuretics do not shorten duration of renal failure)
Anion overdose: toxic ingestions of bromide, fluoride, iodide are reabsorbed in thick ascending limb (NKCC2 cotransporter). Coadminister loop diuretics and saline solutions to replace urinary losses of Na and to provide Cl, so as to avoid extracellular fluid volume depletion
Hypercalcemic states
What is the prototype of thiazide diuretics?
Hydrochlorothiazide
Describe the pharmaokinetics of thiazide diuretics
All can be given orally
Chlorothiazide is not very lipid-soluble and must be given in relatively large doses (only thiazide available for parenteral administration)
-longest lasting thiazide with half-life of approximately 47 hrs
Secreted in PCT by organic acid secretory system (competes with secretion of uric acid, which may elevate serum uric acid levels)
Describe the pharmacodynamics (MOA) of thiazide diuretics
MOA: inhibits Na/Cl cotransporter (NCC) and inhibits NaCl reabsorption from luminal side of epithelial cells in DCT
Enhance reabsorption of Ca2+ (in PCT due to volume contraction) and can unmask hypercalcemia due to other causes (hyperparathyroidism, carcinoma, sarcoidosis)
Some are weak inhibitors of CA
Describe toxicity of thiazide diuretics
Hypokalemic metabolic alkalosis and hyperuricemia similar to loop diuretics
Impaired carbohydrate tolerance: thiazides decrease glucose tolerance, causing hyperglycemia, and may unmask latent diabetes during treatment
- This effect may be due to impaired pancreatic release of insulin and diminished tissue utilization of glucose.
- hyperglycemia may be partially reversible with correction of hypokalemia
Hyperlipidemia: cause 5-15% increase in total serum cholesterol and LDL except for indapamide
Hyponatremia: deficiency of Na in blood due to a combination of hypovolemia-induced elevation of ADH (which increases AQP2 levels and subsequently increases blood volume), reduction in diluting capacity of kidney (because of thiazide), and increased thirst
Hypercalcemia and hyperuricemia
Weakness, fatigability, paresthesias, allergic actions, and impotence may occur
Sulfonamide hypersensitivity
Describe contraindications of thiazide diuretics
May diminish effects of anticoagulants, agents used to treat gout, and insulin, and increase effects of loop diuretics
Use with caution in pts with diabetes
Thiazide efficacy may be reduced in combination with NSAIDs and COX-2 inhibitors due to inhibition of prostaglandin synthesis (similar to loop diuretics)
Excessive use is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure
Describe clinical indications of thiazide diuretics
HTN and heart failure
Nephrolithiasis (formation of renal calculi or stones) due to idiopathic hypercalciuria
Nephrogenic diabetes insipidus
Describe the use of hydrochlorothiazide (thiazide diuretic) for nephrogenic diabetes insipidus
mech for hydrocholorthiazide (HCTZ) use in nephrogenic diabetes insipidus: acts by inhibiting Na/Cl transporter in distal convoluted tubule.
- Administration of HCTZ to any individual will increase diuresis and subsequently reduce extracellular fluid volume
- Reduction in volume will result in less volume filtered at glomerulus and decrease in GFR
- decrease in GFR will cause increase in proximal tubule sodium and water reabsorption (tubuloglomerular feedback)
- This will lead to less sodium and water delivery to collecting dut and will decrease urine output
What is the mineralocorticoid receptor (MR) antagonist prototype? (Potassium-sparing diuretic)
Spironolactone
What is the Na channel inhibitor prototype (potassium-sparing diuretic)?
Amiloride
What are the pharmokinetics of spironolactone and eplerenone (potassium-sparing diuretics)?
Both agents given orally
Inactivation occurs in liver and several days are needed before benefits are observed
Eplerenone is a spironolactone analog with greater selectivity for MR
What are the pharmacokinetics of amiloride and triamterene (potassium-sparing diuretics)?
Oral preparations
Triamterene is metabolized extensively in liver and has a shorter half-life than amiloride (must be given more frequently than amiloride, which is not metabolized)
Describe the pharmacodynamics/MOA of potassium-sparing diuretics spironolactone and eplerenone
MOA: MR antagonists are synthetic steroids that act as competitive inhibitors of aldosterone binding to MR
MR is a nuclear hormone receptor responsible for regulating expression of multiple gene products, such as Na (ENaC) and Na/K ATPase pumps in epithelial cells in late distal tubule and CCT (and other cell types)
As a result, MR antagonists reduce Na reabsorption to interstitium in CCT and therefore, reduce K (and H, Ca, Mg) secretion (remember, secretion is coupled with Na entry into this segment)
MR antagonists are only diuretics that do not require access to tubular lumen to induce diuresis
Describe the pharmacodynamics (amiloride and triamterene)
MOA: directly inhibits Na entry by blocking epithelial Na channels (ENaC) in apical membrane of CCT
Reduce Na reabsorption to interstitium in CCT and therefore, reduce K (and H, Ca, Mg) secretion (same as MR antagonists)
Describe toxicity of potassium-sparing diuretics
Mild, moderate, or even life-threatening hyperkalemia
- Risk is increased by renal disease or by use of agents that reduce renin (Beta-blockers, NSAIDs) or angiotensin II activity (ACE inhibitors, angiotensin receptor blockers (ARBs))
- Can combine K-sparing diuretics with other diuretics that increase K secretion
Metabolic acidosis due to reduced H secretion
MR antagonists are steroids that can also act on other hormone receptors, causing gynecomastia, impotence, and benign prostatic hyperplasia (eplerenone has less antiandrogenic effects)
Triamterene may precipitate in urine and cause kidney stones, and when combined with indomethacin, can cause acute renal failure
What are the contraindications of potassium-sparing diuretics?
Pts with chronic renal insufficiency are vulnerable to severe or fatal hyperkalemia
Concomitant use of K-sparing diuretics with Beta-blockers, NSAIDs, ACEIs, or ARBs is discouraged
Pts with liver disease may have impaied metabolism of spironolactone and amterene
Strong inhibitors of CYP3A4 can increase blood levels of eplerenone
What are the clinical indications of potassium-sparing diuretics?
Most useful in states of mineralocorticoid excess or hyperaldosteronism, due either to primary hypersecrtion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or to secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephritic syndrome, or other conditions associated with diminished effective intravascular volume)
Thiazides and loop diuretics can cause secondary hyperaldosteronism, which can increase renal wasting of K. K-sparing diuretics can be used to blunt K secretory response
MR antagonists are used to treat heart failure
What is the prototype for osmotic agents?
Mannitol
Describe the pharmacokinetics of osmotic agents
Poorly absorbed and must be given parenterally (oral mannitol causes osmotic diarrhea)
Not metabolized. Excreted in glomerular filtrate within 30-60 minutes
The proximal tubule and descending limb of loop of Henle are freely permeable to water. Any osmotically active agent that is filtered by glomerulus but not reabsorbed does what?
Causes water to be retained in nephron and promotes water diuresis
Describe the pharmacodynamics/MOA of osmotic agents
Increases osmotic pressure of glomerular filtrate, which inhibits tubular reabsorption of water and electrolytes and increases urinary output
Oppose ADH effects in CCT
Increase in water diuresis increases urine flow rate and descreases contact time between fluid and tubular epithelium, which also reduces Na reabsorption
Resulting natriuresis is of lesser magnitude than water diuresis, eventually leading to excessive water loss and hypernatremia
Describe the toxicity of osmotic agents
Extracellular volume expansion: mannitol extracts water from cells and prior to diuresis, leads to expansion of extracellular volume and hyponatermia
Dehydration, hyperkalemia, and hypernatremia (can be avoided by monitoring serum ion composition and fluid balance)
What are the contraindications of osmotic agents?
Severe renal disease (anuria), severe dehydration, severe pulmonary edema or congestion
What are the clinical indications of osmotic agents?
Increase or maintain urine volume (to prevent anuria that may result from delivery of large pigment loads to kidneys due to hemolysis or rhabdomyolysis. Removal of toxins)
Reduction of intracranial and intraocular pressures
Describe antidiuretic hormone agonists
Effects are increased water reabsorption
Vasopressin and desmopressin (synthetic analog of vasopressin) mediate vasoconstriction of vascular smooth muscle and increase water permeability and reabsorption in CCT (AQP2 channels)
Treatment of choice for pituitary diabetes insipidus and used to treat polyuria, polydipsia (chronic excessive thirst and intake of fluid), hypernatermia, nocturnal enuresis
Describe the antidiuretic hormone antagonist conivaptan
ADH receptor antagonist and has been approved for use in medical conditions that (heart failure, SIADH) cause water retention as result of ADH excess, which can result in hyponatremia
Administered parenterally with a half-life of 5-10 hours
MOA: antagonist at ADH receptors (V1a and V2) in CCT
Toxicity: can cause hypernatremia, nephrogenic diabetes insipidus
Demeclocycline is a tetracycline antibiotic that has anti-ADH effects, but why is it inappropriate to use in situations of heart failure and SIADH?
It has high incidence of renal failure
Describe using loop agents and thiazide diuretics in combination
Can be combined if pts fail or become refractory to usual dose of loop diuretics
In combo, will often produce diuresis when either agent acting alone is minimally effective. 2 reasons:
1. Salt and water reabsorption in either thick ascending loop (blocked by loop diuretics) or DCT (blocked by thiazides) can increase when other is blocked. Inhibition of both can produce more than additive diuretic response
2. Thiazides often produce mild natriuresis (sodium excretion) in PCT that is usually masked by increased absorption in thick ascending loop. This combo can therefore block Na reabsorption from all three segments (PCT, ascending loop, and DCT)
Combination can cause profuse diuresis and therefore, routine outpatient use is not recommended (K wasting is extremely common)
Describe potassium-sparing diuretics in combo with loop agents or thiazides
Hypokalemia is a common side effect of loop agents and thiazide diuretics, which can initially be managed with dietary NaCl restriction or KCl supplementation
When hypokalemia is unmanageable in this way, addition of K-sparing diuretics can lower K secretion
This combo is generally safe but should be avoided in pts with renal insufficiency and in those receiving angiotensin antagonists
A common use for diuretics is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, vascular diseases that reduce blood delivery to kidney. How is this sensed physiologically?
This reduction is sensed as a lack of effective arterial blood volume and leads to salt and water retention, followed by edema formation
Describe the edematous state of heart failure
Heart failure reduces cardiac output, which results in a decrease in blood pressure and blood flow to kidney
Decreases in BP and blood flow is sensed as hypovolemia and leads to renal retention of salt and water
Pulmonary or interstitial edema occurs when plasma volume increase and kidney continues to retain salt and water, which then leaks from vasculature
Describe the edematous state of kidney disease and diuretics
Most kidney diseases cause retention of salt and water
When loss of renal function is severe, there is insufficient glomerular filtration to sustain a natriuretic response and diuretic agents are of little benefit
Pts with mild cases of renal disease can be effectively treated with diuretics when they retain sodium
Diuretics are beneficial in glomerular diseases, such as SLE or DM, that exhibit renal retention of salt and water
Loop and thiazide diuretics are beneficial in individuals that develop hyperkalemia associated with early stage renal failure
Describe the edematous state of hepatic cirrhosis and diuretics
Diuretics are useful when edema and ascites (accumulation of fluid in abdominal cavity) become severe due to liver disease
Aggressive use of diuretics can be disatrous in pts with liver disease (more so than heart failure)
Describe nonedematous state of hypertension and diuretics
Thiazides are often used because of their diuretic and mild vasodilator activities
Loop diuretics are often reserved for pts with renal insufficiency or heart failure
Diuretics are often used in combo with vasodilators (hydralazine, minoxidil) because vasodilators cause significant salt and water retention
Describe nonedematous state of nephrolithiasis and diuretics
2/3 of kidney stones contain calcium phosphate or calcium oxalate
Thiazide diuretics enhance Ca reabsorption in DCT and reduce urinary Ca concentration, making them appropriate agents in treatment of kidney stones
Describe nonedematous state of hypercalcemia
Loop diuretics reduce Ca reabsorption and promote Ca diuresis but can also cause marked volume contraction when used alone (counterproductive)
Saline can be administered simultaneously with loop diuretics to maintain effective Ca diuresis
Describe nonedematous state of diabetes insipidus
Can be due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus)
Supplementary ADH or one of its analogs is only effective in central diabetes insipidus
Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes inspidus
